CHANGING TIMES
INDEPENDENT JOURNALISM THAT DIGS DEEP
SATURDAY, SEPTEMBER 25TH, 2021
(I have highlighted in Yellow areas of interest)
Covid-19: as billions are vaccinated, adverse effects and virus variants cause concern
This article has been updated. Latest update 24/9/2021.
- The Pfizer-BioNTech, AstraZeneca-Oxford, and Moderna vaccines are being administered under emergency use authorisations in the UK. The UK regulator has also approved use of the Janssen Biotech vaccine under a conditional marketing authorisation.
- The Moderna vaccine and the Covid vaccine developed by the Johnson & Johnson subsidiary Janssen Biotech are being administered in the US under emergency use authorisations. The FDA approved the Biologics Licence Application submitted by BioNTech for the mRNA BNT162b2 vaccine.
- The European Commission has granted conditional marketing authorisations for the Pfizer-BioNTech, AstraZeneca-Oxford, Moderna, and Janssen Biotech vaccines.
- The Therapeutic Goods Administration in Australia has granted the Pfizer-BioNTech and AstraZeneca vaccines provisional approval.
- China’s top drug regulator has granted the Beijing Institute of Biological Products’ vaccine, BBIBP-CorV, conditional marketing approval.
- In India, six Covid vaccines have been approved for restricted emergency use.
- Vaccine manufacturers are seeking strategies to combat virus variants.
- Israel is giving 3rd vaccine doses as boosters.
- The WHO’s VigiBase, VAERS, EudraVigilance, and other databases list hundreds of thousands of reported adverse reactions after Covid vaccination, including thousands of deaths.
- AstraZeneca is doing mix-and-match experiments with vaccine doses from other companies.
- Pfizer and BioNTech and Moderna have been conducting trials involving children aged 6 months to 11 years. The FDA has authorised emergency use of the Pfizer-BioNTech vaccine for teenagers aged 12 to 15 years and the European Commission has expanded its conditional marketing authorisation for the vaccine to include the same age group.
- There are concerns that there may be disease enhancement with some vaccines.
- Covid vaccination ‘passports’ or certificates have been introduced in some countries and regulations limiting access to certain places and facilities to those who have been vaccinated are becoming increasingly widespread.
Massive Covid vaccination drives are continuing around the world, mostly under emergency use authorisations.
According to the Our World in Data website, more than six billion Covid vaccine doses have been administered worldwide. About 27.9 million doses are administered every day and 44.1% of the world’s population has received at least one dose.
As politicians, health authorities, and a mostly enthusiastic public express joy and relief at what they view as the beginning of the end of the pandemic, sceptics point to the growing number of adverse reactions after Covid vaccination, the risks of long-term adverse effects, and the lack of conclusive evidence that vaccination is preventing SARS-CoV-2 infection and virus spread.
The World Health Organisation’s global pharmacovigilance database, VigiBase, lists more than two million individual case reports of adverse reactions following Covid vaccination, including more than 10,800 deaths.
The global death toll from Covid-19 is now put at more than 4.7 million.
Differences in viewpoints about Covid vaccination, and particularly about the implementation of Covid vaccine certificates and the prospect of generalised mandatory vaccination, are causing relationship breakdowns, including traumatic splits in families.
Those who have chosen not to receive a Covid vaccination are shamed and the hesitant are pressured. Financial and other incentives to encourage people to get a Covid vaccination are becoming increasingly widespread.
Most mainstream journalists dismiss or condemn all vaccine hesitancy as wrong and, on social media, serious abuse is levelled at those who argue that they have the right to refuse Covid vaccination. Employers are increasingly making Covid vaccination a requirement for their staff.
There is particular disquiet about DNA and RNA vaccines, which have never previously been approved for human use.
There are concerns that there will, with spike protein vaccines against SARS-CoV-2, be pathogenic priming, also known as disease enhancement.
During studies of spike protein vaccines against SARS-CoV-1, the exposure of vaccinated animals to the virus led to increased morbidity and mortality.
There is also worry about mix-and-match experiments and potential problems when people are given one dose of one vaccine and a booster of a different one, or two doses of one vaccine and a booster of a different one.
The British-Swedish pharmaceutical giant AstraZeneca has conducted a clinical trial combining its AZD1222 vaccine, now known as Covid-19 Vaccine AstraZeneca or Vaxzevria, with Russia’s Sputnik V to assess the safety and immunogenicity of the combination.
The Sputnik V team had already tweeted about this in November 2020:
The developers of Sputnik V announced in February that trials testing the combination of the AstraZeneca-Oxford and Sputnik V vaccines had begun.
The CEO of Russia’s sovereign wealth fund, the Russian Direct Investment Fund (RDIF), Kirill Dmitriev, had earlier said that the trials would take place in Azerbaijan and the United Arab Emirates and, later on, in Saudi Arabia.
AstraZeneca said: “Both AZD1222 and Sputnik V are adenoviral vector vaccines that contain genetic material of the SARS-CoV-2 virus spike protein. The adenovirus itself is unable to replicate so it can only act as a carrier of genetic material.”
On August 20, the RDIF, AstraZeneca and R-Pharm, an international pharmaceutical company headquartered in Russia, announced preliminary results from a trial in Azerbaijan of the combined use of the AstraZeneca-Oxford vaccine and the single-dose version of Sputnik V, ‘Sputnik Light’, which uses an adenovirus type 26 (rAd26) vector.
The trial in Azerbaijan began in February 2021. The RDIF said that, to date, 64 volunteers had been vaccinated and the enrolment of volunteers was ongoing.
“Preliminary data from the first twenty participants shows antibodies to the SARS-CoV-2 virus spike protein (S-protein) elicited in 100% of cases,” the RDIF said.
“The interim analysis of data has previously demonstrated a high safety profile for the combined use of the vaccines with no serious adverse events or cases of coronavirus infection after vaccination.”
The AstraZeneca vaccine uses a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein.
When the adenovirus enters vaccinated people’s cells it delivers the spike protein genetic code. The spike protein primes the immune system to attack the SARS-CoV-2 virus if it later infects the body.
On August 11, the RDIF proposed to Pfizer that they start a trial with Sputnik Light as booster. “Delta cases surge in US & Israel shows mRNA vaccines need a heterogeneous booster to strengthen & prolong immune response. #SputnikV pioneered mix&match approach, combo trials & showed 83.1% efficacy vs Delta,” the Sputnik V team tweeted.
The RDIF has co-sponsored mix-and-match trials with Moderna and the Chinese company Sinopharm and is also reported to be set to start a joint trial with CanSino Biologics in China to test a combined regimen of their vaccines.
On August 4, the RDIF announced the initial safety results of the study in Argentina of the immune response and safety of regimens combining Sputnik Light with the AstraZeneca, Sinopharm, and Moderna.
“The data collected by the Ministry of Health of the Buenos Aires province demonstrates that both the combination of Sputnik Light with other vaccines and vaccination with two injections of only Sputnik Light shows a high safety profile with no serious adverse events following the vaccination,” the RDIF said.
On May 18, Spanish researchers gave a presentation about the CombivacS trial, in which participants were given one dose of the AstraZeneca-Oxford vaccine followed at least eight weeks later by a dose of the Pfizer-BioNTech vaccine.
The team, led by researchers from the from the Carlos III Health Institute said that the preliminary findings from the trial, which started on April 17 and involved 673 people, indicated that there was a potent immune response.
They wrote: “The first results indicate that this heterologous vaccination regimen is highly immunogenic and does not present problems of post-vaccination reactogenicity different from those already reported in the homologous use (alone) of these same vaccines; that is, the response of the immune system is greatly enhanced after the second dose of the Comirnaty [Pfizer-BioNTech] vaccine, while the observed adverse effects are within what is expected, are mild or moderate and are mostly restricted to the first first two–three days after receiving the vaccine.
“In no case has a hospital admission secondary to the use of this vaccination regimen been reported within this clinical trial.”
The researchers said their findings needed to be treated with caution, but the immune response observed in the CombivacS trial was in the same range as that occurring when two doses of the same vaccine were administered.
A total 441 people received the Pfizer-BioNTech vaccine and there were 232 people in the control group who didn’t receive it. The increase in the levels of antibodies and neutralising antibodies was analysed in 663 people.
Researchers at the University of Oxford have been conducting a trial in the UK in which eight different combinations are being tested, including single-vaccine, two-dose regimens with different time intervals and mix-and-match combinations of one dose of the Pfizer-BioNTech vaccine and one dose of the AstraZeneca-Oxford vaccine (referred to in the study as prime and boost doses).
The researchers have been gathering data about the effects of different intervals between the first and second doses in a mixed-vaccine regimen compared with control groups in which the same vaccine is used for both doses.
The 13-month Com-COV study, partly funded with £7 million from the UK government, was announced by the UK’S Department of Health and Social Care on February 4.
The UK minister for Covid-19 vaccine deployment, Nadhim Zahawi, said: “Nothing will be approved for use more widely than the study, or as part of our vaccine deployment programme, until researchers and the regulator are absolutely confident the approach is safe and effective.”
Robert H. Shaw et al. reported on the Com-COV study in an article in The Lancet, published on May 12.
During a trial conducted in February 2021, 463 participants were randomly assigned to four groups with a 28-day prime-boost interval, and 367 participants were randomised to groups with an 12-week prime-boost interval.
All 463 participants in the 28-day prime-boost interval group received their prime vaccine, and 461 participants received their boost vaccine.
The participants are aged 50 years and older, with no or mild-to-moderate, well controlled comorbidity. They were recruited across eight sites.
Shaw et al. presented initial reactogenicity and safety data ahead of publication of the primary immunological findings.
They found that people in the mix-and-match groups experienced higher rates of vaccine-related adverse effects, such as fever, than those who received two doses of the same vaccine.
The researchers said that feverishness was reported by 37 (34%) of 110 recipients of the AstraZeneca-Oxford vaccine as a prime dose and the Pfizer-BioNTech vaccine as a booster compared with 11 (10%) of 112 recipients of the AstraZeneca-Oxford vaccine for both prime and booster doses.
Feverishness was reported by 47 (41%) of 114 recipients of the Pfizer-BioNTech vaccine as a prime dose and the AstraZeneca-Oxford vaccine as a booster compared with 24 (21%) of 112 recipients of the Pfizer-BioNTech vaccine for both prime and booster doses, Shaw et al. said.
Similar increases were observed for chills, fatigue, headache, joint pain, malaise, and muscle ache, the researchers added. “There were no hospitalisations due to solicited symptoms, and most of this increase in reactogenicity was observed in the 48 h after immunisation.” they said.
Shaw et al. noted that the data were obtained in participants aged 50 years and older, and reactogenicity might be higher in younger age groups.
They added that a mixed vaccination schedule was being advocated in Germany, France, Sweden, Norway, and Denmark for people who had received a first dose of the AstraZeneca-Oxford vaccine. This was in light of concerns about thrombotic thrombocytopenia.
It was reassuring that all reactogenicity symptoms were short lived, and there were no concerns from the limited haematology and biochemistry data available, they added.
Shaw et al. reported again on the study in a preprint published in The Lancet on June 25. They reported on the results of the trial involving 463 participants in the 28-day prime-boost interval group.
They said that the regimen in which a Pfizer-BioNTech dose was followed by an AstraZeneca-Oxford dose did not meet “non-inferiority criteria”.
They added, however, that the geometric mean concentrations (GMCs) of both heterologous schedules (a dose of the AstraZeneca-Oxford vaccine followed by a dose of the Pfizer-BioNTech vaccine and vice versa) were higher than that of a licensed vaccine schedule (two doses of the AstraZeneca-Oxford vaccine) “with proven efficacy against Covid-19 disease and hospitalisation”.
The researchers explained that the GMC of post-boost SARS-CoV-2 anti-spike IgG (the immunoglobulin G antibody) on day 28 was “non-inferior” to that in those who had received two doses of the AstraZeneca- Oxford vaccine.
They said that, in the case of participants primed with the Pfizer-BioNTech vaccine, they failed to show non-inferiority of the heterologous schedule (a Pfizer-BioNTech dose followed by a dose of the AstraZeneca-Oxford vaccine) as against two doses of the Pfizer-BioNTech vaccine.
The researchers said their data supported flexibility in the use of heterologous prime-boost vaccination using the AstraZeneca-Oxford and Pfizer-BioNTech vaccines.
They said there were four serious adverse events across all groups, but none of them were considered to be related to immunisation.
Scientists at the University of Oxford and Imperial College London reported that combining an RNA-based vaccine and a viral-vector vaccine generated a strong immune response in mice.
“We demonstrate that antibody responses are higher in two dose heterologous vaccination regimens than single dose regimens, with high titre neutralising antibodies induced,” the researchers said in a preprint published on bioRxiv on January 29.
“Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells which is superior to the response induced in homologous vaccination regimens in mice.”
The University of Oxford is meanwhile launching a study that will investigate the delivery of the AstraZeneca-Oxford vaccine using a nasal spray. It will involve thirty volunteers aged 18 to forty years.
All of the volunteers will receive the same vaccine that is currently being delivered by intramuscular injection and will be followed for four months.
The study’s chief investigator, Sandy Douglas, said: “Some immunologists believe that delivering the vaccine to the site of infection may achieve enhanced protection, especially against transmission, and mild disease.”
He added: “There are a variety of people who will find an intranasal delivery system more appealing, which may mean vaccine uptake is higher in those groups.”
Global vaccination drives
In the United States, where Covid vaccination with the Pfizer-BioNTech vaccine began on December 14, with healthcare workers and the staff of nursing home given priority, more than 387 million doses have been given so far.
In the UK, where Covid vaccination began on December 8, more than 93 million doses have been administered.
In China, more than 2.1 billion Covid vaccine doses are reported to have been administered. More than 88 million doses are reported to have been administered in Russia.
India started administering Covid vaccinations on January 16 and more than 837 million doses have been administered so far.
Brazil started administering the CoronaVac vaccine, developed by the Chinese company Sinovac Biotech, on January 17 and, since then, more than 227 million doses have been administered.
The Seychelles, Israel, and the United Arab Emirates and Bahrain are the four countries that have vaccinated their populations the fastest.
Israel saw a sharp drop in daily mortality and infection rates and the number of Covid-19 patients in serious condition dropped below 100 on May 3. However, on June 25, the authorities reimposed an indoor mask requirement after more than two hundred new Covid-19 cases were recorded the day before. This was the highest daily total recorded since April 7. The health ministry also called on Israelis to wear face coverings when attending mass gatherings outdoors and urged people in at-risk groups to avoid gatherings altogether.
On July 16, the health ministry reported 1,118 new cases of Covid-19, which was the highest daily number in nearly four months. On July 20, there were 1,410 new cases.
On July 21, the number of active Covid-19 cases was 9,134. Sixty-eight patients were reported to be seriously ill. This included 18 patients who were in critical condition, 12 of whom were on respirators. The official Covid-19 death toll in Israel was reported to be 6,454. On July 22, the number of active infections was reported to be 9,742. The number of patients in a serious condition had risen to 75, and the death toll increased to 6,457, the ministry said. On August 8, the ministry said there were 348 serious Covid-19 cases.
On August 29, there were reported to be 80,579 active Covid-19 cases in Israel, with 1,175 people hospitalised, 726 of whom were reported to be in a serious condition (149 on ventilators). According to the health ministry, the death toll had risen to 6,958.
On September 2, worldometers.info, put the death toll at 7,086 the number of active cases at 86,388 and the number of serious or critical cases at 675.
According to health ministry figures released on September 14, 10,556 new Covid-19 cases were diagnosed the day before and 690 patients were seriously ill with the disease. Worldometers.info put the number of active cases at 83,316 and the total number of deaths at 7,433.
At the end of July, Israel started giving a third booster dose to people aged 60 years and above who were vaccinated with a second dose more than five months earlier. On August 13, eligibility for a third vaccine dose was extended to those aged over 50 years and younger people employed in geriatric and health care institutions, or who suffer from underlying medical conditions.
On August 29, Israel made booster doses of the Covid-19 vaccine available to everyone age 12 and up who received the second shot at least five months earlier. As of September 11, more than two million Israelis had received a third dose.
The director of the Ziv Medical Center in Safed, Salman Zarka, told Kan public radio that Israelis now needed to prepare for a fourth Covid vaccine dose, which he said might be modified to better protect against new variants of SARS-CoV-2.
According to Channel 12 news, internal health ministry data shows that 14 Israelis have developed Covid-19 a week after receiving their booster shot. The network said that two of the 14 people had been hospitalised.
A team of Israeli researchers say that their findings indicate a “strong effect of waning immunity” in all age groups six months after administration of the Pfizer-BioNTech vaccine.
In a preprint published on medRxiv on August 30, Yair Goldberg et al. say that quantifying the effect of waning immunity on vaccine effectiveness is “critical for policy makers worldwide facing the dilemma of administering booster vaccinations”.
They say the results presented in their paper were the basis of the decision by Israel’s Ministry of Health to give a third dose of Covid-19 vaccine to people aged 60 or over who had been vaccinated at least five months previously.
The researchers explained that, after a period with almost no SARS-CoV-2 infections, a resurgent Covid-19 outbreak began mid-June 2021.
The researchers analysed data on all the positive PCR test results between July 11 and 31, 2021, from Israeli residents who were fully vaccinated before June 2021.
They looked at the infection rates and severe Covid-19 outcomes for people who were vaccinated in different time periods.
“We extracted from the database all documented SARS-CoV-2 infections diagnosed in the period in which the Delta variant was dominant, and the severity of the disease following infection,” the researchers wrote.
“Elderly individuals (60+) who received their second dose in March 2021 were 1.6 (CI: [1.3, 2]) times more protected against infection and 1.7 (CI: [1.0, 2.7]) times more protected against severe Covid-19 compared to those who received their second dose in January 2021.”
Data analysed related to 4,785,245 people, of whom 12,927 had a positive PCR test and 348 deteriorated to a severe condition.
The researchers refer to a paper about the longer-term follow-up of participants in the Phase 2/3 randomised trial of the Pfizer-BioNTech vaccine in which a reduction in vaccine efficacy from 96% (as of seven days to less than two months after vaccination) to 90% (as of two months to less than four months after vaccination) and 84% (as of four months to about seven months after vaccination) was reported.
“There is also a preliminary report of waning effectiveness of the same vaccine from a health maintenance organisation in Israel, and evidence of a decay in vaccine-induced neutralisation titers during the first six months following the second dose,” Goldberg et al. wrote.
The researchers say that, in contrast to early findings from the UK, in Israel about two thirds of the cases of severe Covid-19 during the study period were among people who received two doses of the Pfizer-BioNTech vaccine.
“Two major differences exist between the vaccination policies of Israel and the UK,” Goldberg et al. added. “First, the current analysis used data from July 2021, a time when, for the majority of the Israeli population, at least five months passed from the second dose to the outbreak of the Delta variant.
The UK data were collected during April–June 2021 with a much shorter time from vaccination to the outbreak, the researchers said.
“Second, Israel has followed the original Pfizer protocol of administering the second dose three weeks after the initial vaccination in the vast majority of recipients, while in the UK the time between doses has been typically longer,” they added.
Data released by Israel’s health ministry in July indicated that close to 40% of people who developed Covid-19 during the most recent outbreak were vaccinated, according to local media.
Of more than 7,700 new cases, 3,000 were in patients who had been vaccinated, according to media reports. Just 72 cases were in people who had previously been infected with SARS-CoV-2.
According to a report from Israel’s health ministry released on July 21, the Pfizer-BioNTech vaccine is, on average, only 39% effective against SARS-CoV-2 infection and 40.5% effective in preventing symptomatic Covid-19.
The report said the vaccine provided 88% protection against hospitalisation from Covid-19 and 91.4% protection against severe Covid-19 illness.
The report also indicates waning protection against SARS-CoV-2 infection, showing just 16% effectiveness against infection transmission among those who received a second dose in January, 44% effectiveness for those vaccinated in February, 67% effectiveness if the second dose was received in March, and 75% for those vaccinated in April.
Other Israeli data shows that, among those aged over 65 years, there are 69 serious cases of Covid-19 per million people among those vaccinated and 72 serious cases per million people among the non-vaccinated. It’s also been reported that about 90 per cent of new confirmed Covid-19 cases in those aged over 50 years were in people who were fully vaccinated.
In the Seychelles, there was a surge in Covid cases in May and restrictions, including school closures, were reimposed. On June 25, public health and social measures were reinforced. This was in light of community transmission of SARS-CoV-2, an increasing number of deaths from Covid-19, and confirmation that virus variants were circulating in the population.
In Iceland, a large percentage of those recorded as being SARS-CoV-2 positive were fully vaccinated.
In north Africa, Morocco started its vaccination drive after the delivery of shipments of the BBIBP-CorV vaccine developed by Sinopharm and the AstraZeneca-Oxford vaccine, which is branded as Covishield in India. By June 11, more than 16 million doses had been administered.
Algeria started its Covid vaccination drive on January 30, administering Russia’s Sputnik V vaccine to a 65-year-old retiree at a health unit in the town of Bilda. By June 11, about 2.5 million doses had been administered.
Egypt began the vaccination of medical staff on January 25, administering the BBIBP-CorV vaccine at a hospital in the northeastern province of Ismailia. By June 11, more than three million doses had been administered in the country.
On May 13, Egypt received 1,768,800 doses of the AstraZeneca-Oxford vaccine doses via the COVAX Facility, which is a mechanism established by Gavi, the Vaccine Alliance (GAVI), the global Coalition for Epidemic Preparedness Innovations (CEPI), and the WHO that aims to provide governments with early access to Covid vaccines produced by multiple manufacturers.
A month earlier, the country received its first shipment containing 854,400 doses. The country is set to receive a total of 4.5 million doses of the AstraZeneca-Oxford vaccine via the COVAX Facility.
On February 4, the Palestinian Authority received 10,000 doses of the Sputnik V vaccine and, on March 29, it received 100,000 doses of Sinopharm’s Covid-19 vaccine, donated by China.
UNICEF said that, on March 17, the authority had received the first shipment of 37,440 doses of the Pfizer-BioNTech vaccine and 24,000 doses of the AstraZeneca-Oxford vaccine from the COVAX Facility. Further consignments of COVAX vaccine doses were planned to cover 20 per cent of the Palestinian population of approximately 1 million people, UNICEF said, and all consignments were for both the West Bank and the Gaza Strip.
The Palestinian Authority began vaccinating health workers in the occupied West Bank on February 2 after receiving 5,000 doses of the Moderna vaccine from Israel.
The French news agency Agence France Presse reported that the authority was expecting about two million vaccine doses ordered from various manufacturers in addition to vaccines provided via COVAX.
About 320,000 doses of the Pfizer-BioNTech vaccine have been allocated to four African countries – Cabo Verde, Rwanda, South Africa and Tunisia.
The vaccine has received WHO emergency use approval, but requires countries to be able to store and distribute doses at minus 70 degrees Celsius.
The WHO says the aim is to provide up to 600 million vaccine doses to Africa by the end of 2021.
In addition to the vaccines being supplied by the COVAX Facility, the African Union has secured 670 million vaccine doses for the continent that will be distributed in 2021 and 2022 as countries secure adequate financing.
The African Export-Import Bank said it would provide advance procurement commitment guarantees of up to US$2 billion to the manufacturers on behalf of countries.
Contaminated vials in Japan
In Japan, the use of about 1.62 million doses (three lots) of the Moderna vaccine that were manufactured by Laboratorios Farmacéuticos ROVI in Spain was halted after vials in one lot were found to be contaminated.
Japan’s Ministry of Health, Labour, and Welfare said on August 26 that a foreign substance had been detected in 39 unused vials at eight vaccination sites in five prefectures. This was later found to be particles of stainless steel.
Moderna and the authorised distributor of the vaccine in Japan, Takeda, said that the problems that prompted the suspension of use of the vaccine doses were isolated to one specific lot, but three lots manufactured in the same series were included in the suspension by the ministry “out of an abundance of caution”.
The ministry also said that two men had died after being given a dose of the Moderna vaccine that was from one of the batches whose use was suspended (the doses were not from the vials that were found to be contaminated).
The two men, aged in their thirties, died within days of receiving their second vaccine doses. No foreign matter was found in either of the vials of vaccine used to vaccinate the two men, the ministry said.
Takeda and Moderna said on September 1 that the contamination in the vaccine vials had been found to be particles of high-grade 316 stainless steel, which is commonly used in manufacturing and food processing.
The companies said the most probable cause of the contamination was friction between two pieces of metal installed in the stoppering module of the production line, which was due to an incorrect set-up.
They said the two pieces were the star-wheel and the piece that feeds stoppers into the star-wheel. They companies think the problem occurred during assembly prior to production of batch 3004667 “and was a result of improper alignment during a line changeover before starting this batch”.
Takeda said it planned to recall the three suspended lots (3004667, 3004734, and 3004956) from the market as of September 2, 2021.
ROVI said its investigation showed that the manufacturing problem only impacted the three lots whose use was suspended.
Moderna and Takeda said the “rare presence” of stainless steel particles in the Moderna vaccine did not pose an undue risk to vaccinees and did not adversely affect the benefit/risk profile of the product.
“Metallic particles of this size injected into a muscle may result in a local reaction, but are unlikely to result in other adverse reactions beyond the local site of the injection,” the companies said.
“Stainless steel is routinely used in heart valves, joint replacements and metal sutures and staples. As such, it is not expected that injection of the particles identified in these lots in Japan would result in increased medical risk.”
The companies added; “At this time, there is no evidence that the two tragic deaths following administration of the Moderna Covid-19 vaccine (from lot 3004734) were in any way related to administration of the vaccine.
“The relationship is currently considered to be coincidental. It is important to conclude a formal investigation to confirm this. The investigation is being conducted with the greatest sense of urgency, transparency and integrity and is of the highest priority.”
The companies said earlier that they had not received any product quality complaints about particulate matter in lot 3004734.
On August 28, the Okinawa prefectural government said it had found foreign matter in vials of Moderna’s Covid vaccine. The vials did not come from one of the batches already suspended from use.
The Ministry of Health, Labour, and Welfare said foreign substances were also found in syringes filled with the vaccine. The ministry said it was highly probable that the contamination was caused by part of the rubber stopper on the vial lids or that there was a foreign substance on the syringe.
According to the ministry, the contamination did not originate from the vaccine in unused vials.
To date, more than 200 million doses of the Moderna Covid vaccine have been administered to more than 110 million people in 45 countries.
Booster doses
On August 18, public health and medical experts from the US Department of Health and Human Services (HHS) in the US said a booster Covid-19 vaccine shot would be needed “to maximise vaccine-induced protection and prolong its durability”.
The director of the Centers for Disease Control and Prevention (CDC)¸ Rochelle Walensky, the acting commissioner for the Food and Drug Administration (FDA), Janet Woodcock, and the director of the National Institutes of Health (NIH), Francis Collins, were among those who jointly issued a statement about the planned booster doses.
The health officials said a plan had been developed to begin offering booster doses in the autumn, subject to the FDA conducting an independent evaluation and determination of the safety and effectiveness of a third dose of the Pfizer-BioNTech and Moderna vaccines and the CDC’s Advisory Committee on Immunisation Practices (ACIP) issuing booster dose recommendations “based on a thorough review of the evidence”.
They added: “We are prepared to offer booster shots for all Americans beginning the week of September 20 and starting eight months after an individual’s second dose.
“At that time, the individuals who were fully vaccinated earliest in the vaccination rollout, including many health care providers, nursing home residents, and other seniors, will likely be eligible for a booster.
“We would also begin efforts to deliver booster shots directly to residents of long-term care facilities at that time, given the distribution of vaccines to this population early in the vaccine rollout and the continued increased risk that Covid-19 poses to them.”
The health officials said they also anticipated that booster shots would likely be needed for people who received the Janssen Biotech vaccine.
They said administration of the Janssen Biotech vaccine didn’t begin in the US until March and they expected more data about that vaccine in the coming weeks. “With those data in hand, we will keep the public informed with a timely plan for J&J booster shots as well,” the officials said.
On September 17, the Vaccines and Related Biological Products Advisory Committee (VRBPAC ) in the US voted unanimously in favour of Pfizer-BioNTech Covid vaccine boosters for people aged 65 years or above and individuals who are at high risk of developing severe Covid-19. The boosters would be administered at least six months after the completion of primary vaccination.
The committee had earlier voted by 16 members to two against booster shots being made available to all those aged 16 years and above.
On September 9, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK said that the Pfizer-BioNTech and AstraZeneca-Oxford vaccines could be used as “safe and effective booster doses”.
The MHRA’s chief executive, June Raine, said it would now be for the UK’s Joint Committee on Vaccination and Immunisation (JCVI) to advise on whether booster vaccinations would be given and if so, which vaccines should be used.
“We know that a person’s immunity may decline over time after their first vaccine course. I am pleased to confirm that the Covid-19 vaccines made by Pfizer and AstraZeneca can be used as safe and effective booster doses,” Raine said.
Britain’s Health and Social Care Secretary, Sajid Javid, said on September 1 that he had accepted the JCVI’s recommendation that a third vaccine dose should be offered to people aged 12 and above who have severely weakened immune systems.
The JCVI said: “Until more data is available, any provision of a third primary dose to persons who are immunosuppressed will draw on the assumption that a third dose is unlikely to confer significant harms or disadvantages, but may offer the possibility of benefit.
“These uncertainties in harms and benefits will need to be communicated as part of informed consent, and expectations regarding the value of a third primary dose taken into account.”
The committee said that, for people aged 18 years and above, it advised a preference for mRNA vaccines for the third primary dose, with the option of the AstraZeneca-Oxford vaccine for people who had received that vaccine previously “where this would facilitate delivery”.
The JCVI added that, “in exceptional circumstances”, people who had previously received an mRNA Covid vaccine could be offered a third primary dose of the AstraZeneca-Oxford vaccine following a decision by a health professional on a case-by-case, individualised basis. For those aged 12 to 17 years, the Pfizer-BNT162b2 vaccine remained the preferred choice, the JCVI said.
The British government announced on September 14 that a Covid vaccine booster programme, using the Pfizer-BioNTech vaccine, would begin soon for the over-50s along with vulnerable people, including frontline health workers.
CDC guidelines
The recommendation of the CDC is now that everyone should wear a mask in indoor public settings in areas of “substantial or high transmission” of SARS-CoV-2, regardless of vaccination status. It had previously said that only unvaccinated people needed to wear masks indoors.
On May 13, Rochelle Walensky, had said that anyone who was fully vaccinated could participate in indoor and outdoor activities, large or small, without wearing a mask or physical distancing.
Talking about the change in the CDC’s guidelines about masking, announced on July 27, the director of the National institute of Allergy and Infectious diseases (NIAID), Anthony Fauci, said: “Now that we have a Delta variant, that has changed the entire landscape because when you look at the level of virus in the nasopharynx of a vaccinated person who gets a breakthrough infection with Delta, it is exactly the same as the level of virus in a unvaccinated person who’s infected.”
Fauci says the level of virus in the nasopharynx of a person infected with the Delta variant is a thousand times the level it was with Alpha.
He said on CNN: ” We’re not changing the science … the virus changed.” He said that people should still get vaccinated “to save your life, to prevent you from being hospitalised, prevent you from dying, because the one thing that clearly works very well with this vaccine is that, even with the Delta variant, it prevents you, if you do get infected, from getting severe disease, enough to put you in the hospital”.
Associate professor of neurobiology and bioengineering at Stanford University, Michael Lin, tweeted that, “characteristically”, the CDC was couching its new recommendation with “self-justifying distortions of the science to try to deflect away their slowness to properly comprehend and analyse the data”.
Knowledge of Delta’s two times higher basic reproduction number (R0) was established already, “as was knowledge it could break through full RNA vaccination to not just cause disease but transmit onward”, Lin tweeted.
“So I cannot agree with the statement that ‘Today, we have new science related to the Delta’. Unless CDC defines ‘today’ as 2 months ago, or ‘science’ as observations made only within the US. Science is global, and today should mean today.”
Walensky said on July 30 that the findings of a study about a Covid-19 outbreak in Massachusetts had contributed to the CDC’s new masking recommendation.
The data demonstrated that Delta infection resulted in similarly high SARS-CoV-2 viral loads in vaccinated and unvaccinated people, Walensky said.
“High viral loads suggest an increased risk of transmission and raised concern that, unlike with other variants, vaccinated people infected with Delta can transmit the virus,” she added.
In a report published by the CDC on July 30, Catherine M. Brown et al. said that, in July 2021, following multiple large public events in a town in Barnstable County, Massachusetts, 469 Covid-19 cases were identified among Massachusetts residents who had travelled to the town from July 3 to 17.
Numerous large gatherings were held in the town, which was not identified in the report, and the events attracted thousands of tourists from across the US.
“Persons with Covid-19 reported attending densely packed indoor and outdoor events at venues that included bars, restaurants, guest houses, and rental homes,” Brown et al. wrote.
On July 3, the Massachusetts Department of Public Health had reported a 14-day average Covid-19 incidence of zero cases per 100,000 persons per day in residents of the town, the researchers said. By July 17, the 14-day average incidence had increased to 177 cases per 100,000 persons per day.
A total 346 (74%) of the reported cases occurred in fully vaccinated people (who had received two doses of an mRNA vaccine or a single dose of the Janssen Biotech vaccine 14 days before exposure).
Vaccination coverage among eligible Massachusetts residents was 69%, the researchers said.
Overall, 274 (79%) of the vaccinated people with breakthrough infection were symptomatic, Brown et al. said. They added that, among five patients with Covid-19 who were hospitalised, four were fully vaccinated. No deaths were reported.
Among those who were hospitalised, the unvaccinated patients and two of those who were vaccinated had underlying medical conditions.
Brown et al. said that Ct values obtained with RT-PCR diagnostic tests might provide a crude correlation to the amount of virus present in a sample and could also be affected by factors other than viral load.
“Although the assay used in this investigation was not validated to provide quantitative results, there was no significant difference between the Ct values of samples collected from breakthrough cases and the other cases,” the researchers said.
“This might mean that the viral load of vaccinated and unvaccinated persons infected with SARS-CoV-2 is also similar. However, microbiological studies are required to confirm these findings.”
Walensky said the CDC’s masking recommendation was updated “to ensure the vaccinated public would not unknowingly transmit virus to others, including their unvaccinated or immunocompromised loved ones”.
In earlier updates about quarantine recommendations, the CDC had said that fully vaccinated people “who meet criteria” would no longer be required to quarantine following exposure to someone with Covid-19.
“Additional considerations for patients and residents in healthcare settings are provided,” the CDC added.
According to CNN, the “criteria” were that the person must be fully vaccinated and at least two weeks must have passed since the second dose (in cases where two doses are required).
CNN quoted the CDC as saying it was not known how long protection lasted, so people who had their last vaccine dose three months or more earlier should still quarantine if they were exposed to a case of Covid-19.
“They also should quarantine if they show symptoms,” CNN quoted the CDC as saying.
The recommendation was criticised as being ill thought out and premature.
On March 8, the CDC had updated its guidelines about what people could and could not do after vaccination.
The guidelines stated at that time that people who had been fully vaccinated could do the following:
- gather indoors with fully vaccinated people without wearing a mask.
- gather indoors with unvaccinated people from one other household (for example, visiting with relatives who all live together) without masks, unless any of those people or anyone they live with has an increased risk for severe illness from Covid-19.
They added that, if a person was around someone with Covid-19, they did not need to stay away from other people or get tested unless they had symptoms. “However, if you live in a group setting (like a correctional or detention facility or group home) and are around someone who has Covid-19, you should still stay away from others for 14 days and get tested, even if you don’t have symptoms,” the CDC added.
While there was literal jubilation in many quarters about the new guidelines, there were also many people who were shocked at the separation of people according to their vaccination status.
The CDC issued its new guidelines despite admitting that they were still learning how effective the Covid vaccines were against SARS-CoV-2 variants, how well the vaccines prevented people from spreading the virus, and how long any protection they offered might last.
On May 1, the CDC transitioned from monitoring all reported Covid-19 vaccine breakthrough infections to investigating only those in patients who are hospitalised or die. It says this is “to help maximise the quality of the data collected on cases of greatest clinical and public health importance”.
The CDC said it would continue to lead studies in multiple US sites “to evaluate vaccine effectiveness and collect information on all Covid-19 vaccine breakthrough infections regardless of clinical status”.
The CDC defines a breakthrough case as “a person who has SARS-CoV-2 RNA or antigen detected on a respiratory specimen collected ≥14 days after completing the primary series of a US Food and Drug Administration (FDA)-authorised Covid-19 vaccine”.
Andre Watson, who is the founder and CEO of the regenerative medicine and pandemic defence biotechnology company Ligandal, based in San Francisco, tweeted in response to the CDC’s decision:
The CDC said that, as of August 23, more than 171 million people in the United States had been fully vaccinated against Covid-19 and that, up to that date, it had received reports from 49 US states and territories of 11,050 patients with Covid-19 vaccine breakthrough infection who were hospitalised or died.
In an internal CDC presentation, first reported on by the Washington Post on July 29, the CDC estimated that there were 35,000 symptomatic breakthrough infections per week among fully vaccinated adults in the US.
The CDC says the number of reports of Covid-19 vaccine breakthrough infections it receives are likely to be an undercount of all SARS-CoV-2 infections among fully vaccinated people. “National surveillance relies on passive and voluntary reporting, and data might not be complete or representative,” the CDC said.
Data on patients with vaccine breakthrough infection who were hospitalised or died will be updated regularly. Studies are being conducted in multiple U.S. sites that will include information on all vaccine breakthrough infections regardless of clinical status to supplement the national surveillance.
There is controversy over a statement made in a CDC Morbidity and Mortality Weekly Report that people are considered to be unvaccinated when it has been fewer than 14 days since they received the first dose of a two-dose Covid vaccine series or one dose of a single-dose vaccine, or if no vaccination registry data were available.
This means that if someone is infected by SARS-CoV-2, is hospitalised, or dies within those 14 days they are categorised as unvaccinated. This categorisation has serious implications for cases in which death or illness is caused by a Covid vaccine.
In a report entitled ‘SARS-CoV-2 Infections and Hospitalizations Among Persons Aged ≥16 Years, by Vaccination Status – Los Angeles County, California, May 1–July 25, 2021’ by Jennifer B. Griffin et al., published on August 27, it is stated: “Persons were considered fully vaccinated ≥14 days after receipt of the second dose in a 2-dose series (Pfizer-BioNTech or Moderna Covid-19 vaccines) or after 1 dose of the single-dose Janssen (Johnson & Johnson) Covid-19 vaccine; partially vaccinated ≥14 days after receipt of the first dose and <14 days after the second dose in a 2-dose series; and unvaccinated <14 days receipt of the first dose of a 2-dose series or 1 dose of the single-dose vaccine or if no vaccination registry data were available.”
In its Morbidity and Mortality Weekly Report posted online on May 25, and providing data up to April 30, the CDC said it had received more than 10,000 reports of SARS-CoV-2 infection among people who were fully vaccinated with a Covid-19 vaccine.
As of April 30, 10,262 breakthrough infections were reported to the CDC from 46 US states and territories. A total 6,446 of the cases (63%) occurred in women and the median age of those infected was 58.
Based on preliminary data, 2,725 (27%) vaccine breakthrough infections were asymptomatic, 995 (10%) of the patients were known to be hospitalised, and 160 (2%) of the patients died. Among the 995 hospitalised patients, 289 (29%) were asymptomatic or hospitalised for a reason unrelated to Covid-19. The median age of patients who died was 82 years.
The CDC said that 28 (18%) of those who died were asymptomatic or died from a cause unrelated to Covid-19.
Sequence data were available from 555 reported cases, the CDC said. In 356 cases (64%) the viruses were identified as SARS-CoV-2 Variants of Concern. This included 199 variants (56%) identified as B.1.1.7, 88 (25%) identified as B.1.429, 28 (8%) identified as B.1.427, 28 identified as P.1, and 13 (4%) identified as B.1.351.
The CDC said that, during the surveillance period, SARS-CoV-2 transmission continued at high levels in many parts of the US, with about 355,000 Covid-19 cases reported nationally during the week of April 24–30, 2021.
“Even though FDA-authorised vaccines are highly effective, breakthrough cases are expected, especially before population immunity reaches sufficient levels to further decrease transmission,” the CDC said.
“However, vaccine breakthrough infections occur in only a small fraction of all vaccinated persons and account for a small percentage of all Covid-19 cases (5–8).
“The number of Covid-19 cases, hospitalisations, and deaths that will be prevented among vaccinated persons will far exceed the number of vaccine breakthrough cases.”
The CDC says its findings about breakthrough infections are subject to at least two limitations. “First, the number of reported Covid-19 vaccine breakthrough cases is likely a substantial undercount of all SARS-CoV-2 infections among fully vaccinated persons,” it said.
“The national surveillance system relies on passive and voluntary reporting, and data might not be complete or representative. Many persons with vaccine breakthrough infections, especially those who are asymptomatic or who experience mild illness, might not seek testing.”
Secondly, the CDC said, SARS-CoV-2 sequence data were available for only a small proportion of the reported cases.
In Illinois in the US the Department of Public Health said that, as of July 28, 169 fully vaccinated people had died from Covid-19 or Covid-19 complications and 644 had been hospitalised with the disease. A total 51.13% of the Illinois population had been fully vacccinated, the health department added.
In April, the CDC issued new guidance to laboratories in which it recommended reducing the RT-PCR cycle threshold (Ct) value to 28 cycles for fully vaccinated people being tested for SARS-CoV-2 infection.
In a reverse transcriptase–polymerase chain reaction (RT-PCR) test RNA is converted to complementary DNA (cDNA) by reverse transcription, then the cDNA is amplified (copied) by the polymerase chain reaction.
The result of one PCR cycle is two double-stranded sequences of target DNA, each containing one newly made strand and one original strand. The cycle is repeated numerous times (usually 20–30) as most processes using PCR need large quantities of DNA.
Globally, the accepted cut-off level for the Ct value for SARS-CoV-2 ranges between 35 and 40, depending on instructions from the manufacturers of testing equipment. If the virus is detected at a low Ct value, this means that the viral load is high.
In discussions in India between the Maharashtra government and the Indian Council of Medical Research (ICMR) the ICMR said that lowering the Ct threshold might lead to infections being missed. A benchmark of 35, for instance, meant that more patients would be considered positive than if the benchmark were 24, the ICMR said.
The argument in favour of lowering the Ct threshold is that there will be fewer false positives, but the CDC has been accused of making the change so that there will be fewer reports of vaccine breakthrough cases in the US.
It’s possible, however, that the lower threshold will not influence the number of infections detected using nasal swabs. This is borne out by research conducted by Wenling Wang et al. about the detection of SARS-CoV-2 in different types of clinical specimens.
Wang et al. reported on their research in a letter published on March 11, 2020, on the JAMA Network, published by the American Medical Association.
The researchers found that higher viral loads were found in nasal swab testing than in testing of other specimen types so infections were detected at the lower Ct threshold.
They wrote: “The mean cycle threshold values of all specimen types were more than 30 (<2.6 × 104 copies/mL) except for nasal swabs with a mean cycle threshold value of 24.3 (1.4 × 106 copies/mL), indicating higher viral loads.”
UK study finds high virus levels in vaccinated people infected with Delta
Findings from a study conducted in the UK indicate that, if fully vaccinated people are infected with the Delta variant, they can harbour SARS-CoV-2 virus levels that are as high as those in unvaccinated people infected with Delta.
The study, which was released as a pre-print and has not been peer reviewed, was conducted by researchers from several universities and organisations, including Oxford University, the UK’s Office for National Statistics, and the Department of Health and Social Care. The vaccines studied were the Pfizer-BioNTech, AstraZeneca-Oxford, and Moderna vaccines.
The researchers compared the protection provided by Covid-19 vaccines before and after May 17, 2021, when Delta became the predominant variant in the UK.
Referring to the Pfizer-BioNTech and AstraZeneca-Oxford vaccines, the researchers said that Delta infections after two vaccine doses had similar peak levels of virus to those in unvaccinated people. With the Alpha variant, they said, peak virus levels in those infected post-vaccination were much lower.
“With Delta, infections occurring following two vaccinations had similar peak viral burden to those in unvaccinated individuals,” Koen B. Pouwels et al. wrote. “SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with Delta.”
The researchers said their findings had potential implications for onward transmission risk, “given the strong association between peak Ct and infectivity”. The impact on infectivity to others was unknown, they said, but required urgent investigation.
“A greater percentage of virus may be non-viable in those vaccinated, and/or their viral loads may also decline faster as suggested by a recent study of patients hospitalised with Delta,” they said.
Pouwels said that whilst vaccinations reduced the chance of getting Covid-19, they did not eliminate it. “More importantly, our data shows the potential for vaccinated individuals to still pass Covid-19 onto others, and the importance of testing and self-isolation to reduce transmission risk,” he said.
The researchers analysed 2,580,021 test results from nose and throat swabs taken from more than 384,543 people aged 18 years or older between December 1, 2020, and May 16, 2021, and 811,624 test results from 358,983 people between May 17, 2021, and August 1, 2021.
They said their findings indicated that a single dose of the Moderna vaccine had similar or greater effectiveness against the Delta variant compared to a single dose of the Pfizer-BioNTech or AstraZeneca-Oxford vaccine.
They added that two doses of the Pfizer-BioNTech vaccine were shown to have greater initial effectiveness against new SARS-CoV-2 infections, but this declined faster compared with two doses of the AstraZeneca-Oxford vaccine.
The time between doses was not shown to affect effectiveness in preventing new infections, they added, but younger people were shown to be more protected by vaccination than older people.
The researchers also said that two doses of the Pfizer-BioNTech or AstraZeneca-Oxford vaccine provided at least the same level of protection as having developed Covid-19 through natural infection.
People who were vaccinated after being infected with SARS-CoV-2 had more protection than vaccinated individuals who had not previously contracted Covid-19, they said.
Israeli researchers from Maccabi Healthcare Services and Tel Aviv University published a preprint on medRxiv on August 25 in which they report about natural immunity against SARS-CoV-2 compared to vaccine-induced immunity.
They reported that those studied who had recovered from Covid-19 had superior protection against the Delta variant compared to those who received the Pfizer-BioNTech vaccine.
The researchers conducted a retrospective observational study comparing three groups of people: SARS-CoV-2-naïve individuals who received a two-dose regimen of the Pfizer-BioNTech vaccine, previously infected individuals who had not been vaccinated, and previously infected individuals who had received a single dose of the Pfizer-BioNTech vaccine.
They found that vaccinees who had not been infected with SARS-CoV-2 before vaccination had a 13.06-fold increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021.
Gazit et al. also found that the increased risk of developing symptomatic Covid-19 disease was also significant.
When infection occurred at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, the researchers said.
They added that, with this timescale, vaccinees who had not been infected with SARS-CoV-2 before vaccination had a 5.96-fold increased risk for breakthrough infection and a 7.13-fold increased risk of developing symptomatic Covid-19 disease.
SARS-CoV-2-naïve vaccinees were also at a greater risk for Covid-19-related hospitalisations compared to those that were previously infected, Gazit et al. said.
They said that the advantageous protection afforded by natural immunity that their analysis demonstrated could be explained by the more extensive immune response to the SARS-CoV-2 proteins than that generated by the anti-spike protein immune activation conferred by the vaccine.
“However, as a correlate of protection is yet to be proven, including the role of B-cell and T-cell immunity, this remains a hypothesis,” they added.
The researchers said their study had several limitations. “First, as the Delta variant was the dominant strain in Israel during the outcome period, the decreased long-term protection of the vaccine compared to that afforded by previous infection cannot be ascertained against other strains,” they wrote.
Secondly, they said, their analysis addressed protection afforded solely by the Pfizer- BioNTech. It did not address other vaccines or long-term protection following a third dose.
“Additionally, as this is an observational real-world study, where PCR screening was not performed by protocol, we might be underestimating asymptomatic infections, as these individuals often do not get tested,” they added.
“Lastly, although we controlled for age, sex, and region of residence, our results might be affected by differences between the groups in terms of health behaviours (such as social distancing and mask wearing), a possible confounder that was not assessed.”
Gazit et al. said that their finding that individuals who were previously infected with SARS-CoV-2 seemed to gain additional protection from a subsequent single-dose vaccine regimen corresponded to previous reports, but they could not demonstrate significance in their cohort.
Misunderstandings about efficacy
There is widespread misunderstanding among the general public about what vaccine efficacy means and many people misguidedly believe that, once vaccinated, they can cast aside their masks and hug their relatives and friends without risk. The reality is that vaccination may only prevent severe Covid-19 disease.
The main efficacy percentages initially vaunted by the front-running manufacturers relate to the number of confirmed cases of Covid-19 that occurred during the trials and an analysis of how many of those cases occurred among those vaccinated and how many were among those who received a saline placebo or, in the case of some of the AstraZeneca-BioNTech trials, a meningitis vaccine. The main percentages provided from the trials relate to disease prevention, not the prevention of infection.
Associate editor of The BMJ Peter Doshi wrote in an opinion piece published on November 26, 2020, that Pfizer and Moderna were reporting relative risk reduction rather than absolute risk reduction, which, Doshi said, appeared to be less than 1%.
Do Covid vaccines prevent transmission of SARS-CoV-2 from person to person?
Andre Watson says Covid vaccines have not been robustly shown to prevent asymptomatic infection, only clinical illness.
In a briefing document released on December 8, 2020, about the Pfizer-BioNTech vaccine, ahead of the VRBPAC meeting on December 10, the FDA states that “data are limited to assess the effect of the vaccine against transmission of SARS-CoV-2 from individuals who are infected despite vaccination”.
Referring to the efficacy data provided by Pfizer, the FDA said: “At this time, data are not available to make a determination about how long the vaccine will provide protection, nor is there evidence that the vaccine prevents transmission of SARS-CoV-2 from person to person.”
The briefing document states: “Demonstrated high efficacy against symptomatic Covid-19 may translate to overall prevention of transmission in populations with high enough vaccine uptake, though it is possible that if efficacy against asymptomatic infection were lower than efficacy against symptomatic infection, asymptomatic cases in combination with reduced mask wearing and social distancing could result in significant continued transmission.
When asked by NBC’s Lestor Holt, during an interview aired in early December 2020, whether someone could still transmit the virus after vaccination the CEO of Pfizer, Albert Bourla, said the company was not certain about this and it was something that needed to be examined.
Several reports have since been published that are seen to indicate that Covid vaccination can prevent SARS-CoV-2 infection in those vaccinated and therefore reduce virus transmission.
In its Morbidity and Mortality Weekly Report dated April 2, 2021, which was posted online on March 29, the CDC reports on the efficacy of the Moderna and Pfizer-BioNTech Covid vaccines in preventing SARS-CoV-2 infection.
In the study, which was carried out in eight locations in the US, 3,950 health care personnel, first responders, and other essential and frontline workers self-tested weekly for SARS-CoV-2 infection for 13 consecutive weeks from December 14, 2020.
Of the 3,950 participants, 2,479 (62.8%) received both recommended mRNA vaccine doses and 477 (12.1%) received only one dose. A total 62.7% of vaccinated participants received the Pfizer-BioNTech vaccine and 29.6% received Moderna vaccine.
Among the unvaccinated participants, 1.38 SARS-CoV-2 infections were confirmed per 1,000 person-days, the CDC says. Among the fully vaccinated participants, 0.04 infections per 1,000 person-days were reported, and among those who had only received one vaccine dose, 0.19 infections per 1,000 person-days were reported.
161 PCR-confirmed SARS-CoV-2 infections were identified among unvaccinated participants. During the 13 days after the first or second vaccine dose, when immune status was considered indeterminate, 33 PCR-confirmed infections were identified and excluded from the outcome.
Five PCR-confirmed infections were reported in participants 14 days or more after the first dose among those who did not receive their second dose during the study period.
Three PCR-confirmed infections were reported 14 days or more after the first dose and up to receipt of the second dose. Three PCR-confirmed infections occurred in participants who received both vaccine doses (≥14 days after the second dose).
“Estimated adjusted vaccine effectiveness of full immunisation was 90% (95% confidence interval [CI] = 68%–97%); vaccine effectiveness of partial immunisation was 80% (95% CI = 59%–90%),” the CDC said.
The CDC says the findings in its report are subject to at least three limitations. Firstly, it says, vaccine effectiveness point estimates should be interpreted with caution given the moderately wide confidence intervals “attributable in part to the limited number of postimmunisation PCR-confirmed infections observed”.
“Second, this also precluded making product-specific vaccine effectiveness estimates and limited the ability to adjust for potential confounders; however, effects were largely unchanged when study site was included in an adjusted vaccine effectiveness model and when adjusted for sex, age, ethnicity, and occupation separately in sensitivity analyses,” the CDC said.
“Finally, self-collection of specimens and delays in shipments could reduce sensitivity of virus detection by PCR; if this disproportionately affected those who received the vaccine (e.g., because of possible vaccine attenuation of virus shedding), vaccine effectiveness would be overestimated.”
Another report, published in The Lancet on February 18, is about a study conducted in Israel. The researchers studied Covid-19 and SARS-CoV-2 infection and rates in healthcare workers who received the Pfizer-BioNTech vaccine.
They say their data show “substantial early reductions in SARS-CoV-2 infection and symptomatic Covid-19 rates following first vaccine dose administration”.
Sharon Amit et al. studied a retrospective cohort of 9,109 vaccine-eligible healthcare workers, comparing vaccinated versus unvaccinated.
The researchers say that, between 15 and 28 days after the first vaccine dose. they saw an 85% reduction of symptomatic Covid-19 and overall infections were reduced by 75%.
There were 170 SARS-CoV-2 infections among the healthcare workers between December 19, 2020, and January 24, 2021. Ninety-nine of them reported symptoms and were designated as Covid-19 cases. Of the 170 healthcare workers who became infected, 89 were unvaccinated, 78 tested positive after the first dose, and three tested positive after the second dose.
Adjusted rate reductions of SARS-CoV-2 infections were 30% and 75% for days 1–14 and days 15–28 after the first dose, respectively.
The rate reductions for Covid-19 disease were 47% and 85% for days 1–14 and days 15–28 after the first dose, respectively.
Amit et al. say the limitations of their study include its observational nature. They also say that a lack of active laboratory surveillance in the cohort might have resulted in an underestimation of asymptomatic cases.
“Data on vaccine efficacy in preventing asymptomatic SARS-CoV-2 infection are scarce, and our results of rate reductions in SARS-CoV-2 infections, which include asymptomatic HCWs, need further validation through active surveillance and sampling of vaccinated people and unvaccinated controls to ascertain the actual reduction of asymptomatic infection in vaccinated individuals,” the researchers said.
“The early rate reductions seen in HCWs might differ from vaccine efficacy reported in the general population due to their higher exposure risk or due to exposure to more virulent or infectious strains.”
Amit et al. said that early reductions of Covid-19 rates provided support for delaying the second dose in countries facing vaccine shortages, but added: “Longer follow-up to assess long-term effectiveness of a single dose is needed to inform a second dose delay policy.”
Another paper, published as a preprint in The Lancet on February 22, is also about the Pfizer-BioNTech vaccine and reports on the SIREN prospective cohort study carried out among staff working in publicly funded hospitals in England.
A total 23,324 people from 104 hospitals were included in the analysis.
Researchers from Public Health England and Oxford University said the study “demonstrates that the BNT162b2 vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults”.
Victoria Jane Hall et al. said the cohort was vaccinated when the dominant variant in circulation was B1.1.7 and the vaccine demonstrated effectiveness against the variant.
The researchers said that a single dose of the Pfizer-BioNTech vaccine demonstrated effectiveness of 72% 21 days after first dose and 86% seven days after the second dose in the antibody negative cohort.
At the beginning of the follow up period, participants were paced in either the positive cohort (antibody positive or with history of infection) or the negative cohort (antibody negative with no prior positive test).
Participants were asked to complete online questionnaires at enrolment and at fortnightly intervals, capturing data on demographics, symptoms, testing, and household, community, and occupational exposure.
Follow-up started on December 7, 2020, the day before vaccine roll-out began in England, with all participants contributing at least one day of follow-up unvaccinated.
At the start of follow-up, 8,203 participants were assigned to the positive cohort and 15,121 were placed in the negative cohort.
At least one vaccine dose was administered to 20,641 participants by February 5. A total 94% of them received the Pfizer-BioNTech vaccine and 6% received the AstraZeneca-Oxford vaccine.
Two vaccine doses were administered to 8% of participants by February 5 (99.9% of them received the Pfizer-BioNTech vaccine and 0.1% received the AstraZeneca-Oxford vaccine).
There were 977 new infections in the unvaccinated group. In the vaccinated group there were 71 new infections 21 days after the first dose and nine new infections seven days after the second dose.
The researchers said that, with fewer of the cohort vaccinated with the Astra-Zeneca-Oxford vaccine, and the later roll-out resulting in less follow-up time accrued, they were unable to investigate the effectiveness of that vaccine within the study.
Hall et al. said: “We provide strong evidence that vaccinating working age adults will substantially reduce asymptomatic and symptomatic SARS-CoV-2 infection and therefore reduce transmission of infection in the population.
“However, it does not eliminate infection risk completely and therefore personal protective equipment, non-pharmaceutical interventions and regular asymptomatic testing will need to be continued until prevalence of SARS-CoV-2 is extremely low to reduce the risk of transmission in healthcare settings.”
In a preprint published on medRxiv on May 1, Matt D.T. Hitchings et al. report on the effectiveness of the CoronaVac vaccine “in the setting of high SARS-CoV-2 P.1 variant transmission in Brazil”. They studied a cohort of healthcare workers in Manaus, where the P.1 variant accounted for 75% of genotyped SARS-CoV-2 samples at the peak of its epidemic.
A total 53,176 healthcare workers were studied in the analysis of the effectiveness of at least one vaccine dose and 53,153 were studied in the two-dose analysis.
For the early analysis (at least one vaccine dose), RT-PCR tests were done on 1,752 healthcare workers who reported a symptomatic illness at the time of testing and 904 healthcare workers who did report a symptomatic illness at the time of testing.
Of the 1,823 and 974 tests performed for healthcare workers with and without symptomatic illness, respectively, 564 (31% of 1,823) and 212 (22% of 974), respectively, were positive.
The researchers selected 780 healthcare workers who had undergone a total of 786 RT-PCR tests and established 393 case-control pairs with symptomatic illness. They selected 266 healthcare workers who had undergone a total of 270 RT-PCR tests to establish 135 pairs without symptomatic illness.
Among the 53,153 healthcare workers eligible for the two-dose analysis, 47,170 (89%) received at least one dose of CoronaVac and 2,656 individuals (5%) underwent RT-PCR testing from January 19, 2021 to April 13, 2021. Of 3,195 RT-PCR tests, 885 (28%) were positive.
For the two-dose analysis, the researchers established 418 case-control pairs healthcare workers with symptomatic illness and 138 pairs of healthcare workers without symptomatic illness.
They added: “A finding that vaccinated individuals were much more likely to be infected than unvaccinated individuals in the period 0-13 days after first vaccination (aOR [adjusted odds ratio] 2.11, 95% CI 1.36-3.27) suggests that among this population of healthcare workers, those at higher risk might take up vaccine earlier, leading to underestimation of its effectiveness.”
In a paper entitled ‘Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens’, published in PLOS Biology on July 27, 2015, Andrew F. Read et al. say that vaccines that keep hosts alive but allow virus transmission can allow very virulent strains to circulate in a population. Such vaccines are often referred to as “leaky vaccines”.
Read et al. explain that when vaccines prevent transmission, as is the case for nearly all vaccines used for humans, evolution towards increased virulence is blocked.
However, they say, when vaccines leak, allowing at least some pathogen transmission, they can create the ecological conditions that allow “hot strains” to emerge and persist.
“The future challenge is to identify whether there are other types of vaccines used in animals and humans that might also generate these evolutionary risks.”
Read et al. reported on experiments with the Marek’s disease virus in poultry that show that modern, commercial leaky vaccines allow the onward transmission of strains otherwise too lethal to persist.
The immunisation of chickens against the Marek’s disease virus enhanced the fitness of more virulent strains, Read et al. reported.
Authorisations in the US, Britain, and Australia
The mRNA-1273 vaccine manufactured by the American company Moderna, and the single-dose Covid vaccine developed by the Johnson & Johnson subsidiary Janssen Biotech are being administered under emergency use authorisations granted by the FDA.
On August 23, the FDA approved the Biologics Licence Application (BLA) submitted by the German biotech firm BioNTech for the mRNA BNT162b2 vaccine. This was the first approval of a BLA for a Covid vaccine in the US. The vaccine had earlier only been administered under an emergency use authorisation (EUA).
The fact that the EUA is still in force means that there will now be two versions of the vaccine in use: the licensed vaccine, Cominarty, and the EUA-authorised vaccine that has been administered to date. The licensed vaccine is not yet available. The brand name Cominarty had not previously been used in the US, but it has been used in Europe and Australia.
In a letter to Pfizer, the FDA’s chief scientist, Denise M. Hinton, said: “The licensed vaccine has the same formulation as the EUA-authorised vaccine and the products can be used interchangeably to provide the vaccination series without presenting any safety or effectiveness concerns.
“The products are legally distinct with certain differences that do not impact safety or effectiveness. ”
Robert Malone, who did ground-breaking work in development of the core mRNA vaccine technologies, tweeted: ” … Along with licensure comes liability for the manufacturer. If one receives a vaccine labelled under the EUA (old stock) – it is under EUA. If you get a vaccine from a bottle labelled COMIRNATY, it is approved and there is liability from the manufacturer.”
All the Covid vaccines being administered under an EUA have a “liability shield”, Malone explains.
The director of the FDA’s Center for Biologics Evaluation and Research, Peter Marks, said: “Our scientific and medical experts conducted an incredibly thorough and thoughtful evaluation of this vaccine. We evaluated scientific data and information included in hundreds of thousands of pages, conducted our own analyses of Comirnaty’s safety and effectiveness, and performed a detailed assessment of the manufacturing processes, including inspections of the manufacturing facilities.”
The FDA said it had reviewed updated data from the clinical trial that supported the EUA and included a longer duration of follow-up in a larger clinical trial population.
“Specifically, in the FDA’s review for approval, the agency analysed effectiveness data from approximately 20,000 vaccine and 20,000 placebo recipients ages 16 and older who did not have evidence of the Covid-19 virus infection within a week of receiving the second dose,” the FDA said.
“The safety of Comirnaty was evaluated in approximately 22,000 people who received the vaccine and 22,000 people who received a placebo 16 years of age and older.”
Based on results from the clinical trial, the vaccine was 91% effective in preventing Covid-19 disease, the FDA said.
The FDA said that more than half of the clinical trial participants were followed up for safety outcomes for at least four months after the second dose and, overall, about 12,000 recipients were followed up for at least six months.
Pfizer and BioNTech plan to seek licensure of a third dose of their Covid vaccine for people aged 16 years and above and for administration of the vaccine for children and adolescents aged 12 to 15 years “once the required data out to six months after the second vaccine dose are available”.
Just before the FDA’s approval of the Pfizer-BioNTech vaccine Peter Doshi wrote an opinion piece in which he said there was “no legitimate reason to hurry to grant a licence to a coronavirus vaccine”.
Doshi says the FDA should have demanded adequate, controlled studies with long-term follow-up, and made data publicly available, before granting full approval to any Covid-19 vaccine.
The FDA should be demanding that the companies complete the two-year follow-up, as originally planned, Doshi said. “Even without a placebo group, much can still be learned about safety,” he wrote.
“They should demand adequate, controlled studies using patient outcomes in the now substantial population of people who have recovered from Covid.”
Doshi is critical of the FDA’s decision not to convene its advisory committee to discuss the data ahead of approving the Pfizer-BioNTech vaccine.
He says that, prior to the publication on July 28 of a preprint entitled ‘Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine’, his view and that of about thirty clinicians, scientists, and patient advocates, was that there were simply too many open questions about all Covid-19 vaccines to support approving any this year.
“The preprint has, unfortunately, addressed very few of those open questions, and has raised some new ones,” Doshi wrote. It reported decreased appetite, lethargy, asthenia, malaise, night sweats, and hyperhidrosis as new adverse events attributable to BNT162b2 that were not identified in earlier reports, but provided no data tables showing the frequency of these, or other, adverse events, he added.
“In the preprint, high efficacy against ‘severe Covid-19’ is reported based on all follow-up time (one event in the vaccinated group vs 30 in placebo), but the number of hospital admissions is not reported so we don’t know which, if any, of these patients were ill enough to require hospital treatment.”
On the vaccine preventing death from Covid-19, there was too little data to draw conclusions, Doshi said. The crucial question, however, was whether the waning efficacy seen in the primary endpoint data also applied to the vaccine’s efficacy against severe disease, he added.
“Unfortunately, Pfizer’s new preprint does not report the results in a way that allows for evaluating this question,” Doshi said.
“Here we are, with FDA reportedly on the verge of granting a marketing licence 13 months into the still ongoing, two year pivotal trial, with no reported data past 13 March 2021, unclear efficacy after six months due to unblinding, evidence of waning protection irrespective of the Delta variant, and limited reporting of safety data.”
The Pfizer-BioNTech vaccine has been granted a temporary authorisation for emergency use by the MHRA in the UK.
The MHRA also approved the AstraZeneca vaccine, which was co-invented by the University of Oxford and its spin-out company, Vaccitech. The authorisation is for emergency use for individuals aged 18 years and above.
In January, the agency also approved the Moderna vaccine for emergency use for individuals aged 18 years and above. The MHRA recommended administration of the second dose 28 days after the first dose.
On May 28, the MHRA approved the use in Britain, under a conditional marketing authorisation (CMA), of the Janssen Biotech vaccine. The agency said the UK government had secured 20 million doses of the vaccine.
The MHRA said that the vaccine “meets the expected standards of safety, quality and effectiveness”. The Commission on Human Medicines (CHM) had reviewed the MHRA’s decision and endorsed it, the agency added.
The MHRA said the CMA was valid only in Britain only and was approved via the European Commission (EC) Decision Reliance Route. This is when the marketing authorisation application made by the company references the decision made by the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP). The MHRA reviews the application, taking the EC’s decision into consideration, before making an independent decision about the quality, safety, and effectiveness of the vaccine.
The Janssen Biotech vaccine is authorised in Northern Ireland under the CMA granted by the EMA on March 11.
The European Commission has also granted CMAs for the Pfizer-BioNTech, AstraZeneca-Oxford, and Moderna vaccines.
The Therapeutic Goods Administration (TGA) in Australia announced on January 25 that it had granted provisional approval for the Pfizer-BioNTech vaccine BNT162b2 (Cominarty) for use for individuals aged 16 and older (it has since provisonally approved the vaccine for children and adolesents aged 12 to 15).
On February 16, it announced that it had also granted provisional approval for use of the AstraZeneca vaccine for individuals 18 years and older. Both approvals are valid for two years.
The TGA said the AstraZeneca vaccine should be given in two separate doses. “TGA’s regulatory approval allows the second dose to be administered from 4 to 12 weeks after the first,” the administration said.
“The Australian Technical Advisory Group on Immunisation has recommended that the interval between first and second dose is 12 weeks. However if this interval is not possible, for example because of imminent travel, cancer chemotherapy, major elective surgery, a minimum interval of four weeks between doses can be used,” the TGA added.
Both approvals are subject to certain strict conditions, such as the requirement for the companies to continue providing longer term efficacy and safety information to the TGA from their ongoing clinical trials and post-market assessment.
Both vaccines had been shown to prevent Covid-19, the TGA said, but it was not yet known whether they prevent transmission or asymptomatic disease.
Pfizer says that BNT162b2 has now been granted a conditional marketing authorisation, emergency use authorisation, or temporary authorisation in more than forty countries. “Regulatory reviews are underway in several countries, with more authorisations anticipated in the coming weeks,” the company added.
The FDA’s emergency use authorisation for Moderna’s mRNA-1273 was issued on December 18 and allows the vaccine to be distributed in the US and to be given to individuals aged 18 years and older.
On February 27, the FDA issued an emergency use authorisation for the Janssen Biotech vaccine. This allows the vaccine to be distributed in the US for use in individuals aged 18 years or above.
The FDA said the safety data supporting the EUA included an analysis of 43,783 participants enrolled in an ongoing randomised, placebo-controlled study being conducted in South Africa, Mexico, the US, and several countries in South America.
“The participants, 21,895 of whom received the vaccine and 21,888 of whom received saline placebo, were followed for a median of eight weeks after vaccination. The most commonly reported side effects were pain at the injection site, headache, fatigue, muscle aches and nausea. Most of these side effects were mild to moderate in severity and lasted 1-2 days,” the FDA said.
The effectiveness data includes an analysis of 39,321 participants in ongoing studies. Among these participants, 19,630 received the vaccine and 19,691 received a saline placebo.
“Overall, the vaccine was approximately 67% effective in preventing moderate to severe/critical Covid-19 occurring at least 14 days after vaccination and 66% effective in preventing moderate to severe/critical Covid-19 occurring at least 28 days after vaccination,” the FDA said.
“Additionally, the vaccine was approximately 77% effective in preventing severe/critical Covid-19 occurring at least 14 days after vaccination and 85% effective in preventing severe/critical Covid-19 occurring at least 28 days after vaccination.”
There were 116 cases of Covid-19 in the vaccine group that occurred at least 14 days after vaccination, and 348 cases of COVID-19 in the placebo group during the same time period.
There were 66 cases of Covid-19 in the vaccine group that occurred at least 28 days after vaccination and 193 cases in the placebo group during the same time period. Starting 14 days after vaccination, there were 14 severe/critical cases in the vaccinated group versus sixty in the placebo group. Starting 28 days after vaccination, there were five severe/critical in the vaccine group versus 34 cases in the placebo group.
“At this time, data are not available to determine how long the vaccine will provide protection, nor is there evidence that the vaccine prevents transmission of SARS-CoV-2 from person to person,” the FDA said.
Headlines vaunt progress, but there are doubts about safety
There is a widespread belief that adverse effects after Covid vaccination are a sign of a positive immune response, but there are experts who warn against underestimating such reactions and say Covid vaccines are inherently dangerous.
Two of the biggest vaccine manufacturers – AstraZeneca and the American multinational corporation Johnson & Johnson – had to halt trials of their Covid vaccines because of the illness of participants. Both are viral vector vaccines.
Most mainstream headlines have vaunted the progress being made in the vaccination drives, but social media is awash not only with reports of troubling health problems after vaccination but also with stories of post-vaccination deaths, particularly in homes for the elderly.
A total 17 countries halted use of the AstraZeneca-Oxford vaccine because of reports of people suffering severe blood clots after vaccination.
The countries are Germany, France, Spain, Norway, Denmark, Iceland, Austria, Ireland, Estonia, Lithuania, Luxembourg, Latvia, the Netherlands, Italy, Bulgaria, Sweden, and Portugal.
Also, AstraZeneca halted the trial in Britain in which its vaccine was being tested on children.
On April 14, Denmark stopped using the AstraZeneca-Oxford vaccine and, on May 3, the Danish Health Authority said it was also excluding the Janssen Biotech vaccine from its vaccination programme.
The authority said it had concluded that the benefits of using the Janssen Biotech vaccine did not outweigh the risk of causing the possible adverse effect (thrombosis with low platelets), in those who received it.
The health authority said it had reviewed the use of the Janssen Biotech vaccine in the country’s Covid-19 vaccination programme based on international data and statements released in the previous month and a team of Danish experts had contributed to the evaluation of the vaccine.
The authority’s deputy director-general, Helene Probst, said: “In the midst of an epidemic, this has been a difficult decision to make, especially since we have also had to discontinue using the Covid-19 vaccine from AstraZeneca.
The decision to exclude the Janssen Biotech vaccine from Denmark’s vaccination programme did not rule out its possible future use, Probst said.
“New knowledge may emerge, or the situation in Denmark may change, for example, in terms of infection pressure, disease burden, epidemic control, or other vaccines’ availability,” she said.
If strict requirements were met, the authority might use the vaccine in clinical trials, she added.
Reuters reported that, at a meeting on May 3, lawmakers agreed to allow voluntary use of the Janssen Biotech and AstraZeneca-Oxford vaccines.
On June 25, Denmark’s National Board of Health issued the following statement: “On 14 April 2021 and 3 May 2021, the Danish Health and Medicines Authority decided to continue the general vaccination programme against Covid-19 without Covid-19 Vaccine Janssen and Vaxzevria … After a thorough update of the data base and the professional assessments, the National Board of Health maintains that assessment.”
The board said that, based on updated data from the US and the EU as well as assessments from the EMA and the US health and drug authorities, it could be established with certainty that both the Janssen Biotech and AstraZeneca-Oxford vaccines cause the vaccine-induced immune thrombotic thrombocytopenia (VITT) syndrome.
In Belgium, the Superior Health Council had recommended that the AstraZeneca-Oxford vaccine should only be given to people younger than 55, but later made an about-turn and said it would be administered to older people.
Belgian health ministers said on May 27, however, that the Janssen Biotech Covid vaccine would only be administered to people aged 41 years and above.
Belgium’s health ministers said the country’s inter-ministerial conference had decided to temporarily administer the Janssen Biotech vaccine to people aged 41 years and above pending a more detailed benefit-risk analysis by the EMA.
The decision followed the death in Belgium of a 37-year-old woman who suffered from blood clotting with low platelets after administration of the Janssen Biotech vaccine. She was the wife of a Slovenian diplomat in Brussels.
The EMA said: “The EMA and the Belgian and Slovenian medicines agencies are currently reviewing this first fatal case reported within the EU together with other case reports of blood clots, as part of regular intensified monitoring activities.”
Indonesia delayed the rollout of the AstraZeneca-Oxford vaccine and Venezuela announced that it would not authorise its use.
On May 16, Indonesia announced that it had temporarily halted distribution and use of one batch of the AstraZeneca-Oxford vaccine (batch CTMAV547) to run tests for toxicity following reports of adverse effects after vaccination.
The country’s health ministry said the batch consisted of 448,480 vaccine doses that arrived in Indonesia on April 26 as part of a delivery of more than 3.85 million doses, made via the COVAX Facility.
The Democratic Republic of Congo postponed the start of its vaccination campaign (using the AstraZeneca-Oxford vaccine), which had been scheduled to begin on March 15, and began the rollout more than a month later, on April 19.
Thailand temporarily delayed the rollout of the AstraZeneca-Oxford vaccine, but it then changed course and the country’s prime minister and members of his cabinet received their first doses at the launch of the vaccination drive on March 16.
France said on March 18 that it would resume use of the vaccine following the statement by the EMA that its benefits continued to outweigh the risk of side effects, but the country’s National Authority for Health recommended that only people aged 55 and over should receive it. Germany, Italy, Spain, Portugal, Ireland, and the Netherlands also said they would resume use of the vaccine. Bulgaria began using the vaccine again on March 19.
Germany has since suspended routine use of the AstraZeneca-Oxford vaccine for people aged below sixty.
The German news agency dpa reported that people aged under 60 could still receive the vaccine, but only “at the discretion of doctors, and after individual risk analysis and thorough explanation”.
Both France and Germany have since recommended that younger people who have had a first dose of the AstraZeneca-Oxford vaccine be given a different vaccine for their follow-up dose.
The World Health Organisation (WHO) has called for studies on mixing and matching vaccines and says there is not yet any comprehensive data on which it could base any recommendations.
Canada’s National Advisory Committee on Immunisation (NACI) has recommended that the AstraZeneca-Oxford vaccine should not be given to adults under 55 years of age “while the safety signal of vaccine-induced prothrombotic immune thrombocytopenia” following its use is investigated further.
On April 2, the Netherlands temporarily suspended use of the AstraZeneca-Oxford vaccine for people aged under sixty.
The Italian government said on June 11 that the AstraZeneca-Oxford vaccine should only be administered to people aged 60 years and above.
This was after the death of a teenager who was reported to have suffered thrombosis with thrombocytopenia and a brain haemorrhage after receiving the vaccine.
Reuters reported that Camilla Canepa died on June 10 aged 18 after being given the vaccine on May 25.
The news agency quoted the the Italian government’s chief medical adviser, Franco Locatelli, as saying that people under the age of 60 who had received a first dose of the AstraZeneca-Oxford vaccine should be given a different vaccine for the second dose.
The Dutch pharmacovigilance centre Lareb said it had received five reports of extensive thrombosis with low platelet counts after administration of the AstraZeneca-Oxford vaccine and, in one case, a woman died. Lareb said the events occurred seven to ten days after vaccination.
Lareb said it had previously received three reports involving a combination of thrombosis with a reduced number of platelets.
The agency said: “The picture resembles heparin-induced thrombocytopenia (HIT). With HIT, the immune system is activated so strongly that the body produces antibodies against its own platelets. However, in two of the five Dutch reports, no antibodies were found that match the HIT-like picture. This is not yet clear for three reports.”
In April, the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) began investigating thromboembolic events after administration of the Janssen Biotech vaccine.
The EMA said that four serious cases of unusual blood clots with low blood platelets had been reported after administration of the vaccine and, in one case, the patient died.
“One case occurred in a clinical trial and three cases occurred during the vaccine rollout in the USA,” the EMA said. “One of them was fatal.”
At its meeting on April 20, the PRAC concluded that a warning about unusual blood clots with low levels of blood platelets should be added to the product information for the Janssen Biotech vaccine. The PRAC also concluded that these events should be listed as very rare side effects of the vaccine.
“In reaching its conclusion, the committee took into consideration all currently available evidence including eight reports from the United States of serious cases of unusual blood clots associated with low levels of blood platelets, one of which had a fatal outcome,” the EMA said.
“The product information will be updated to reflect this information and will include a warning and an update of the side effects.”
She added that the eight patients in the US were aged between 18 and 49.
The PRAC noted that the blood clots occurred mostly at unusual sites such as in veins in the brain, the abdomen, and arteries, together with low levels of blood platelets and sometimes bleeding.
The EMA said that the reported combination of blood clots and low blood platelets after vaccination with the Janssen Biotech vaccine was very rare, and the overall benefits of the vaccine in preventing Covid-19 outweighed the risks of side effects.
The executive director of the EMA, Emer Cooke, said that no cases of blood clots and low blood platelets after administration of the Janssen Biotech vaccine had been seen in the EU, but there had as yet been very little rollout there of the vaccine.
Peter Arlett from the EMA said that, as of April 13, the total number of cases of thrombosis with thrombocytopenia were eight after administration of the Janssen Biotech vaccine (all in the US), 287 after administration of the AstraZeneca-Oxford vaccine, including 142 in the European Economic Area, 25 cases after administration of the Pfizer-BioNTech vaccine, and five cases after administration of the Moderna vaccine.
Johnson & Johnson said that no clear causal relationship had been established between these “rare events” and the Janssen Biotech vaccine.
In May 2021, the product information for the AstraZeneca-Oxford vaccine was updated “with regard to the very rare risk of TTS”, the EMA said.
In September, the PRAC said the product information should be further updated and the statement that reported TSS cases occurred mostly in women under 60 years of age should be removed “since the age and sex imbalance seemed smaller than previously observed”.
The EMA said this conclusion was based on the latest analyses of spontaneously reported TTS cases, which included 43% of the cases occurring in males and 37% in vaccinated persons older than 60 years, “and on data analyses in the scientific literature which did not identify a large difference of TTS cases by sex”.
The agency said that, as of July 31, 1,503 cases of TTS had been reported worldwide.
On April 23, the EMA announced that the CHMP recommended that people should receive a second dose of the AstraZeneca-Oxford vaccine between four and 12 weeks after the first dose “in line with the product information”.
“The CHMP considered recommendations to give the second dose of Vaxzevria after a longer interval than the recommended four-12 weeks, to not give a second dose at all, or to give an mRNA vaccine as a second dose,” the EMA said.
On April 13, the FDA and the CDC issued a joint statement saying they were recommending a pause in use of the Janssen Biotech vaccine “out of an abundance of caution”.
Peter Marks and the principal deputy director of the CDC, Anne Schuchat, said at that time that the CDC and the FDA were reviewing data involving six reported cases in the US of “a rare and severe type of blood clot in individuals” after they received the Janssen Biotech vaccine. In one case the patient died and one patient was in a critical condition, they said.
“Treatment of this specific type of blood clot is different from the treatment that might typically be administered. Usually, an anticoagulant drug called heparin is used to treat blood clots. In this setting, administration of heparin may be dangerous, and alternative treatments need to be given,” they added.
On April 23, the FDA and CDC lifted the pause. They said that, “following a thorough safety review”, they had determined that the recommended pause should be lifted and use of the vaccine should resume.
The agencies said then that the available data suggested that the chance of thrombosis-thrombocytopenia syndrome (TTS) occurring was very low, but the FDA and CDC would remain vigilant in continuing to investigate the risk.
Marks and Schuchat had earlier said that people who had received the Janssen Biotech vaccine who developed severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider.
He added: “It’s plainly obvious to us already that what we’re seeing with the Janssen vaccine looks very similar to what was being seen with the AstraZeneca vaccine … the AstraZeneca is a chimpanzee adenoviral vectored vaccine; the Janssen is a human adenoviral vectored vaccine.”
In updates to its website on May 27, 2021, the CDC said recent reports indicated a plausible causal relationship between the Janssen Biotech vaccine and blood clots with low platelets, which had caused deaths.
The CDC said that, as of September 15, there had been 47 confirmed reports in the US of people developing TTS after receiving the Janssen Biotech vaccine. More than 14.7 million doses of the vaccine had been administered in the US, the CDC added.
The CDC added that two confirmed cases of TTS had been reported to VAERS after administration of the Moderna vaccine after more than 367 million doses of mRNA Covid vaccines had been administered in the US.
- “Based on available data, there is not an increased risk for TTS after mRNA Covid-19 vaccination,” the CDC said.
On April 14, Johnson & Johnson said it had been reviewing the blood clotting cases with European health authorities and had decided to “proactively delay” the rollout of its vaccine in Europe and pause vaccinations in all Janssen Covid-19 vaccine clinical trials while it updated guidance for investigators and participants.
On April 20, the company announced that it would resume the vaccine rollout in Europe. “Following the PRAC recommendation, the company will resume shipment of the Janssen Covid-19 vaccine in the European Union, Norway and Iceland,” Johnson & Johnson said. “The updated EMA and healthcare professionals guidance will be available to national healthcare authorities.”
Reuters and Bloomberg reported on April 27 that two new cases of blood clots linked to the Janssen Biotech Covid-19 vaccine were being investigated by federal health officials in the US.
At a press conference on April 7, Emer Cooke said the PRAC had concluded that the benefits of vaccination with the AstraZeneca-Oxford vaccine outweighed overall the risk of side effects.
The PRAC concluded that clotting disorders were “very rare” side effects of the AstraZeneca-Oxford vaccine and the risk of dying from Covid-19 was greater than the risk of mortality from the vaccine.
Cooke said the PRAC concluded that reported cases of unusual blood clotting following vaccination with the AstraZeneca-Oxford vaccine should be listed as possible side effects of the vaccine.
Sabine Straus said that, although most of the cases occurred in people aged under 60 years, and in women, because of the different ways the vaccine was being used in different countries the PRAC did not conclude that age and gender were clear risk factors.
The PRAC carried out an in-depth review of 62 cases of CVST and 24 cases of splanchnic vein thrombosis (which involves one or more abdominal veins) that were reported to the European database of suspected adverse drug reaction reports, EudraVigilance, up to March 22, 2021. In 18 of the cases, the patient died.
About 25 million people had received the vaccine in the European Economic Area (EEA) and the UK at that point.
As of April 4, 2021, 169 cases of CVST and 53 cases of splanchnic vein thrombosis were reported to EudraVigilance. At that moment, 34 million people had received the vaccine in the EEA and the UK. The PRAC said that the more recent data did not change its recommendations.
The PRAC said one plausible explanation for the combination of blood clots and low blood platelets was an immune response to vaccination leading to a condition similar to one seen sometimes in patients treated with heparin: HIT.
The committee said it had asked AstraZeneca to conduct new studies and the EMA had commissioned research to further investigate the blood clotting reactions.
A UK government spokesperson said the benefits of the vaccine far outweighed the risks for the vast majority of adults but it was preferable for people under the age of 30 with no underlying health conditions to be offered an alternative vaccine where possible.
Pirmohamed noted that the risk of clots and lowered platelets was much higher with Covid-19 than with “these extremely rare events which are occurring with the vaccine”. He said that 7.8% of Covid-19 patients suffered blood clots on the lungs and 11.2% suffered deep venous thrombosis (DVT) in the legs.
The chairman of the Covid-19 subcommittee of the JCVI, Wei Shen Lim, said that people who had received their first dose of the AstraZeneca-Oxford vaccine should continue to be offered the second dose according to the set schedule.
In May, the JCVI updated its advice and said that people aged under 40 years should be offered an alternative to the AstraZeneca-Oxford vaccine.
On March 29, Canada’s National Advisory Committee on Immunisation recommended that use of the AstraZeneca-Oxford vaccine should be halted for people under the age of 55.
Sweden’s Public Health Agency said on March 25 that it would resume giving the vaccine to people aged over 65, but it was recommending continued suspension of use of the vaccine for other age groups until additional data is available.
Health officials in Finland said on March 24 that use of the vaccine would resume in that country, but it would only be administered to people aged over 65. In Iceland, the health minister said people aged over seventy could again receive the AstraZeneca-Oxford vaccine.
The Danish Medicines Agency said the “clinical picture” in the case of a woman who died shortly after receiving the AstraZeneca-Oxford vaccine was unusual.
The acting director of pharmacovigilance at the Danish Medicines Agency, Tanja Erichsen, said the Danish woman who died “had an unusual clinical picture with a low platelet count, blood clots in small and large vessels as well as bleeding”.
Danish officials said on March 25 that they would prolong their suspension of use of the vaccine for three weeks so that a potential link with blood clotting could be further evaluated.
Tanja Erichsen, said a connection between the vaccine and the very rare blood clot cases couldn’t be ruled out.
A second death after vaccination with the AstraZeneca-Oxford vaccine was reported, but the Danish health authorities said they had no evidence that the vaccine was responsible for either of the two deaths.
On March 11, the Norwegian Institute of Public Health (NIPH) put use of the AstraZeneca-Oxford vaccine on hold in its Covid vaccination programme.
On April 15, the institute recommended stopping further use of the vaccine in the vaccination programme in the country.
In a report published on May 10, a Norwegian expert committee recommended that the government should not include any vaccines using an adenoviral vector in the national vaccination programme.
The expert committee on adenoviral vector vaccines said the incidence of blood clotting with low platelets and the risk of death after administration of the vaccines was currently uncertain.
It noted that, in Norway, as of May 10, and according to the Norwegian Medicines Agency, four such deaths had been observed after vaccination of approximately 135,000 people with the AstraZeneca-Oxford vaccine. Seventy-eight percent of those who had received the vaccine were women in the health sector.
According to the committee’s report, a total eight cases of thrombosis with low platelets had been observed in Norway. This is a prevalence of more than one in 20,000, which is higher than that found in most other countries.
The committee noted that documentation for the Janssen Biotech vaccine, which has not yet been used in Norway, was more sparse than that relating to the AstraZeneca-Oxford vaccine because fewer doses had been administered so far, but observations suggested fewer adverse effects than with the AstraZeneca-Oxford vaccine.
The committee said it was not possible to identify who had an increased risk of developing serious side effects – VITT – either before or after vaccination.
It recommended that vaccines based on adenoviral vectors, e.g. from AstraZeneca and Janssen Biotech, should be made available outside the vaccination programme but should only be administered to individuals who are able to consent.
Committee members were divided about the criteria that should be used as a basis for voluntary use of the adenoviral vaccines outside the vaccination programme. A majority said that the current infection pressure in Norway probably indicated that it would only exceptionally be justifiable to offer optional adenoviral vector vaccines.
A minority of four committee members said the adenoviral vector vaccines should be given to anyone who wished to take them. “It is of particular importance to ensure that the individual is given adequate and up-to-date information,” those members added.
The Norwegian Medicines Agency and the NIPH said in March that there had been an unexpected death from a brain haemorrhage of a patient in Tynset after vaccination with the AstraZeneca-Oxford vaccine.
On March 18, the Norwegian national newspaper VG reported that physician and professor Pål Andre Holme, who led the team who investigated the cases of the three health workers who were hospitalised with serious blood clots and low levels of blood platelets after receiving the AstraZeneca-Oxford vaccine, believes the vaccine triggered an unexpected and powerful immune response. One of the three patients died on March 15.
In five European countries, use of a specific batch of the AstraZeneca-Oxford vaccine was suspended pending investigations.
The Austrian health authority suspended the use of batch number ABV5300 after a person was diagnosed with multiple thrombosis (formation of blood clots within blood vessels) and died ten days after vaccination, and another person was hospitalised with pulmonary embolism (blockage in arteries in the lungs) after being vaccinated. This patient is reported to be recovering.
As of March 9, 2021, two other reports of thromboembolic event cases had been received for batch number ABV5300, the EMA said.
Batch ABV5300 was delivered to 17 EU countries and comprises one million doses of the vaccine.
Four other EU countries – Estonia, Lithuania, Luxembourg, and Latvia – also suspended use of batch ABV5300 as a precautionary measure, while a full investigation was ongoing.
Italy suspended use of two other batches of the AstraZeneca-Oxford vaccine.
Quoting an unnamed source close to the matter, the Reuters news agency said the Italian health authorities had ordered the withdrawal of a batch of the vaccine following the deaths of two men in Sicily who had recently been vaccinated.
The Italian Medicines Agency (AIFA) confirmed that it was halting the use of a batch of doses as a precautionary measure, adding that no link had been established between the vaccine and subsequent “serious adverse events”, Reuters reported.
Reuters said that, according to its source, the health authorities’ decision followed the deaths of a 43-year-old navy officer and a 50-year-old policeman, who had both received vaccines from the ABV2856 batch.
The news agency also said use of a different batch of the AstraZeneca-Oxford vaccine had been suspended in Italy’s Piedmont region, where a teacher died shortly after vaccination.
According to local media reports, prosecutors opened a criminal investigation into alleged manslaughter in the case of the teacher’s death.
The wife of 57-year-old Sandro Tognatti is reported to have told news outlets that her husband received the vaccine in his home town of Biella on March 13. When he went to bed that night he had a high fever, she is quoted as saying, and the next day an ambulance was called for him and he later died.
The WHO’s Global Advisory Committee on Vaccine Safety (GACVS) Covid-19 subcommittee said on March 19 that the AstraZeneca Covid-19 vaccine (including Covishield, which is the vaccine’s brand name in India) continued to have a positive benefit-risk profile, “with tremendous potential to prevent infections and reduce deaths across the world”.
The subcommittee said: “The available data do not suggest any overall increase in clotting conditions such as deep venous thrombosis or pulmonary embolism following administration of Covid-19 vaccines.
“Reported rates of thromboembolic events after Covid-19 vaccines are in line with the expected number of diagnoses of these conditions. Both conditions occur naturally and are not uncommon. They also occur as a result of Covid-19. The observed rates have been fewer than expected for such events.”
It said that, while very rare and unique thromboembolic events in combination with thrombocytopenia, such as CVST, had also been reported following vaccination with the AstraZeneca vaccine in Europe, it was not certain that they had been caused by vaccination.
The subcommittee said that, in addition to the doses of the AstraZeneca vaccine that had been administered in Europe, more than 27 million doses of Covishield had been administered in India.
AstraZeneca said in March that “a careful review” of all available safety data relating to more than 17 million people in the EU and the UK who had received its vaccine had shown “no evidence of an increased risk of pulmonary embolism, deep vein thrombosis (DVT), or thrombocytopenia, in any defined age group, gender, batch, or in any particular country”.
The company said that, in clinical trials the number of thrombotic events was small and were lowest in the vaccinated group. “There has also been no evidence of increased bleeding in over 60,000 participants enrolled,” the company said.
AstraZeneca said there were no confirmed quality issues relating to any batch of the company’s vaccine used across Europe or in the rest of the world.
“Additional testing has, and is, being conducted by ourselves and independently by European health authorities and none of these re-tests have shown cause for concern,” the company said.
“During the production of the vaccine more than sixty quality tests are conducted by AstraZeneca, its partners and by more than twenty independent testing laboratories.
“All tests need to meet stringent criteria for quality control and this data is submitted to regulators within each country or region for independent review before any batch can be released to countries.”
AstraZeneca said in a press release on March 22 that the results of the Phase 3 trial of AZD1222 demonstrated efficacy of 79% in preventing symptomatic Covid-19 and 100% efficacy in preventing severe disease and hospitalisation.
“This interim safety and efficacy analysis was based on 32,449 participants accruing 141 symptomatic cases of Covid-19,” the company said. “The trial had a 2:1 randomisation of vaccine to placebo. Vaccine efficacy was consistent across ethnicity and age. Notably, in participants aged 65 years and over, vaccine efficacy was 80%.”
The full data has not yet been made available and AstraZeneca did not specify the number of trial participants who received the placebo who developed severe Covid-19 or had to be hospitalised
AstraZeneca said its vaccine was well tolerated, and the independent data safety monitoring board (DSMB) identified no safety concerns related to the vaccine.
“The DSMB conducted a specific review of thrombotic events, as well as cerebral venous sinus thrombosis with the assistance of an independent neurologist,” the company said. The DSMB found no increased risk of thrombosis or events characterised by thrombosis among the 21,583 participants receiving at least one dose of the vaccine. The specific search for CVST found no events in this trial.”
The National Institute of Allergy and Infectious Diseases (NIAID) said on March 22 that the DSMB had notified the NIAID, the Biomedical Advanced Research and Development Authority (BARDA), and AstraZeneca that it was concerned by information released by AstraZeneca on initial data from its Covd-19 vaccine clinical trial.
AstraZeneca responded: “The numbers published yesterday were based on a pre-specified interim analysis with a data cut-off of 17 February. We have reviewed the preliminary assessment of the primary analysis and the results were consistent with the interim analysis. We are now completing the validation of the statistical analysis.
“We will immediately engage with the independent data safety monitoring board to share our primary analysis with the most up-to-date efficacy data. We intend to issue results of the primary analysis within 48 hours.”
On March 25, AstraZeneca issued a new press release in which it said that the efficacy of its vaccine against symptomatic Covid-19 was 76%.
“Positive high-level results” from the primary analysis of the Phase 3 trial confirmed vaccine efficacy consistent with the pre-specified interim analysis announced on March 22, the company said.
The primary analysis was pre-specified in the protocol and would be the basis for a regulatory submission for emergency use authorisation to the FDA in the coming weeks, it added.
“This primary efficacy analysis included the accrual of 190 symptomatic cases of Covid-19 from the 32,449 trial participants, an additional 49 cases to the previously announced interim analysis. Participants were randomised on a 2:1 ratio between the vaccine and placebo group,” AstraZeneca said.
“The primary endpoint, vaccine efficacy at preventing symptomatic Covid-19 was 76% (confidence interval (CI): 68% to 82%) occurring 15 days or more after receiving two doses given four weeks apart.”
Results were comparable across age groups, AstraZeneca said, with vaccine efficacy of 85% (CI: 58% to 95%) in adults 65 years and older.
“There are 14 additional possible or probable cases to be adjudicated so the total number of cases and the point estimate may fluctuate slightly,” the company added.
“A key secondary endpoint, preventing severe or critical disease and hospitalisation, demonstrated 100% efficacy. There were eight cases of severe Covid-19 observed in the primary analysis with all of those cases in the placebo group.”
Research in Germany and Austria
On April 9, two teams of researchers who studied 11 patients in Germany and Austria and five in Norway who had all received the AstraZeneca-Oxford vaccine published papers in The New England Journal of Medicine.
Both teams of scientists found that the patients had unusual antibodies that trigger clotting reactions.
Of the 11 patients in Germany and Austria, nine were women, with a median age of 36 years.
Between five and 16 days after vaccination, ten of the patients presented with one or more thrombotic events. One patient had a fatal intracranial haemorrhage. All the patients had concomitant thrombocytopenia. None of the patients had received heparin before symptom onset.
Of the patients with one or more thrombotic events, nine had cerebral venous thrombosis, three had splanchnic vein thrombosis, three had pulmonary embolism, and four had other thromboses. Six of the patients died. Five patients had disseminated intravascular coagulation.
The researchers who studied the German and Austrian patients were led by Andreas Greinacher, who heads the Institute of Immunology and Transfusion Medicine at the Greifswald University Hospital in Germany.
Greinacher et al. suggested that some of the virus particles in the vaccine dose might break apart and release their DNA, triggering the production of antibodies.
They wrote that interactions between the vaccine and platelets or between the vaccine and platelet factor 4 (PF4) could play a role. The vaccine recipients who had clotting reactions had antibodies to PF4, the researchers found.
“One possible trigger of these PF4-reactive antibodies could be free DNA in the vaccine,” Greinacher et al. wrote.
As Chongxu Shi et al. point out in an article published in Frontiers in Immunology on October 7, 2020, extracellular DNA has been shown to contribute to the process of immunothrombosis.
Alternatively, Greinacher et al. said, antibodies might already be present in the patients and the vaccine may boost them.
The researchers suggested naming “this novel entity” VITT to avoid confusion with heparin-induced thrombocytopenia.
Nina H. Schultz et al. in Norway studied five patients who presented with venous thrombosis and thrombocytopenia seven to ten days after receiving a first dose of the AstraZeneca-Oxford vaccine.
The patients were health care workers aged 32 to 54 years. All of them had high levels of antibodies to platelet factor 4-polyanion complexes, Schultz et al. said. Four of the patients had severe cerebral venous thrombosis with intracranial haemorrhage and three of them died. None of the patients had previous exposure to heparin.
One of the patients – a 32-year-old man – had severe thrombocytopenia and thrombosis of several branches of the portal vein and in the splenic vein, the azygos vein, and the hemiazygos vein. After treatment, his platelet count returned to normal and an abdominal CT scan indicated partial resolution of the thrombosis. He was discharged from hospital on day 12.
Greinacher and 23 other scientists from Germany published a preprint on Research Square on April 20 in which they state clearly that, rarely, the AstraZeneca-Oxford vaccine causes VITT that – like autoimmune heparin-induced thrombocytopenia – “is mediated by platelet-activating anti-platelet factor 4 (PF4) antibodies”.
“Antigen formation in a proinflammatory milieu offers an explanation for anti-PF4 antibody production,” Greinacher et al. wrote. “High-titer anti-PF4 antibodies activate platelets and induce neutrophil activation and NETs [Neutrophil extracellular traps] formation, fuelling the VITT prothrombotic response.”
NETs are networks of extracellular fibres, primarily composed of DNA from neutrophils, which bind pathogens.
The scientists say their findings indicate that it is the adenovirus vector-based vaccines that are at risk of inducing VITT through adenovirus and/or other PF4-DNA interactions.
Greinacher et al. say their biophysical analyses showed “formation of complexes between PF4 and vaccine constituents, including virus proteins that were recognised by VITT antibodies”.
They say their research showed that EDTA increased microvascular leakage in mice allowing for the circulation of virus and virus-producing cell culture-derived proteins.
“In the presence of platelets, PF4 enhanced VITT antibody-driven procoagulant NETs formation, while DNase activity was reduced in VITT sera, with granulocyte-rich cerebral vein thrombosis observed in a VITT patient.”
The scientists laid out the sequence of events that their data suggests is mediating VITT. They say that, in step one, a neo-antigen is generated.
“ChAdOx1 nCov-19 vaccine activates platelet by multiple mechanisms including platelet interaction with adenovirus, cell-culture derived proteins (currently, it is unknown which of the > 1,000 proteins identified in the vaccine are involved in platelet activation), and EDTA.”
Activated platelets then release PF4, the scientists say.
In step 2, they say, an inflammatory co-signal is generated that further stimulates the immune response.
Greinacher explained further to Changing Times: “The first signal is the inflammatory signal. The vaccine constituents form antigenic complexes with PF4. This is facilitated by the open junctions and endothelial cells. This allows the immune cells to see the PF4.
The body erroneously thinks it is reacting to massive amounts of pathogens in the body, so the immune system overshoots, Greinacher explains.
The scientists say that proteins found in the vaccine include virus proteins, but also proteins originating from the human kidney-derived production cell line T-REx HEK-293.
Blood dissemination of vaccine components is not unique to the AstraZeneca-Oxford vaccine, they say.
“A ChAdOx1 vector variant (with a hepatitis B vector insert) was detectable by PCR in multiple organs, including liver, heart, and lymph nodes at days two and 29 after intramuscular injection in mice in preclinical studies reported by others,” they wrote.
The scientists say that, in step three, extracellular DNA in NETs binds PF4 “and resulting DNA/PF4 complexes further recruit anti-PF4 antibodies with lower avidity”.
The scientists say their study does have limitations. “The detailed specifications of the ChAdOx1 nCov-19 vaccine are not publicly available and potential impact of about 20 µg human cell culture proteins per vaccination dose remain to be assessed by the responsible regulatory agencies,” they state.
“Furthermore, we did not analyse the constituents of other adenovirus-based Covid-19 vaccines such as the Covid-19 Vaccine Janssen and the Sputnik V vaccine (these were not available to us). More importantly, quality control of vaccines requires the comprehensive methodological expertise of regulatory agencies.”
In another paper published on Research Square on April 9, Greinacher and a separate group of scientists concluded: “The antibody responses to PF4 in SARS-CoV-2 infection and after vaccination with Covid-19 Vaccine AstraZeneca differ.
Molecular geneticist Roland Baker says many scientists have suspected that the SARS-CoV-2 spike protein was involved in production of antibodies that cross-reacted with PF4.
“At this point we have to look at all the possible suspects and dismiss them as the cause one at a time by a process of elimination. The spike was an important contender.
“The finding by Andreas Greinacher et. al. puts to rest concerns that other vaccines producing a spike would have a similar risk. They clearly do not.
Baker points out in a tweet, however, that the AstraZeneca-Oxford (ChAdOx1) and Janssen Biotech (Ad26.COV2.S) vaccines use substantially different vectors and spikes.
“Ad26.COV2.S features a human Ad26 vector of species D engaging CD46 as its cellular receptor with coding for a membrane-bound SARS-CoV-2 S protein in the prefusion conformation stabilised by two proline substitutions that does not shed S1 due to a KO furin cleavage site,” Baker tweeted.
“ChAdOx1 features a chimpanzee adenovirus vector of species E engaging Coxsackie and adenovirus receptor (CAR) as its cellular receptor and possibly others with coding for a membrane-bound wild-type S protein in the prefusion conformation which may may shed the S1 subunit.
“Shedding of the S1 subunit occurs during native infection and AstraZeneca may shed the S1 subunit as well.”
Postmortems in Italy
Italian researchers have reported on the findings of postmortems into the deaths from VITT of a 50-year-old man and a 37-year old woman in Sicily.
In their report, published in the journal Haematologica, Cristoforo Pomara et al. say the main macroscopic finding in both cases was that “venous thrombosis was much more widespread and catastrophic than diagnosed by imaging during life”.
The researchers wrote: “Microscopic findings showed vascular thrombotic occlusions occurring in the microcirculation of multiple organs and increased inflammatory infiltrates.”
Pomara et al. said. that, in both cases the patients had a very low platelet count, very high D-dimer, and low fibrinogen with signs of consumption coagulopathy, better known as disseminated intravascular coagulation (DIC). Both patients also had detectable anti-PF4/polyanion antibodies unrelated to the use of heparin.
The previously healthy female patient, who had no history of significant disease or drug intake, developed low back pain and a strong headache ten days after vaccination.
“She became progressively drowsy and ultimately unconscious, and was, therefore, admitted to the emergency room of her local hospital,” Pomara et al. reported.
“A CT scan showed an occlusive thrombus in the superior sagittal venous sinus and a very large haemorrhage in the frontal cerebral lobe. Transported comatose by helicopter to a larger hub hospital she underwent craniotomy in order to control intracranial hypertension and remove the frontal lobe haemorrhage.
The two patients tested negative for SARS-Cov-2 molecular assays and antibodies to the nucleocapsid and spike proteins, thus ruling out recent exposure to SARS-CoV-2, the researchers added.
“There was neither clinical and laboratory evidence of inherited or acquired thrombophilia nor of intake of prothrombotic medicines,” they said.
“Venous thrombosis was accompanied by severe intracranial bleeding, which was the final cause of death in both and developed after the administration of therapeutic doses of heparin in patient 1 but concomitantly with cerebral vein thrombosis and no anticoagulant in patient 2,” Pomara et al. added.
On September 24, 2021, VigiBase listed 2,068,596 reports of adverse events following Covid vaccination, including 10,833 deaths (listed under ‘General disorders and administration site conditions’).
Of the 2,068,596 reports of adverse events after Covid vaccination listed on VigiBase as of September 24, 112,154 were reports of vascular disorders, 98,356 were reports of cardiac disorders, and 82,988 were reports of blood and lymphatic system disorders.
Reproductive system and breast disorders (extract):
Pregnancy, peurperium (postpartum), and perinatal conditions (extract):
The database of the Centers for Disease Control and Prevention’s Vaccine Adverse Event Reporting System (VAERS) in the US lists 726,965 total adverse event reports after Covid vaccination. The figure, updated on September 24, relates to reports up to September 17. A total 3,271,004 individual-symptom events are listed (many reports include more than one symptom).
VAERS puts the number of reports, in all locations, of death following Covid vaccination at 15,386 as of September 17 (6,981 from US states and territories or a location reported as unknown and 8,405 from foreign locations). A total 10,507 deaths followed administration of the Pfizer-BioNTech vaccine, 3,794 followed administration of the Moderna vaccine, and 1,050 followed administration of the Janssen Biotech vaccine. In 44 cases, the name of the vaccine manufacturer was not specified in the report. (There’s a discrepancy between the 15,386 figure and the latter 15,395 total.)
A total 2,043 of the reported deaths occurred on the same day as vaccination, 2,121 occurred the following day, 369 occurred within seven days, and 987 occurred within ten to 14 days.
According to Worldometers.info, there had been 703,043 deaths from Covid-19 in the US as of September 24.
In the update to its website on July 19, the CDC said that 12,313 reports of death after Covid vaccination had been reported to VAERS. More than 338 million doses of Covid vaccines had been administered in the US, it added. By July 21, the CDC had changed the number of reported deaths to 6,207. It gave no explanation for the change. The figures given on the CDC website do not include adverse event reports from foreign locations.
In its update on September 20, the CDC said more than 386 million doses of Covid-19 vaccines had been administered in the US up to that date and VAERS had received 7,899 reports of death (0.0020%) among people who received a Covid-19 vaccine.
“A review of available clinical information, including death certificates, autopsy, and medical records, has not established a causal link to Covid-19 vaccines,” the CDC said. “However, recent reports indicate a plausible causal relationship between the J&J/Janssen Covid-19 Vaccine and TTS, a rare and serious adverse event – blood clots with low platelets – which has caused deaths.”
In a report published on July 30, Anne M. Hause et al. from the CDC’s Covid-19 response team said that, as of July 16, 2021, there had been 9,246 reports to VAERS that related to 12- to 17-year-olds who had received the Pfizer-BioNTech vaccine.
A total 8,383 (90.7%) of these reports related to non-serious adverse events and 863 (9.3%) related to serious adverse reactions, including deaths, Hause et al. said.
Approximately 8.9 million 12- to 17-year-olds in the US had received the Pfizer-BioNTech vaccine as of July 16, Hause et al. said.
Fourteen 12- to 17-year-olds died after receiving the Pfizer-BioNTech vaccine, the researchers said. Four of them were aged 12–15 years and ten were aged 16–17 years.
The cause of death has not been determined in six of the cases. Of the eight other cases, two of the deaths are believed to have been from an intracranial haemorrhage, two from a pulmonary embolism, one from heart failure, and one from hemophagocytic lymphohistiocytosis and disseminated mycobacterium chelonae infection. Two of the deaths were suicides.
“Impressions regarding cause of death did not indicate a pattern suggestive of a causal relationship with vaccination; however, cause of death for some decedents is pending receipt of additional information,” Hause et al. said. “ACIP conducted a risk-benefit assessment based in part on the data presented in this report and continues to recommend the Pfizer-BioNTech Covid-19 vaccine for all persons aged ≥12 years.”
Hause et al. said their report had several limitations. “First, VAERS is a passive surveillance system and is subject to underreporting and reporting biases; however, under EUA, health care providers are required to report all serious events following vaccination,” the researchers wrote.
“Second, medical review of reported deaths following vaccination is dependent on availability of medical records, death certificates, and autopsy reports, which might be unavailable or not available in a timely manner.
“Third, lack of a statistical safety signal in planned monitoring does not preclude a safety concern.”
On VAERS, 376,766 reports (up to September 17 and in all locations) relate to adverse events after administration of the Pfizer-BioNTech vaccine (1,762,738 individual-symptom events), 292,711 refer to the Moderna vaccine (1,237,100 individual-symptom events), 56,699 refer to the Janssen Biotech vaccine (265,929 individual-symptom events), and 1,528 relate to an unknown vaccine manufacturer (7,303 individual-symptom events). There’s a discrepancy between the 726,965 total and this one (727,704).
The total number of reported adverse reactions resulting in permanent disability is put at 20,789. VAERS lists 14,691 cases after administration of the Pfizer-BioNTech vaccine, 4,730 after administration of the Moderna vaccine, and 1,337 after administration of the Janssen Biotech vaccine. In 54 cases, the vaccine manufacturer was not specified. There’s again a discrepancy in the totals.
VAERS lists 5,537 cases of seizures after Covid vaccination. Some other events such as ‘generalised tonic-clonic seizure’ (624), seizure-like phenomena (420), and partial seizures (131), are listed separately.
There are 5,936 reports of a pulmonary embolism and 4,640 reports of thrombosis, with separate listings for specific types of thrombosis, such as deep vein thrombosis (4,091), pulmonary thrombosis (536), and cerebral venous sinus thrombosis (387).
There are 4,068 reports of a cerebrovascular accident, 7,234 reports of sleep disorders, 8,027 cases of herpes zoster, 1,158 cases of blindness, 1,643 cases of deafness, 1,515 cases of spontaneous abortion and 48 cases of stillbirth, 5,779 cases of heavy menstrual bleeding, 1,467 cases of intermenstrual bleeding, 3,371 cases of irregular menstruation, and 1,857 cases of delayed menstruation. There are also 3,919 cases of Bell’s palsy listed on VAERS and 1,128 cases of Guillain-Barré syndrome (GBS).
GBS is a rare immune disorder that causes nerve inflammation and can result in pain, numbness, muscle weakness and difficulty walking. It can occur after an infection or the administration of other vaccines, including influenza vaccines.
The National Institutes of Health (NIH) in the US has awarded one-year supplemental grants totalling $1.67 million to five institutions to explore potential links between Covid-19 vaccination and menstrual changes. One project will focus specifically on adolescents.
“Some women have reported experiencing irregular or missing menstrual periods, bleeding that is heavier than usual, and other menstrual changes after receiving Covid-19 vaccines,” the NIH said.
Immune responses to a Covid-19 vaccine could affect the interplay between immune cells and signals in the uterus, leading to temporary changes in the menstrual cycle, the NIH added. “Other factors that may cause menstrual changes include pandemic-related stress, lifestyle changes related to the pandemic, and infection with SARS-CoV-2,” it said.
Researchers will assess the prevalence and severity of post-vaccination changes to menstrual characteristics including flow, cycle length, pain and other symptoms. “These analyses will account for other factors that can affect menstruation – such as stress, medications and exercise – to determine whether the changes are attributable to vaccination,” the NIH said.
The CDC said in the update to its website on September 20 that, as of September 15, about 201 preliminary reports of GBS had been identified on VAERS after administration of the Janssen Biotech Covid vaccine.
In a report of the ACIP meeting held on July 22, the number of reports of GBS after administration of the Janssen Biotech vaccine was put at 100. Ninety-five of the cases were reported to be serious and there was one fatality.
The FDA said in its briefing document for the VRBPAC meeting about the Moderna vaccine: “Throughout the safety follow-up period to date, there were three reports of facial paralysis (Bell’s palsy) in the vaccine group and one in the placebo group. Currently available information is insufficient to determine a causal relationship with the vaccine.”
Bell’s palsy, which is also known as acute peripheral facial palsy of unknown cause, is a condition that causes a temporary weakness or paralysis of the muscles in the face. It causes one side of the face to droop or become stiff. In most cases, Bell’s palsy is temporary and symptoms usually start to improve within a few weeks, and there is usually full recovery in about six months. A small number of people continue to have Bell’s palsy symptoms for life. In rare cases, both sides of the face become paralysed.
The FDA added in its briefing document: “There were no other notable patterns or numerical imbalances between treatment groups for specific categories of adverse events (including other neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to mRNA-1273.
“There are currently insufficient data to make conclusions about the safety of the vaccine in subpopulations such as children less than 18 years of age, pregnant and lactating individuals, and immunocompromised individuals.”
It added: “Of the seven serious adverse events in the mRNA-1273 group that were considered as related by the investigator, the FDA considered three to be vaccine related: intractable nausea and vomiting (one participant), facial swelling (two participants).
“For the serious adverse events of rheumatoid arthritis, peripheral edema/dyspnea with exertion, and autonomic dysfunction, a possibility of vaccine contribution cannot be excluded. For the event of B-cell lymphoma, an alternative etiology is more likely. An SAE of Bell’s palsy occurred in a vaccine recipient, for which a causal relationship to vaccination cannot be concluded at this time.”
The FDA says that the serious adverse events were uncommon (1% in both treatment groups) and “represented medical events that occur in the general population at similar frequency as observed in the study”.
The FDA also reported on four cases of Bell’s palsy that occurred in the vaccine group during the Pfizer-BioNTech trial. No cases occurred in the placebo group. The FDA says it will recommend surveillance for cases of Bell’s palsy among those vaccinated.
According to the FDA, the four cases did not represent a frequency above that expected in the general population. The FDA referred to the cases, which occurred at three, nine, 37, and 48 days after vaccination, as “non-serious adverse events”.
“One case (onset at three days post-vaccination) was reported as resolved with sequelae within three days after onset, and the other three were reported as continuing or resolving as of the November 14, 2020, data cut-off with ongoing durations of 10, 15, and 21 days, respectively,” the FDA states.
“The observed frequency of reported Bell’s palsy in the vaccine group is consistent with the expected background rate in the general population, and there is no clear basis upon which to conclude a causal relationship at this time, but FDA will recommend surveillance for cases of Bell’s palsy with deployment of the vaccine into larger populations.”
The Times of Israel reported on January 15 on a survey conducted by the Maccabi health fund of the first 600 people in the country to get their second vaccine dose.
Seventy percent of those surveyed reported some pain at the injection site or such effects as fever, nausea, or dizziness within the first 72 hours after getting the shot. There were 13 reported cases of Bell’s palsy. Three people reported a bitter metallic taste in the mouth, two had breathing difficulties and one person fainted.
According to statistics released by Israel’s health ministry on January 14, 1,127 of nearly two million people vaccinated filed reports about adverse effects, most of which the ministry described as minor. The most common side effects reported were weakness, dizziness, headaches, and fever, the ministry said.
The health ministry found that 82,567 people were infected with SARS-CoV-2 within a week of getting their first vaccine dose and the number dropped to 4,500 after 15 days, The Times of Israel reported.
On September 17, there were 5,753 reports of Bell’s palsy occurring after Covid vaccination listed on VigiBase.
There are 3,700 reports of myocarditis after Covid vaccination listed in the VAERS data up to September 17. VAERS lists 26 reports of viral myocarditis, five cases of eosinophilic myocarditis, three reports of autoimmune myocarditis, three cases of infectious myocarditis, one case of giant cell myocarditis, one case of septic myocarditis, one case of immune-mediated myocarditis, and one case of post-infection myocarditis.
The VAERS data also includes 2,425 reports of pericarditis, 33 cases of pleuropericarditis, 30 cases of viral pericarditis, ten cases of constrictive pericarditis, three cases of infective pericarditis, and one case of purulent pericarditis.
In updates to its website on May 27, 2021, the CDC said it had received increased reports of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the tissue surrounding the heart) in adolescents and young adults after Covid-19 vaccination. These cases had been reported after vaccination with the Pfizer-BioNTech and Moderna vaccines.
“Most patients who received care have responded well to medicine and rest and quickly improved,” the CDC said. “We continue to recommend Covid-19 vaccination for individuals 12 years of age and older.”
The CDC announced on June 10 that it would hold an emergency meeting of ACIP on June 18 to discuss reports of heart inflammation after Covid vaccination, but the meeting was cancelled and the matter was discussed during the ACIP meeting from June 23–25.
More than half of the cases reported to VAERS after administration of a second dose of either the Pfizer-BioNTech or Moderna vaccines were in people between the ages of 12 and 24, the CDC said in advance of the ACIP meeting. Those age groups accounted for less than 9% of doses administered.
The median age of patients who experienced the inflammation after a second vaccine dose was 24, according to the VAERS data and 79% of the cases were in male patients.
The CDC said its preliminary findings suggested the following:
- the median age of reported patients is younger and the median time to symptom onset is shorter among those who developed symptoms after dose 2 as compared with when the patient received only one vaccine dose;
- there is a predominance of male patients in the younger age groups, especially after dose 2;
- there are more observed reports than expected cases after dose 2 in the 16–24 age group;
- there are more cases after dose 2 than after the first dose (about 16 cases per million after second doses); and
- limited outcome data suggests that most patients (at least 81%) fully recovered.
During the presentations at the June 23 meeting, the co-chair of the CDC’s Covid-19 Vaccine Safety Technical (VaST) Work Group, Grace Lee, said that available data suggested a “likely association of myocarditis plus pericarditis with mRNA vaccination in adolescents and young adults”.
Lee said the clinical presentation of myocarditis cases after vaccination had been distinct, occurring most often within one week after dose two, with chest pain as the most common presentation.
During the meeting a summary was presented of initial surveillance findings after vaccination of 12- to 15-year-olds with the Pfizer-BioNTech vaccine.
Statistics from VAERS were presented.
The deputy director of the Immunisation Safety Office at the CDC, Tom Shimabukuro, noted that, as of June 11, there had been 484 preliminary reports of myocarditis and pericarditis among vaccinated people aged under 30 years.
Of the 484 total cases, 323 met the CDC’s definition of myocarditis and/or pericarditis, Shimabukuro said.
A total 309 of the patients were hospitalised and, at the time the data was analysed, 295 of the patients had been discharged. Nine of the patients remained in hospital, including two who were in intensive care.
Details were also provided of the incidence of myocarditis in Israel after Covid vaccination.
Sara Oliver from the CDC’s National Center for Immunisation and Respiratory Diseases (NCIRD) spoke about what was being recommended if someone developed myocarditis after the first dose of an mRNA Covid vaccine.
She said that, until additional safety data were available, experts recommended that administration of the second dose should be deferred. She said administration of the second dose could be be considered in certain circumstances, but experts recommended that patients who chose to receive the second dose of an mRNA Covid vaccine should wait at least until the episode of myocarditis was completely resolved.
She said that people who develop pericarditis after the first dose of a Covid mRNA vaccine “may proceed with administration of the second dose after resolution of pericarditis-related symptoms”. The risk of clinically significant sequelae related to pericarditis was low, she said.
Oliver also said that those with a history of pericarditis prior to Covid vaccination can receive any FDA-authorised Covid vaccine. “People who have a history of myocarditis unrelated to Covid vaccination and who have recovered may receive any FDA-authorised COVID-19 vaccine,” Oliver added.
The CDC says that currently “the benefits still clearly outweigh the risks for Covid-19 vaccination in adolescents and young adults”.
While a group of doctors and nurses issued a statement after the ACIP meeting echoing the CDC’s view and saying they “strongly encourage everyone age 12 and older who are eligible to receive the vaccine under emergency use authorisation to get vaccinated”, other medical professionals have condemned the CDC’s recommendations.
Retired cardiac surgeon and immunologist Hooman Noorchashm from Pennsylvania tweeted: “Just because C19 vaccine ‘benefits outweigh the risks, numerically’ DOES NOT mean that @CDCgov @US_FDA should tolerate totally avoidable risks. THIS, is how minority harm is born and sustained!”
He added: “Over 5 myocarditis cases in 100,000 COVID vaccinated young persons is NOT RARE!”
Noorchashm also tweeted the following:
Noorchashm says there should be screening before Covid vaccination, including testing for troponin levels in the blood. He has proposed a #ScreenB4Vaccine algorithm to identify the naturally immune and infected.
“It is highly likely, as a some powerful anecdotal cases and observational studies are showing already, that persons previously/recently infected with the virus are more susceptible to vaccine-induced adverse reactions, and immunological damage, including myocarditis,” Noorchashm wrote in an article published on Medium on June 23.
It is a rational clinical prediction, Noorchashm says, that those who develop myocarditis after the second Covid vaccine shot likely have early evidence of heart damage in their blood following the first shot.
“It is reasonable to add a troponin blood screen to the #ScreenB4Vaccine algorithm within 10–14 days after the first shot – and especially in the case of children or adults, who may be concerned about the possibility of myocarditis,” Noorchashm wrote.
“If this test comes back positive, it is clear indication of myocardial injury and warrants skipping the second shot, or delaying it until the troponin value is normalised.”
There have been reports of myocarditis after flu vaccination and federal health officials in the US stated in March 2003 that ten military personnel and two civilians developed heart inflammation after smallpox vaccination.
The CDC said the military personnel had mild myocarditis within six to 12 days after receiving a smallpox vaccine and all of them recovered completely. The two civilians also improved or recovered, officials said at the time.
A doctor and translational researcher (molecular bio, neurooncology) in the US, who uses the Twitter handle @AMcA32449832, tweeted about her analysis of the myocarditis/pericarditis/myopericarditis statistics.
On June 25, the FDA announced revisions to its fact sheets for the Moderna and Pfizer-BioNTech vaccines. The agency said the fact sheet for vaccination providers now includes a warning about myocarditis and pericarditis and the one for vaccine recipients and caregivers includes information about the two conditions.
“Additionally, the fact sheets for recipients and caregivers for these vaccines note that vaccine recipients should seek medical attention right away if they have chest pain, shortness of breath, or feelings of having a fast-beating, fluttering, or pounding heart after vaccination.”
In a presentation to the ACIP on August 30, John R. Su from the CDC’s Covid -19 Vaccine Task Force said there had been 2,574 reports of myocarditis with pericarditis (myopericarditis) or pericarditis to VAERS as of August 18 (1,903 cases of myopericarditis and 671 cases of pericarditis).
He presented the following slides:
CDC researcher Hannah Rosenblum said that myocarditis could occur in patients with SARS-CoV-2 infection and at higher rates than in those who received mRNA vaccination. She said that the risk of myocarditis after SARS-CoV-2 infection was 6 to 34 times higher than after administration of an mRNA vaccine.
Rosenblum compared the outcomes for young adults with myocarditis who had Covid-19 and those who developed the condition after Covid vaccination. In the former case, the mean length of stay in hospital was five days, about 5% of patients required mechanical ventilation, and deaths occurred, Rosenblum said. When young adults developed myocarditis after Covid vaccination, the mean stay in hospital was one to two days, and there were no deaths
The CDC said in the update to its website on September 20 that, as of September 15, VAERS had received 1,491 reports of myocarditis or pericarditis among people aged 30 years and younger who had received a Covid-19 vaccination.
“Through follow-up, including medical record reviews, CDC and FDA have confirmed 890 reports of myocarditis or pericarditis. CDC and its partners are investigating these reports to assess whether there is a relationship to Covid-19 vaccination.”
In the report published by the CDC on July 30, Hause et al. said 397 (4.3%) of the reports related to 12- to 17-year-olds who had received the Pfizer-BioNTech vaccine were about cases of myocarditis.
A total 609 (70.6%) of the reports of serious events were among males and their median age was 15 years, the researchers said.
Writing about the limitation of their report, Hause et al. said that, while a “statistically significant data mining alert” had not been observed for myocarditis following administration of the Pfizer-BioNTech vaccine, myocarditis had been identified in multiple surveillance systems as an adverse event following the use of mRNA Covid-19 vaccines.
Hause et al. said their study was not designed to identify all cases of myocarditis and only reports that listed the MedDRA term “myocarditis” were included.
They noted that v-safe was a voluntary self-enrollment programme that required children aged under 15 years to be enrolled by a parent or guardian and relied on vaccine administrators to promote it. “Therefore, v-safe data might not be generalisable to the overall vaccinated adolescent population,” Hause et al. said.
Findings by a group of researchers in the US, which were published in the Journal of the American Medical Association (JAMA) on August 4, indicated that myocarditis after Covid vaccination occurred more than had been previously reported.
The CDC had estimated that the incidence was about 0.48 cases per 100,000 vaccine doses, but George Diaz et al. found that it occured at a rate of one case per 100,000 doses.
They also found that the rate of pericarditis after Covid vaccination was 1.8 cases per 100,000 vaccine doses and, when myocarditis and pericarditis occurred together, the incidence was 2.8 cases per 100,000 vaccine doses.
Diaz et al. reviewed the electronic hospital records of more than two million people who received at least one Covid-19 vaccination. They found 37 cases of vaccine-related pericarditis and 20 cases of vaccine-related myocarditis.
Diaz et al. wrote: “Among 2,000,287 individuals receiving at least one Covid-19 vaccination, 58.9% were women, the median age was 57 years … 76.5% received more than one dose, 52.6% received the BNT162b2 vaccine (Pfizer/BioNTech), 44.1% received the mRNA-1273 vaccine (Moderna), and 3.1% received the Ad26.COV2.S vaccine (Janssen/Johnson & Johnson).
“Twenty individuals had vaccine-related myocarditis (1.0 [95% CI, 0.61-1.54] per 100,000) and 37 had pericarditis (1.8 [95% CI, 1.30-2.55] per 100,000).”
Diaz et al. said that myocarditis occurred a median of 3.5 days after vaccination.
Eleven of the cases of myocarditis occurred after administration of the Moderna vaccine and nine occurred after administration of the Pfizer-BioNTech vaccine. Fifteen of those affected were male, and the median age was 36 years.
Four people developed symptoms after the first vaccine dose and 16 developed symptoms after the second. Nineteen patients were admitted to hospital and all were discharged after a median of two days. There were no readmissions or deaths.
Two patients received a second vaccination after the onset of myocarditis and neither had a worsening of symptoms.
At the last available follow-up (median 23.5 days) after symptom onset, 13 patients had symptom resolution and seven were improving, Diaz et al. said.
Pericarditis developed after the first vaccine dose in 15 cases and after the second dose in 22 cases.
Twenty-three of the cases occurred after administration of the Pfizer-BioNTech vaccine,12 occurred after administration of the Moderna vaccine, and two cases occurred after administration of the Janssen Biotech vaccine.
Median onset was twenty days after the most recent vaccination. Twenty-seven of those affected were male and the median age was 59 years.
Thirteen of the patients were admitted to hospital, none to intensive care. The median hospital stay was one day. None of the patients died.
Seven patients with pericarditis received a second vaccination. At the last available follow-up (median 28 days), seven patients had resolved symptoms and 23 were improving.
The mean monthly number of cases of myocarditis or myopericarditis during the pre-vaccine period was 16.9 compared with 27.3 during the vaccine period, Diaz et al. said. The mean numbers of pericarditis cases during the same periods were 49.1 and 78.8 respectively.
Diaz et al. said that the limitations of their study included cases missed in outside care settings and missed diagnoses of myocarditis or pericarditis, which would underestimate the incidence, as well as inaccurate vaccination information in electronic medical records.
As of September 17, VigiBase listed 6,223 cases of myocarditis and 4,549 cases of pericarditis.
On July 9, the EMA said the PRAC had concluded that myocarditis and pericarditis could occur “in very rare cases” following vaccination with the Pfizer-BioNTech and Moderna vaccines.
The EMA said the PRAC had reviewed reports in the EEA of 145 cases of myocarditis and 138 cases of pericarditis after administration of the Pfizer-BioNTech vaccine and 19 cases of myocarditis and 19 cases of pericarditis after administration of the Moderna vaccine.
As of May 31, 2021, about 177 million doses of the Pfizer-BioNTech vaccine and 20 million doses of the Moderna vaccine had been administered in the EEA, the agency added.
In addition, the PRAC also looked into cases worldwide, the EMA said.
“In five cases that occurred in the EEA, people died. They were either of advanced age or had concomitant diseases. Available data suggest that the course of myocarditis and pericarditis following vaccination is similar to the typical course of these conditions, usually improving with rest or treatment.”
The EMA said that, “at this point in time”, no causal relationship with myocarditis or pericarditis could be established with the AstraZeneca-Oxford or Janssen vaccines. “The committee has requested additional data from the companies marketing these vaccines,” the agency added. The EMA says that the benefits of all authorised Covid-19 vaccines continue to outweigh their risks.
The EMA also said the PRAC had recommended a change to the product information for the AstraZeneca-Oxford vaccine to include a warning “to raise awareness among healthcare professionals and people taking the vaccine of cases of Guillain-Barré syndrome (GBS) reported following vaccination”.
The agency said in its safety update about the AstraZeneca-Oxford vaccine on September 8 that the product information would be updated to include GBS as a side effect.
The EMA said that, as of July 31, 833 cases of GBS had been reported worldwide after administration of the AstraZeneca-Oxford vaccine. About 592 million doses of the vaccine had been administered worldwide by that date, the agency said.
The EMA said that the frequency category allocated for GBS was “very rare” (i.e. occurring in less than 1 in 10,000 people). The agency said the PRAC recommended that the existing warning in the package leaflet should be updated with the following advice: “Patients are asked to talk to their healthcare professionals before they are given Vaxzevria if they previously had GBS after being given Vaxzevria”.
The EMA also said in its September 8 update that pain in the legs and arms or stomach and influenza-like symptoms had also been included in the product information as side effects of the AstraZeneca-Oxford vaccine.
The agency added that, since its marketing authorisation in the EU on January 29, and as of September 2, more than 68.4 million doses of the AstraZeneca-Oxford vaccine had been administered in the EEA.
On July 12, Johnson & Johnson said that it had updated its Covid-19 vaccine fact sheets to include information (required by the FDA) about cases of GBS and the signs and symptoms of the syndrome. “Updates with this new information will be implemented in other regions of the world according to local regulatory procedures,” the company said.
The company noted that most cases of GBS occurred within 42 days after vaccination. It said that the chance of people developing GBS after administration of the Janssen Biotech vaccine was “very low”.
Fact sheet for recipients and caregivers
Fact sheet for healthcare providers administering the vaccine
The fact sheet for vaccination providers now also also includes thrombosis with thrombocytopenia and capillary leak syndrome in its list of possible severe allergic reactions to the Janssen Biotech vaccine.
Seventy-six cases of GBS after administration of the Janssen Biotech vaccine are listed on VAERS, up to July 2.
In April, media in Israel said the country’s health ministry was investigating more than sixty cases of myocarditis after administration of the Pfizer-BioNTech vaccine.
Local media said an unpublished report from the ministry stated that there had been 62 cases of myocarditis reported after administration of the vaccine. Fifty-six of the cases occurred after administration of the second dose and most of the people affected were men aged under 30 years, media reports added.
According to Channel 12, sixty of the patients recovered and were discharged from hospital, but two of them (a woman aged 22 years and a man aged 35) died.
The Times of Israel reported on June 2 that Israel’s health ministry has concluded that there was a probable link between the second dose of the Pfizer-BioNTech vaccine and dozens of cases of myocarditis in males aged under 30 years.
One of the patients who developed myocarditis after receiving the Pfizer-BioNTech vaccine died, The Times of Israel reported, but the ministry said a link between the vaccination and the person’s death had not been conclusively proven.
The ministry says that, from December 2020 to May 2021, there were 275 cases of myocarditis reported across Israel, 148 of which occurred shortly after the patient was vaccinated.
According to The Times of Israel, 27 cases, including 11 people with pre-existing conditions, were reported shortly after the first vaccine dose, which had been received by 5,401,150 people in total.
There were 121 cases reported as occurring within 30 days of the second vaccine dose (among 5,049,424 people who received that dose). Sixty of those patients are reported to have had pre-existing conditions.
The health ministry said the vast majority of those affected were men aged under 30, particularly those between the ages of 16 and 19 years. Most of the cases were mild, the ministry added, and patients were released from the hospital after four days.
On January 24, The Jerusalem Post reported on the case of a 17-year-old youth, reported to have no pre-existing illnesses, who was hospitalised after receiving his second Covid vaccine dose.
The youth was admitted to an intensive care unit after feeling intense pains in his chest, the Post reported. The teenager was reported to be in a stable condition.
The Post reported on February 1 that the teenager developed myocarditis five days after receiving his second vaccine dose of a Covid vaccine.
“According to the clinic, it has still not been confirmed that the inflammation was developed as a side effect of the vaccination. However, a number of Covid-19-related myocarditis cases have been reported, according to the US National Institutes of Health,” Maayan Jaffe-Hoffman reported.
Arutz Sheva reported in January on the case of a a 23-year-old man who developed a rare inflammatory syndrome 24 hours after receiving the Pfizer-BioNTech Covid vaccine.
The director of the coronavirus department at the Hadassah Medical Centre, Professor Dror Mevorach, tweeted on January 9 about the case.
Mevorach told Channel 12: “We found out that the young man had contracted the coronavirus asymptomatically before he was vaccinated. It may be accidental, but I would not underestimate it. Care must be taken in vaccination of people who were sick with coronavirus in the past.”
The EMA said on August 11 that the PRAC was investigating three reported conditions to see if they are adverse reactions to the Moderna and Pfizer-BioNTech vaccines. The conditions being assessed are erythema multiforme, glomerulonephritis, and nephrotic syndrome.
Erythema multiforme is a hypersensitivity (allergic) reaction that is characterised by round skin lesions and can also affect mucous membranes in internal body cavities.
Glomerulonephritis is an inflammation of tiny filters in the kidneys and nephrotic syndrome is a disorder that causes the kidneys to leak too much protein in the urine.
The assessments relating to erythema multiforme followed the reporting to EudraVigilance of a small number of cases after vaccination with the Moderna and Pfizer-BioNTech vaccines, the EMA said.
“Reported cases concern suspected side effects, i.e. medical events that have been observed after vaccination, but which are not necessarily related to or caused by the vaccine,” the EMA said.
Further data and analyses had been requested from the marketing authorisation holders to support the ongoing assessment by PRAC, the agency added.
The EMA said the PRAC had also started an assessment of glomerulonephritis and nephrotic syndrome to establish whether they may be side effects of the Moderna and Pfizer-BioNTech vaccines.
“Affected patients may present with bloody or foamy urine, oedema (swelling of the eyelids, feet or abdomen), or fatigue,” the EMA said.
The assessments followed a small number of cases reported after vaccination with the Moderna and Pfizer-BioNTech vaccines, the agency added. These cases were reported in the medical literature and included cases where patients experienced a relapse of pre-existing kidney conditions.
Again, further data and analyses had been requested from the marketing authorisation holders to support the ongoing assessments by the PRAC, the EMA said.
The EMA said that, as of July 29, 48,788 cases of suspected side effects after administration of the Moderna vaccine were reported to EudraVigilance from the EU and the additional countries of the EEA. In 392 of these cases, there was a fatal outcome, the agency said.
By the same date, about 43.5 million doses of the Moderna vaccine had been administered in the EU and the additional countries of the EEA, the EMA said.
The EMA said that, as of July 29, 244,807 cases of suspected side effects after administration of the Pfizer-BioNTech vaccine were reported to EudraVigilance from the EU and the additional countries of the EEA. In 4,198 of these cases, there was a fatal outcome, the agency said.
By the same date, about 330 million doses of the Pfizer-BioNTech vaccine had been administered in the EU and the additional countries of the EEA, the EMA said.
The EMA said that no further updates to the product information for the Moderna and Pfizer-BioNTech vaccines were currently recommended.
Data from Europe
EudraVigilance lists 954,001 adverse reaction reports that relate to the four vaccines authorised for use in Europe.
The database lists 435,779 individual adverse reaction reports up to September 11 for the Pfizer-BioNTech vaccine (tozinameran). Most are from the Netherlands (71,687), followed by Italy (63,984) and France (53,203).
A total 373,285 individual adverse reaction reports up to September 18 are listed for the AstraZeneca-Oxford vaccine, with the most listed in the Netherlands (36,638), followed by France (25,163), and Germany (25,078).
A total 117,243 cases are listed for the Moderna vaccine. Most are from the Netherlands (23,674), followed by France (11,118), and Italy with 7,891.
A total 27,694 cases are listed for the Janssen Biotech vaccine. Most are from the Netherlands (12,097), followed by Portugal with 1,268. and Italy (1,247).
EudraVigilance doesn’t provide an overall total of reported deaths after Covid vaccination or specify the total number of reported deaths after administration of each vaccine.
The database provides totals of reported deaths in the case of individual symptoms or symptom categories. In all the categories detailed here, in most of the adverse reaction reports the person vaccinated was female and most of the reports relate to vaccinees in the 18–64 age group.
The following detailed statistics are up to September 4 and will be updated shortly.
After administration of the AstraZeneca-Oxford vaccine
- Nervous system disorders: 816 deaths; 203,031 adverse reaction reports.
- Respiratory, thoracic, and mediastinal disorders: 612 deaths; 34,229 adverse reaction reports. (The mediastinum is the part of the chest that lies between the sternum and the spinal column, and between the lungs.)
- Vascular disorders: 369 deaths;23,862 adverse reaction reports.
- Infections and infestations: 322 deaths; 24,378 adverse reaction reports.
- Gastrointestinal disorders: 259 deaths; 95,571 adverse reaction reports.
- Blood and lymphatic system disorders: 214 deaths; 11,710 adverse reaction reports.
- Reproductive system and breast disorders: one death; 12,862 adverse reaction reports.
After administration of the Pfizer-BioNTech vaccine
- Nervous system disorders: 1,255 deaths; 165,322 adverse reaction reports.
- Respiratory, thoracic, and mediastinal disorders: 1,355 deaths; 41,791 adverse reaction reports, including 405 cases in the 12–17 age group.
- Vascular disorders: 489 deaths; 26,041 adverse reaction reports.
- Infections and infestations: 1,123 deaths; 31,705 adverse reaction reports.
- Gastrointestinal disorders: 480 deaths; 83,209 adverse reaction reports.
- Blood and lymphatic system disorders: 153 deaths; 25,632 adverse reaction reports.
- Reproductive system and breast disorders: three deaths; 16,727 adverse reaction reports.
After administration of the Moderna vaccine
- Nervous system disorders: 635 deaths; 47,349 adverse reaction reports.
- Respiratory, thoracic, and mediastinal disorders: 599 deaths; 11,713 adverse reaction reports.
- Vascular disorders: 241 deaths; 7,159 adverse reaction reports.
- Infections and infestations: 407 deaths; 8,112 adverse reaction reports.
- Gastrointestinal disorders: 236 deaths; 23,385 adverse reaction reports.
- Blood and lymphatic system disorders: 57 deaths; 5,241 adverse reaction reports.
- Reproductive system and breast disorders: three deaths; 3,141 adverse reaction reports.
After administration of the Janssen Biotech vaccine
- Nervous system disorders: 131 deaths; 15,029 adverse reaction reports.
- Respiratory, thoracic, and mediastinal disorders: 117 deaths; 2,544 adverse reaction reports.
- Vascular disorders: 99 deaths; 2,339 adverse reaction reports.
- Infections and infestations: 55 deaths; 1,591 adverse reaction reports.
- Gastrointestinal disorders: 53 deaths; 6,635 adverse reaction reports.
- Blood and lymphatic system disorders: 28 deaths; 671 adverse reaction reports.
- Reproductive system and breast disorders: four deaths; 755 adverse reaction reports.
Data from the UK
In its weekly summary of Yellow Card reporting, updated on September 23, the MHRA said that, as of September 15, it had received and analysed 363,676 reports of suspected adverse reactions after Covid vaccination.
A total 231,920 reports related to the AstraZeneca-Oxford vaccine. The total number of listed adverse reactions is 825,575 (a single report may contain more than one symptom).
The first report was received on January 4, 2021, the day the vaccine was first administered in the UK.
As of August 25, 114,752 reports of adverse reactions had been submitted relating to vaccination with the Pfizer-BioNTech vaccine, which was first administered in the UK on December 9, 2020. These include a total of 324,654 suspected reactions.
A total 15,916 Yellow Card reports related to the Moderna vaccine. These include a total of 51,034 suspected reactions. The first report was received on April 7.
For the Pfizer-BioNTech, AstraZeneca-Oxford, and Moderna vaccines the overall reporting rate was about three to six Yellow Cards per 1,000 vaccine doses administered, the MHRA said.
There were 1,088 reports of adverse reactions in which the brand of the vaccine was not specified (3,292 total suspected reactions).
The MHRA has received 1,662 UK reports of people dying shortly after Covid vaccination. There were 1,083 reports of death after administration of the AstraZeneca-Oxford vaccine, 534 after vaccination with the Pfizer-BioNTech vaccine, and 17 after administration of the Moderna vaccine. Twenty-eight deaths were reported in cases in which the vaccine brand was unspecified.
The majority of the reports of deaths related to elderly people or people with underlying illness, the MHRA said. Usage of the vaccines had increased, the agency said, and, as such, so had reporting of fatal events with a temporal association with vaccination.
“However, this does not indicate a link between vaccination and the fatalities reported,” the MHRA said. “Review of individual reports and patterns of reporting does not suggest the vaccines played a role in these deaths.”
According to Worldometers.info, 135,803 people were reported to have died from Covid-19 in the UK as of September 23.
The MHRA said that, in the week since the previous summary to September 8, it received a further 1,440 Yellow Cards for the Pfizer-BioNTech vaccine, 751 for the AstraZeneca-Oxford vaccine, 351 for the Moderna vaccine, and 14 where the brand was not specified.
The MHRA said that data from the UK public health agencies showed that at least 48,505,068 people had received their first vaccination in the UK by September 15 and 44,234,077 second doses had been administered.
As of September 15, an estimated 24.8 million first doses of the AstraZeneca-Oxford vaccine and 22.2 million first doses of the Pfizer-BioNTech vaccine had been administered, plus about 24 million and 19.1 million second doses of the AstraZeneca-Oxford and Pfizer-BioNTech vaccines respectively.
About 1.4 million first doses and 1.1 million second doses of the Moderna vaccine have also been administered.
The MHRA said that, up to September 15, it had received Yellow Card reports of 419 cases of major thromboembolic events with concurrent thrombocytopenia in the UK following vaccination with the AstraZeneca-Oxford vaccine, including 45 that occurred after the second vaccine dose. The patients were aged between 18 and 93 years. Seventy-two of the patients died, including six who died after the second vaccine dose.
“Of the 419 reports, 211 occurred in women, and 204 occurred in men,” the MHRA said. “The overall case fatality rate was 17%.” In four cases, the sex of the patient was not identified in the report.
Cerebral venous sinus thrombosis was reported in 150 cases (average age 46 years) and 269 patients (average age 54 years) had other major thromboembolic events with concurrent thrombocytopenia.
The overall incidence after first or unknown doses was 15.1 per million doses, the MHRA said.
“Taking into account the different numbers of patients vaccinated with Covid-19 Vaccine AstraZeneca in different age groups, the data shows that there is a higher reported incidence rate in the younger adult age groups following the first dose compared to the
The MHRA puts the incidence rate after the first dose at 20.5 per million doses in people aged 18–49 years as compared to 10.9 per million doses in those aged 50 years and over.
The number of first doses given to people in the 18–49 years age group is estimated to be 8.5 million while an estimated 16.3 million first doses have been given to patients aged 50 years and above.
“The MHRA advises that this evidence should be taken into account when considering the use of the vaccine,” the agency said. “There is some evidence that the reported incidence rate is higher in females compared to men although this is not seen across all age groups and the difference remains small.”
The overall incidence after second doses was 1.9 cases per million doses, the MHRA said.
“The number of second doses given to those in the 18–49 years age group is estimated to be 8.1 million while an estimated 15.9 million second doses have been given to patients aged 50+ years.”
The MHRA says the incidence rates reported after the second dose should not be directly compared to those reported after the first dose as the time for follow-up and identification of cases after second doses is more limited and differs across age groups.
The agency says that ongoing scientific review has concluded that there is strong evidence of a link between administration of the AstraZeneca-Oxford vaccine and blood clotting events, including cerebral venous sinus thrombosis, with concurrent low levels of platelets.
“Anyone who experienced cerebral or other major blood clots occurring with low levels of platelets after their first vaccine dose of Covid-19 Vaccine AstraZeneca should not have their second dose,” the MHRA said. “Anyone who did not have these side effects should come forward for their second dose when invited.”
The MHRA said the evidence to date did not suggest that the AstraZeneca-Oxford vaccine caused venous thromboembolism without a low platelet count.
Reports of suspected thromboembolic events with concurrent thrombocytopenia (after vaccination with the AstraZeneca-Oxford vaccine) in the UK up to and including September 15.
The MHRA also said that, as of September 15, it had received Yellow Card reports of 18 cases of major thromboembolic events (blood clots) with concurrent thrombocytopenia in the UK following administration of the Pfizer-BioNTech vaccine. Six of the patients were women and 11 were men. In one case, the sex of the patient was not identified in the report. The patients’ age range was 18 to 91 years and two of them died.
The agency also said that, as of September 15, it had received Yellow Card reports of two cases of major thromboembolic events (blood clots) with concurrent thrombocytopenia in the UK after administration of the Moderna vaccine. The two patients were adult males under the age of fifty, the MHRA said.
Table courtesy of Michael Makris.
The MHRA said in its latest summary that, as of September 15, it had received 296 reports of myocarditis and 220 reports of pericarditis after administration of the Pfizer-BioNTech vaccine as well as six reports of viral pericarditis, three reports of carditis, two reports of infective pericarditis, one report of viral myocarditis, one report of non-infective endocarditis, and one report of streptococcal endocarditis. In one of the cases of pericarditis the patient died.
As of September 15, there had been 111 reports of myocarditis and 170 reports of pericarditis after administration of the AstraZeneca-Oxford vaccine. There were also five reports of viral pericarditis and four reports of endocarditis, two reports of bacterial endocarditis, two reports of carditis, one report of viral myocarditis, one report of infectious myocarditis, and one report of acute endocarditis. In one of the cases of myocarditis the patient died.
There were 64 reports of myocarditis, 40 reports of pericarditis, and one report of endocarditis after administration of the Moderna vaccine, the MHRA said.
The MHRA said that, in the UK, the overall reporting rate for myocarditis (including viral myocarditis), after both first and second vaccine doses, was 7.2 cases per million doses of the Pfizer-BioNTech vaccine.
For pericarditis, including viral pericarditis and infective pericarditis, the overall reporting rate was 5.5 cases per million doses of the Pfizer-BioNTech vaccine.
In the case of the Moderna vaccine, the overall reporting rate for myocarditis was 25.1 cases per million doses and for pericarditis 15.7 cases per million doses.
For the AstraZeneca-Oxford vaccine, the overall reporting rate for myocarditis, including viral myocarditis and infectious myocarditis, was 2.3 cases per million doses and for pericarditis, including viral pericarditis, it was 3.6 cases per million doses, the MHRA said.
The MHRA has made revisions to the product information for the Moderna and Pfizer-BioNTech vaccines and it now includes “Inflammation of the heart (myocarditis or pericarditis)” in the possible side effects of both vaccines.
Information for UK recipients of the Pfizer-BioNTech vaccine:
Included in the patient information leaflet for the Moderna vaccine:
The MHRA said that, up to and including September 15, it had received 419 reports of Guillain-Barré syndrome after administration of the AstraZeneca-Oxford vaccine and 25 reports of a related disease called Miller Fisher syndrome.
Up to September 15, the MHRA received 49 reports of GBS following administration of the Pfizer-BioNTech vaccine and three reports of GBS after administration of the Moderna vaccine.
The MHRA said it would continue to review cases of GBS reported after the administration of Covid-19 vaccines “to further assess a possible association between Guillain-Barré syndrome and Covid-19 vaccines”, with independent advice from its Vaccine Benefit-Risk Working Group.
The agency said that, based on the available evidence, it was not able to confirm or rule out a causal relationship with the vaccines.
The product information for the AstraZeneca-Oxford vaccine had been updated to include a precautionary warning that Guillain-Barré syndrome had “very rarely been reported following vaccination”, the MHRA added.
The MHRA also said it had received 12 reports of capillary leak syndrome (a condition in which blood leaks from the small blood vessels into the body) after administration of the AstraZeneca-Oxford vaccine. In two cases, the patient had a history of capillary leak syndrome, the agency said.
The agency added: “This is an extremely rare relapsing-remitting condition and triggers for relapses are not well understood.
On June 11, the EMA said the PRAC had concluded that people who have previously had capillary leak syndrome must not be vaccinated with the AstraZeneca-Oxford vaccine.
The committee also concluded that capillary leak syndrome should be added to the product information as a new side effect of the vaccine, together with a warning to raise awareness among healthcare professionals and patients about the risk.
The EMA said the PRAC carried out an in-depth review of six cases of capillary leak syndrome in people who had received the AstraZeneca-Oxford vaccine. Fourteen reports of capillary leak syndrome were reviewed, but only six had sufficient information for further assessment and were considered to be cases of capillary leak syndrome.
Most of the cases occurred in women, within four days of vaccination. Three of the patients affected had a history of capillary leak syndrome and one of them died.
On July 9, the EMA said the PRAC had recommended that people who had previously had capillary leak syndrome must not be vaccinated with the Janssen Biotech vaccine and that capillary leak syndrome should be added to the product information as a new side effect of the vaccine, together with a warning to raise awareness among healthcare professionals and patients of this risk.
The PRAC reviewed three cases of capillary leak syndrome in people who had received the Janssen Biotech vaccine, which occurred within two days of vaccination. One of those affected had a history of capillary leak syndrome and two of them died. The EMA noted that, as of June 21, more than 18 million doses of the Janssen Biotech vaccine had been administered worldwide.
The EMA also updated healthcare professionals about measures to monitor TTS after administration of the Janssen Biotech vaccine.
“Individuals diagnosed with thrombocytopenia within three weeks after vaccination with Covid-19 Vaccine Janssen should be actively investigated for signs of thrombosis,” the EMA said. “Similarly, individuals who present with thrombosis within three weeks of vaccination should be evaluated for thrombocytopenia.”
In its latest summary, the MHRA said it continued to review reports of Bell’s palsy after Covid vaccination “and to analyse them against the number expected to occur by chance in the absence of vaccination (the ‘natural rate’)”.
The agency said the number of reports of facial paralysis received so far was similar to the expected natural rate and did not currently suggest an increased risk following Covid vaccination.
These suspected reactions have been reported in 27,705 individual Yellow Card reports (as each report may contain more than one suspected reaction). This is following approximately 48.1 million COVID-19 vaccine doses administered to women up to 15 September 2021. The number of reports of menstrual disorders and vaginal bleeding is low in relation to both the number of people who have received COVID-19 vaccines to date and how common menstrual disorders are generally.
The MHRA said it had received 35,707 reports of a variety of menstrual disorders after administration of the three Covid vaccines. These included heavier than usual periods, delayed periods, and unexpected vaginal bleeding.
“These suspected reactions have been reported in 27,705 individual Yellow Card reports (as each report may contain more than one suspected reaction),” the MHRA said.
This was following the administration of about 48.1 million Covid-19 vaccine doses to women up to September 15, the MHRA said.
“The number of reports of menstrual disorders and vaginal bleeding is low in relation to both the number of people who have received Covid-19 vaccines to date and how common menstrual disorders are generally,” the MHRA said.
“The rigorous evaluation completed to date does not support a link between changes to menstrual periods and related symptoms and Covid-19 vaccines.”
The MHRA said the menstrual changes reported after Covid vaccination were mostly transient in nature and there was no evidence to suggest that Covid-19 vaccines would affect women’s fertility and their ability to have children.
“Whilst uncomfortable or distressing, period problems are extremely common and stressful life events can disrupt menstrual periods,” the agency said. Changes to the menstrual cycle had also been reported following infection with SARS-CoV-2 and in people affected by long Covid, the MHRA added.
The MHRA said that the numbers of reports of miscarriage and stillbirth after Covid vaccination were low in relation to the number of pregnant women who had received Covid-19 vaccines to date (more than 72,000) and that such events were a common occurrence in the UK outside of the Covid pandemic.
“There is no pattern from the reports to suggest that any of the Covid-19 vaccines used in the UK, or any reactions to these vaccines, increase the risk of miscarriage or stillbirth,” the MHRA said.
“Sadly, miscarriage is estimated to occur in about 20 to 25 in 100 pregnancies in the UK and most occur in the first 12 to 13 weeks of pregnancy (the first trimester).”
Stillbirths were estimated to occur in about 1 in 200 pregnancies in the UK, the MHRA said.
“A few reports of commonly occurring congenital anomalies and preterm births have also been received,” the agency added. “There is no pattern from the reports to suggest that any of the Covid-19 vaccines used in the UK increase the risk of congenital anomalies or birth complications.”
Pregnant women had reported similar suspected reactions to the vaccines as people who were not pregnant, the MHRA said.
The MHRA said it had received about 3,000 Yellow Card reports from women breastfeeding at the time of vaccination.
“Most of these women reported only suspected reactions in themselves which were similar to reports for the general population, with no effects reported on their milk supply or in their breastfed children,” the agency said.
“A small number of women have reported decreases in their milk supply, most of which were transient, or possible reactions in their breastfed child,” the MHRA said. “A number of factors can affect milk supply and infant behaviour, including general maternal health, amount of sleep, and anxiety.
“The symptoms reported for the children (high temperature, rash, diarrhoea, vomiting, and general irritability) are common conditions in children of this age, so some of the effects reported may have occurred by coincidence.”
A small number of women might experience a reduction in their breast milk production, the MHRA added.
The MHRA said there was no current evidence that Covid vaccination while breastfeeding caused any harm to breastfed children or affected a woman’s ability to breastfeed.
“Covid-19 vaccines do not contain live components and there is no known risk associated with being given a non-live vaccine whilst breastfeeding,” the agency said. “The current advice of the Joint Committee on Vaccination and Immunisation is that breastfeeding parents may be offered any suitable Covid-19 vaccine depending on their age.”
The MHRA also said it had been reviewing reports of skin reactions occurring around the vaccination site that appeared a little while after vaccination. It said most of the reports referred to administration of the Moderna vaccine and the product information for that vaccine had been updated to highlight the possibility of delayed injection site reactions.
“These reactions are suggestive of a delayed hypersensitivity reaction that occurs four–11 days after vaccination,” the MHRA said.
“The reactions are characterised by a rash, swelling and tenderness that can cover the whole upper arm and may be itchy and/or painful and warm to the touch.”
The MHRA said the reactions were usually self-limiting and resolved within a day or two, but, in the case of some patients, the rashes could take slightly longer to disappear.
“Individuals who experience this reaction after their first dose may experience a similar reaction in a shorter time frame following the second dose,” the MHRA said.
“However, none of the reports received have been serious and people should still take their second dose when invited. Those who experience delayed skin reactions after their Covid-19 vaccination which do not resolve within a few days should seek medical advice.”
The MHRA also said there had been rare reports of extensive swelling of the vaccinated limb after administration of the Pfizer-BioNTech vaccine.
“The product information has been updated to include ‘extensive swelling of the vaccinated limb’ as a side effect of the vaccine,” the MHRA said. “This type of swelling is also recognised to occur with other (non-Covid-19) vaccines.”
The MHRA says that, for all Covid-19 vaccines, the overwhelming majority of reports relate to injection-site reactions and generalised symptoms such as ‘flu-like’ illness, headache, chills, fatigue, nausea, fever, dizziness, weakness, aching muscles, and a rapid heartbeat.
“Generally, these happen shortly after the vaccination and are not associated with more serious or lasting illness,” the agency said.
The reports about the AstraZeneca-Oxford vaccine include 175,813 nervous system disorders (196 fatal), 12,865 vascular disorders (65 fatal), 7,441 blood disorders (ten fatal), 9,366 cardiac disorders (166 fatal), 13,936 eye disorders, including 289 cases of blindness, and 9,869 ear disorders, including 785 cases of hearing loss, 4,020 cases of tinnitus, and 2,158 cases of vertigo.
The reports also include 78,841 gastrointestinal disorders (14 fatal), 2,998 immune system disorders (four fatal), 99,612 muscle and tissue disorders (one fatal), 27,819 respiratory disorders (131 fatal), 50,796 skin disorders, 17,315 psychiatric disorders (seven fatal), 18,399 cases of infection (94 fatal) that included 1,560 cases of herpes zoster, 17,352 reports of reproductive and breast disorders that included 1,184 cases of vaginal haemorrhage and 458 cases of breast pain, 1,195 reports of a cerebrovascular accident (46 fatal), 169 reports of cerebral haemorrhage (46 fatal), and 143 reports of an ischaemic stroke (seven fatal). The cardiac disorders include 167 reports of cardiac arrest (34 fatal). There were 671 reports of an anaphylactic reaction (two fatal) and 565 reports of Bell’s palsy (there are also another 335 cases described as facial paralysis).
There are 866 reports of thrombocytopenia (six fatal), 229 reports of immune thrombocytopenia (one fatal), nine cases of thrombotic thrombocytopenic purpura (TTP), and 1,725 reports of non-site specific thrombosis (33 fatal).
There are 13,648 reports listed of adverse reactions related to menstruation and uterine bleeding, including 4,064 reports of heavy menstrual bleeding, 2,811 cases of delayed menstruation, and 1,882 cases of irregular menstruation.
There are also 380 reports of menopausal effects listed, including 284 cases of postmenopausal haemorrhage.
The reports about the Pfizer-BioNTech vaccine include 56,670 nervous system disorders (54 fatal), 5,203 vascular disorders (13 fatal), 11,051 blood disorders (three fatal), 5,481 cardiac disorders (95 fatal), 5,397 eye disorders, including 104 cases of blindness, and 4,495 ear disorders, including 448 cases of hearing loss, 1,632 cases of tinnitus, and 1,158 cases of vertigo.
The reports also include 30,335 gastrointestinal disorders (16 fatal), 1,653 immune system disorders (two fatal), 39,027 muscle and tissue disorders, 13,981 respiratory disorders (49 fatal), 22693 skin disorders (one fatal), 6,716 psychiatric disorders (one fatal), 7,657 cases of infection (85 fatal) that included 1,204 cases of herpes zoster, 19,128 reports of reproductive and breast disorders (one fatal) that include 1,128 cases of vaginal haemorrhage and 516 cases of breast pain, 333 reports of a cerebrovascular accident (14 fatal), 43 reports of cerebral haemorrhage (eight fatal), and 38 reports of an ischaemic stroke (two fatal). There were 418 reports of an anaphylactic reaction (two fatal) and 422 cases of Bell’s palsy (there are also another 325 cases described as facial paralysis).
There are 176 reports of thrombocytopenia (one fatal), 68 reports of immune thrombocytopenia, five cases of TTP, and 369 reports of non-site specific thrombosis (seven fatal).
There are 16,173 reports listed of adverse reactions related to menstruation and uterine bleeding, including 4,109 reports of heavy menstrual bleeding, 3,613 cases of delayed menstruation, and 2,265 cases of irregular menstruation.
There are also 102 reports of menopausal effects listed, including 74 cases of postmenopausal haemorrhage.
Doctor calls for a halt to Covid vaccination
The director of the Evidence-based Medicine Consultancy (E-BMC) and the crowdfunded community interest company EbMC Squared CiC, Dr Tess Lawrie, has written to June Raine calling for an immediate halt to the Covid vaccination programme in the UK.
She also asked Raine to give EbMC Squared CiC full access to the Yellow Card adverse reactions database so that researchers there can conduct a “comprehensive, independent and accurate evaluation” of the data in collaboration with clinical experts.
Lawrie, who is based in Bath, said the MHRA had more than enough evidence via the Yellow Card system to declare the Covid-19 vaccines unsafe for use in humans.
There are at least three urgent questions that the MHRA needs to answer, Lawrie says:
- How many people have died within 28 days of Covid vaccination?
- How many people have been hospitalised within 28 days of Covid vaccination?
- How many people have been disabled by Covid vaccination?
Lawrie says the nature and variety of adverse reactions reported via the Yellow Card System are “supported by other recent scientific papers on vaccine-induced harms, which are mediated through the vaccine spike protein product”.
It is now apparent, Lawrie says, that these products in the blood stream are toxic to humans.
Researchers at EbMC Squared CiC studied the adverse event data published by the MHRA and grouped it into four categories: bleeding, clotting and ischaemic adverse reactions; immune system adverse reactions; ‘pain’ adverse reactions; neurological adverse reactions; adverse reactions involving the loss of sight, hearing, speech, or smell; and adverse reactions related to pregnancy.
Working with data up to May 26, the researchers identified 13,766 bleeding, clotting and ischaemic adverse reactions, 856 of which were fatal.
“Government reports have highlighted the occurrence of cerebral venous sinus thrombosis, apparently accounting for 24 fatalities and 226 ADRs [adverse drug reactions] up to the 26th May 2021,” Lawrie wrote.
The most common Yellow Card categories in which these sorts of ADRs were reported were the nervous system category (152 fatalities, mainly from brain bleeds and clots), and the respiratory and cardiac categories (with 103 fatalities, mainly from pulmonary thromboembolism, in the former and 81 fatalities in the latter), Lawrie adds.
Lawrie said that, as of May 26, there were 54,870 ADRs and 171 fatalities in the ‘immune system’ category.
She said the second highest number of fatalities were in this category, but only four associated deaths were reported in the Yellow Card ‘immune disorders’ category (as of May 26).
The majority (141 fatalities associated with 19,474 ADRs) were reported in the ‘Infections’ category. Among 1,187 people for whom post-vaccination Covid-19 infection was reported, there were 72 fatalities, Lawrie noted.
Lawrie added that many adverse reactions in the ‘infections’ category indicated a reactivation of latent viruses, including herpes zoster (1,827 ADRs), herpes simplex (943 ADRs, including one that was fatal), and rabies (one fatal reaction).
Lawrie also noted that Bell’s palsy, which she says is also associated with latent virus reactivation, is reported in the neurological adverse reaction section of her report.
“Also suggestive of vaccine-induced immunocompromise was the high number of immune-mediated conditions reported, including Guillain-Barré syndrome (280 ADRs, including six deaths), Crohn’s and non-infective colitis (231 ADRs, including two deaths) and multiple sclerosis (113 ADRs),” she said.
Under the ‘pain’ category, the EbMC Squared CiC researchers identified at least 157,579 ADRs.
Lawrie noted that a large number of these were arthralgias (24,902 reports of joint pain) and myalgias (31,168 reports of muscle pain), including 270 reports of fibromyalgia, a long-term condition that causes pain all over the body.
Among reported congenital disorders (conditions that are usually present from birth) there were 11 reports of paroxysmal extreme pain disorder (PEPD), which is an extremely rare inherited disease caused by a genetic mutation leading to dysfunction of voltage-gated sodium channels.
The EbMC Squared CiC researchers noted that 21% percent (185,474) of ADRs were categorised as nervous system disorders in the Yellow Card system.
Lawrie said that most of the fatalities associated with nervous system ADRs occurred as a result of central nervous system haemorrhages (127 of the 186 fatalities reported as nervous system fatalities). The EbMC Squared CiC researchers counted these 127 deaths in the bleeding, clotting and ischaemic category.
In the ‘loss of sight, hearing, speech or smell’ category the EbMC Squared CiC researchers identified 4,771 reports of visual impairment including blindness, 130 reports of speech impairment, 4,108 reports of taste impairment, 354 reports of olfactory impairment, and 704 reports of hearing impairment.
The 307 ADRs included one maternal death, 12 stillbirths (reported as six stillbirths and six foetal deaths, but only three listed as fatal), Lawrie adds.
There was also one newborn death following preterm birth, and 150 spontaneous abortions, she said.
“We have submitted a Freedom of Information request as to the cause of the maternal death and will look into pregnancy and congenital ADRs in more detail in our next report,” she added.
“Due to the need for expedience, we have not detailed all ADRs in this preliminary report. The existing Yellow Card data covering just under a five-month period indicate that the extent of morbidity and mortality associated with the Covid-19 vaccines is unprecedented.
Lawrie said that urgent independent expert evaluation and discussion was required to assess whether Covid vaccines might be causing gene mutations among recipients, “as suggested by the occurrence of usually extremely rare genetic disorders, such as PEPD”.
In addition to the 11 cases of PEPD reported via the Yellow Card system, there were 12 reports of this extremely rare condition on the WHO’s VigiBase and ten on EudraVigilance, Lawrie said.
“Are these ADRs occurring in babies of vaccinated pregnant women, or spuriously among vaccinated adults? she wrote. “This question needs urgent attention.”
Adverse reaction reports from Australia
In its weekly safety report about Covid vaccination, published on September 23, the TGA said that, as of September 19, it had received 61,738reports of adverse reactions after Covid vaccination. This is an increase of 2,539 reports compared with the previous week.
The TGA said that it had received 556 reports of people dying after Covid vaccination. This is an increase of 21 on the number of deaths reported in the update published on September 16.
The administration said it considered that nine of the 556 deaths were linked to immunisation. The nine deaths all occurred after a first dose of the AstraZeneca-Oxford vaccine, the TGA said. Eight were cases of thrombosis with thrombocytopenia syndrome (TTS) and one was a case of immune thrombocytopenia (ITP). Six of those who died from TTS were women.
Table courtesy of @real_GGoswami on Twitter.
One of the deaths from TTS was that of a 72-year-old woman from South Australia whose death was confirmed on July 12. She had a very severe case of TTS involving blood clots in her brain and a very low platelet count. The state coroner is investigating the death.
It is reported that the woman received her first dose of the AstraZeneca-Oxford vaccine on June 24 and was admitted to hospital on July 5.
The woman who died from ITP was 61 years old and had received a first dose of the AstraZeneca-Oxford vaccine, now branded as Vaxzevria in Australia. An external Vaccine Safety Investigation Group (VSIG) of clinical experts and consumer representatives, convened by the TGA on July 2, said that a “very rare but fatal case of immune thrombocytopenia” was “likely linked to the vaccine”.
The agency notes in its latest summary that, as of September 19, 24,792,054 Covid vaccine doses had been administered in Australia (15.1 million first doses and 9.7 million second doses).
There have been 1,196 recorded deaths from Covid-19 in Australia, 909 of which occurred in 2020.
The TGA said in its latest summary that, since the previous week, an additional seven reports of blood clotting and low blood platelets had been assessed as “confirmed or probable TTS likely to be linked to the first dose of Vaxzevria (AstraZeneca)”. None of these cases were fatal. In two of the new cases the people affected were aged under 60 years.
“We continue to closely monitor cases of TTS as Vaxzevria (AstraZeneca) is now being used more frequently in people aged under 60 years,” the TGA said. “To date, we have not observed a significant change in the rate of TTS in people aged 50-59 years. There has been a trend for the rate to decrease in people under 50 years, but due to the low number of cases this is not statistically significant.”
The total number of Australian cases assessed as TTS after administration of the AstraZeneca-Oxford vaccine is now 141 (77 confirmed, 64 probable).
In Australia, the TGA said, the risk of dying from TTS after vaccination was approximately one in a million (people receiving a first dose).
To date, 13 cases of TTS have occurred after the second vaccine dose, the TGA said. Eleven cases had been classified as probable TTS and two cases met the criteria for confirmed TTS.
The TGA said that all the cases had occurred in people older than 50 years and 11 occurred in people aged over 60 years.
Eleven of the patients had clots in common locations, such as the lungs or legs, the TGA said. Two cases were classified as Tier 1.
“The information available to us indicates that only one of these patients required treatment in the intensive care unit, and nine individuals have been discharged from hospital,” the TGA added.
“Our preliminary analysis is consistent with overseas investigations which have shown that the risk of TTS after the second dose is extremely low.”
The TGA said that, when assessed against the criteria used by the CDC in the US, fewer than half of the TTS cases reported to the TGA were classified as Tier 1 cases, which tend to have more serious outcomes.
The CDC defines a case as Tier 1 when there is blood clotting in an unusual location such as the brain or abdomen and there is a low platelet count with or without anti-PF4 antibodies. It defines a case as Tier 2 when there is blood clotting in common locations such as the leg or the lungs and a low platelet count and anti-PF4 antibodies.
“Australian data indicates that patients aged under 50 years of age are more likely to be classified as Tier 1 and/or require treatment in intensive care. However, more than one third of these younger patients have not required treatment in intensive care.”
The TGA said in an earlier report: “Nearly half of the TTS cases in women required treatment in intensive care. Cases meeting the criteria for Tier 1 were 2.5 times more likely to occur in women compared to men.”
Approximately 11.3 million doses of the AstraZeneca-Oxford vaccine had been administered in Australia as of September 19, the TGA said.
The TGA says that most TTS cases have occurred about two to three weeks after vaccination, although the time to onset (or diagnosis) has ranged from one to 83 days.
“To date, cases presenting with a longer time to onset (over 50 days) have been designated as probable cases and have presented with common forms of clots,” the TGA said in an earlier summary. “It can be difficult to distinguish between normal clots and TTS for these cases and they remain under investigation.”
The administration said in an earlier summary that, as more was learnt about TTS internationally, it was considering modifying its case criteria to include, for example, the time to onset of symptoms as part of the criteria for confirming TTS.
“If the criteria are updated, it may result in some cases being reclassified as unlikely to be TTS because they present such a long time after vaccination and/or are likely to be due to other causes,” the TGA said.
The TGA also said in a previous summary that most cases of TTS had occurred in people aged over 50 years because the AstraZeneca-Oxford vaccine had been used almost exclusively in that age group since the recommendation from the Australian Technical Advisory Group on Immunisation (ATAGI) on April 8 that the Pfizer-BioNTech vaccine was preferable for people aged under 50 years.
On June 17, 2021, the ATAGI recommended that the Pfizer-BioNTech vaccine be preferred over the AstraZeneca-Oxford vaccine for people aged 16 to under 60 years old.
Previously it had recommended the Pfizer-BioNTech vaccine in preference to the AstraZeneca-Oxford vaccine for those aged 16 to under 50 years old.
“ATAGI updated their recommendations due to emerging evidence in Australia of a higher risk and severity of TTS with the first AstraZeneca dose in the 50–59 year age group,” the TGA said.
The TGA said that people aged 50–59 years who had already received the first dose of the AstraZeneca-Oxford vaccine should complete their two-dose schedule.
On July 24, the ATAGI changed its message in specific reference to Sydney. It said it reaffirmed its previous advice that, in a large outbreak, the benefits of the AstraZeneca-Oxford vaccine were “greater than the risk of rare side effects for all age groups”.
The advisory group said: “All individuals aged 18 years and above in greater Sydney, including adults under 60 years of age, should strongly consider getting vaccinated with any available vaccine including Covid-19 Vaccine AstraZeneca.
“This is on the basis of the increasing risk of Covid-19 and ongoing constraints of Comirnaty (Pfizer) supplies. In addition, people in areas where outbreaks are occurring can receive the second dose of the AstraZeneca vaccine four to eight weeks after the first dose, rather than the usual 12 weeks, to bring forward optimal protection.”
The TGA said in an earlier report that, in about half of the Tier 1 TTS cases, the patients had clots in the brain (cerebral venous sinus thrombosis) and half had clots in the abdomen (splanchnic vein thrombosis).
“Of those with clots in the brain, around half also had another clot in the leg (deep vein thrombosis) or the lungs (pulmonary embolism),” the TGA added. “The Tier 2 and unclassified TTS cases had only the more common clots like deep vein thrombosis or pulmonary embolism.”
On July 1, the TGA said it had been advised by the MHRA of the death of a woman in the UK five weeks after she received her first dose of the AstraZeneca-Oxford vaccine in Australia. The UK authorities ordered a postmortem.
“At that time, we advised that she had another serious underlying health condition,” the TGA said in an earlier summary. “Information received subsequently indicates that she did not in fact have an underlying condition.”
The TGA says it is investigating reports of suspected ITP after administration of the AstraZeneca-Oxford vaccine. “We will communicate the outcomes of this investigation, including any regulatory actions, when it is complete,” the TGA said.
ITP, in which a person’s immune system mistakenly destroys platelets, which help blood to clot, can occur after the immune system is activated, for example by a viral infection or vaccination, and has been reported after vaccination for hepatitis B, measles, mumps, rubella, and influenza.
The TGA said that, as of September 19, it had received 77 reports of suspected ITP after administration of the AstraZeneca-Oxford vaccine. “These patients had an extremely low platelet count, and signs of thrombocytopenia which may include unusual bruising, a nosebleed, and/or blood blisters in the mouth,” the TGA said.
The TGA earlier reported on the case of a 78-year-old man who died from multi-organ failure after receiving the AstraZeneca-Oxford vaccine. He had signs of capillary leakage.
“Although there was a temporal link with the vaccine, an expert Vaccine Safety Investigation Group was unable to establish a causal link as other causes could not be ruled out,” the TGA said. “The TGA is in discussions with the sponsor about including information on capillary leak syndrome in the product information as a precautionary measure.”
The VSIG has also investigated the case of a 55-year-old-man who died eight days after receiving the AstraZeneca-Oxford vaccine.
The patient had pulmonary embolism (blood clots in his lungs) and evidence from a platelet functional assay suggesting that there were antibodies that activate platelets in the blood (anti-PF4 antibodies).
However, the TGA said, the patient did not have thrombocytopenia so did not meet the diagnostic criteria for TTS currently being used by the TGA and globally.
The TGA said the expert group could not conclusively determine if the patient’s death was related to the vaccine, in particular because of the absence of thrombocytopenia.
“However, it advised that the current criteria for the diagnosis of TTS are likely to evolve as we find out more about this rare condition,” the TGA said. “If the case definition for TTS changes, this case will be re-evaluated at a later date.”
In its latest summary, the TGA does not give a total for the number of reports it has received of suspected myocarditis and/or pericarditis after administration of the Pfizer-BioNTech vaccine. In its previous report, it said the total, as of September 12, was 457. This was 87 more cases than reported as of September 5.
Table courtesy of @real_GGoswami on Twitter.
The TGA stated that, as of September 19, it had received eight reports of suspected myocarditis in adolescents aged 15 to 17 years – seven boys and one girl. Four of the cases occurred after the second dose.
“None of these cases had sufficient clinical evidence to be classified as highly likely to be myocarditis (level 1),” the TGA said.
“We continue to review cases against an internationally accepted case definition for myocarditis to classify how certain it is that these cases reflect myocarditis. More detailed information on our analysis will be published in next week’s report,” the administration said.
The administration noted that, as of September 19, about 13.5 million doses of the Pfizer-BioNTech vaccine had been administered in Australia.
In an earlier summary, the TGA had said that 12 of the reported cases of suspected myocarditis and/or pericarditis were in children – ten boys and two girls aged 15–17 years. Five cases occurred after the first dose and seven after the second dose, the TGA had reported.
“These are rare effects on the heart that typically occur within ten days of vaccination with the mRNA vaccines Comirnaty (Pfizer) and Spikevax (Moderna),” the TGA said in the summary it released on September 16.
“They occur more commonly after the second dose and more often in younger men. Cases are usually transient and resolve following treatment and rest.”
The TGA said it was actively monitoring the safety signal, “particularly now the Comirnaty (Pfizer) vaccine is being rolled out in younger age groups”.
The administration said that cases considered to be highly likely to be myocarditis, based on strong clinical evidence, were classified as level 1.
In the cases categorised as level 2 or 3, less information was available (perhaps only symptom information and limited test results and/or the treating doctor’s viewpoint), the TGA added.
Of the 457 cases of suspected myocarditis and/or pericarditis reported as of September 12, 128 were suspected cases of myocarditis. Ninety were classified as likely to be myocarditis (3 were level 1, 35 were level 2, and 52 were level 3). The patients were aged between 16 and 60 years and most of them experienced symptoms within three to four days after vaccination. More than half of the patients required hospital treatment and five required intensive care.
The TGA said cases were reported more frequently in teenage boys after the second dose. “It is important to note that the number of younger people vaccinated is still relatively low in Australia so this analysis is based on limited data,” the administration added.
Eleven of the 128 suspected cases were deemed unlikely to be myocarditis and 27 could not be classified because there was insufficient information, the TGA said.
The administration said in its latest summary that, as of September 19, it had received 118 reports of Guillain-Barré syndrome occurring after administration of the AstraZeneca-Oxford vaccine.
“These cases will be considered as part of our ongoing monitoring of this safety signal,” the TGA said. “It is expected that some suspected cases may not be related to vaccination, as GBS can also be caused by other common causes of GBS such as viral infections and some types of gastroenteritis.”
The TGA added: “We encourage people to seek medical attention if they experience symptoms that could suggest GBS as early medical care can reduce severity and improve outcomes. Symptoms to look out for include weakness and paralysis in the hands or feet that can progress to the chest and face over a few days or weeks.”
The administration said that, “following rigorous investigations by the TGA and other international drug regulators”, a clear link between GBS and the AstraZeneca-Oxford vaccine had not been established.
Table courtesy of @real_GGoswami on Twitter.
The TGA said in a previous report that, as of August 22, it had received 481 reports of a menstrual disorder or unexpected vaginal bleeding after Covid vaccination.
A total 322 of the reports followed administration of the Pfizer-BioNTech vaccine, 157 followed administration of the AstraZeneca-Oxford vaccine and, in the case of two of the reports, the vaccine brand was not specified.
“The most commonly reported symptoms were heavy periods, irregular bleeding, bleeding between periods and painful periods,” the TGA said. “Vaginal bleeding in postmenopausal women has also been reported.”
The TGA said in an earlier summary that it had received more reports of enlarged lymph nodes after administration of the Pfizer-BioNTech vaccine than after administration of the AstraZeneca-Oxford vaccine – approximately 17 reports per 100,000 doses after the former compared with six reports per 100,000 doses after the latter.
“An investigation by our scientific and clinical staff at the TGA found that the majority of these reports were in younger people most likely reflecting the higher use of Comirnaty (Pfizer) in younger age groups,” the TGA said.
The TGA says that swollen lymph nodes usually develop within a few days after Covid vaccination and resolve without treatment after a week or so.
“Changes in lymph nodes can also be a sign of other medical issues and there is concern that false readings on mammograms following vaccination could lead to additional unnecessary testing,” the TGA added.
“After considering the risks of postponing breast screening, the Royal Australian and New Zealand College of Radiologists recommends that breast screening should not be delayed following Covid-19 vaccination, particularly for women at higher risk of breast cancer and those living in rural and remote regions, where access to screening may be limited.”
A warning about lymphadenopathy is included in the product information for the Pfizer-BioNTech and AstraZeneca-Oxford vaccines.
The TGA also noted in a previous summary that a warning about anxiety-related reactions following vaccination had been added to the product information for the AstraZeneca-Oxford vaccine.
“Reactions such as fainting or feeling faint, hyperventilation or stress-related events may occur in response to the needle injection or with the process of vaccination itself,” the TGA said.
“Stress-related reactions are not unique to Covid-19 vaccination and can occur with any procedure involving a needle. It is important that precautions are in place to avoid injury from fainting.”
The TGA noted in its latest summary that a warning about fainting following vaccination has been added to the product information for the Pfizer-BioNTech vaccine, stating that syncope may occur “in association with administration of injectable vaccines” and “procedures should be in place to avoid injury from fainting”.
The TGA added: “Examination of the medical literature found that stress-related reactions to immunisation can be more common in younger people. Published evidence also suggests that giving immunisations in a mass vaccination centre can be a contributing factor, particularly when there is a cluster of anxiety-related reactions reported.”
In its summary published on June 10, the TGA focused on reports of herpes zoster reactivation (shingles) following Covid-19 vaccination.
The administration said that, as of June 6, it had received 99 reports of herpes zoster after administration of the AstraZeneca-Oxford vaccine and 43 reports after administration of the Pfizer-BioNTech vaccine. “For both vaccines, the majority of these reports were in the 45–64 year age group and 70% were reported in women,” the TGA said.
The administration added: “A preliminary review by the TGA indicates that the number of reports of shingles in vaccinated individuals is actually lower than the expected background rate of herpes zoster in Australia overall. Therefore, there does not seem to be a safety signal suggesting that shingles is a result of vaccination.”
There are adverse event reports relating to Covid vaccination in the TGA’s public Database of Adverse Event Notifications (DAEN).
The TGA said in a previous summary report that, “due to strong public interest in side effects relating to Covid-19 vaccinations”, and improvements in the TGA’s IT systems, the administration was now publishing reports of suspected adverse effects to vaccines and medicines more rapidly.
De-identified reports are now being published 18 days after they are accepted into the TGA’s internal database.
More than 30,000 additional adverse event reports recently became visible on the DAEN.
On August 31, however, the TGA announced that the DAEN–medicines section of the database had become unavailable “due to performance issues resulting from a high number of requests”.
The TGA stated on September 16: “Intense public interest in the DAEN has caused intermittent problems with access and the search function. We have now upgraded the DAEN and full functionality is currently being restored.
“We apologise for any inconvenience and would like to reassure the public that these issues have not affected our ability to receive and analyse adverse event reports.”
The unavailability notice is no longer on the DAEN website, but data searches can still be slow.
The TGA reiterates that publication of an adverse event report does not necessarily mean that the event is related to the vaccine in question.
The following data is up to September 9.
A total 33,136 reports are listed of adverse reactions following administration of the AstraZeneca-Oxford vaccine (32,675 reported to relate to “a single suspected medicine”). The reports include 310 deaths.
In most cases, the reports cite multiple symptoms.
A total 23,304 reports are listed of adverse reactions following administration of the Pfizer-BioNTech vaccine (22,907 reported to relate to “a single suspected medicine”). The reports include 196 deaths.
Again, in most cases, the reports cite multiple symptoms.
There was previously one report (pictured below) on the DAEN of adverse reactions following administration of the Moderna vaccine (Spikevax), which was granted provisional approval by the TGA on August 9, but the vaccine is not currently listed.
There are 317 reports on the DAEN of adverse reactions after Covid vaccination, including 19 deaths, in which the type of Covid-19 vaccine is not specified. A total 307 of the reports are reported to relate to “a single suspected medicine”.
The TGA said in an earlier summary that data from an ongoing survey of Australians who had received a Covid vaccine suggested that adverse effects were more common after the second dose of the Pfizer-BioNTech vaccine than after the first dose. A total 37% of respondents said they had a reaction to the first dose compared to 60% who reported a reaction after the second dose.
The TGA said a similar pattern could be observed in its database, with more reports of adverse effects after the second dose (4.2 per 1,000 doses) as compared to after the first dose (3.1 per 1,000 doses).
The administration states that “the protective benefits of vaccination against Covid-19 far outweigh the potential risks of vaccination”.
The Sydney Local Health District has admitted, and apologised for, the mistaken vaccination of a group of students at St Joseph’s College in Hunters Hill.
A smaller group of Aboriginal students were due to receive the Pfizer-BioNTech vaccine, but “through an error, the wider group of boarders in Year 12, a total of 163 students, were also vaccinated”, the chief executive of the health district, Teresa Anderson, said on July 6.
“All Aboriginal people aged 16 to 49 years of age are eligible for Covid-19 vaccination, according to the Commonwealth government eligibility criteria as they have a higher risk of acquiring, and developing severe disease from, Covid-19,” Anderson said.
“It was agreed that the Aboriginal students would be vaccinated through the state health system at Royal Prince Alfred Hospital’s vaccination hub.”
There was shock at the response of the New South Wales health minister, Brad Hazzard, when a reporter asked him about the error.
Hazzard snapped at the journalist and said: “You know what; the school intended it well. There was a mistake and so what? It’s happened. Out of a million vaccinations. Move on!”
A petition was launched on change.org calling on the prime minister, Scott Morrison, to sack Hazzard immediately “and apologise in writing to all students at St Joseph’s College who wrongfully received the Pfizer Covid vaccine”.
Other adverse reactions
Reuters reported on January 2 that the Mexican authorities said they were studying the case of a 32-year-old doctor who was hospitalised after she received the Pfizer-BioNTech vaccine.
The doctor was admitted to the intensive care unit of a hospital in the northern state of Nuevo Leon after she experienced seizures, difficulty breathing, and a skin rash, Reuters reported.
The health ministry said the initial diagnosis was encephalomyelitis, which is an inflammation of the brain and spinal cord.
In its report on February 5, the Russian state-owned news agency Sputnik gave the doctor’s name: Karla Cecilia Perez. The agency said that previously Perez had experienced allergic reactions to the antibiotics trimethoprim and sulfamethoxazole.
Sputnik News quoted Perez’s brother-in-law Carlos Palestino as saying the family was not insisting that her paralysis was caused by the vaccine. “However, it is necessary to clarify whether it is connected to the inoculation with the vaccine. We are not arguing that it was the reason. There should be a research to confirm it,” Perez was quoted as saying.
Palestino stressed that the doctor’s relatives had decided to draw the attention of the media to what happened to Perez not to discourage people from vaccination but to make sure that Perez would be cared for adequately and that her case would be studied to prevent further incidents.
Covid vaccination at the Advocate Condell Medical Centre in Libertyville, Illinois, was paused after several healthcare workers reported adverse reactions.
Advocate Aurora Health said that four team members at the centre experienced reactions, including tingling and an elevated heart rate, shortly after vaccination. Three of them are now at home and doing well, and one is receiving additional treatment, Advocate Aurora Health said.
“Out of an abundance of caution, we are temporarily pausing vaccinations at Condell, which will allow us time to better understand what may have caused these reactions,” Advocate Aurora Health added. “We have eight other vaccination locations in Illinois and three in Wisconsin and are continuing at those sites as planned with no disruption.”
A nurse at a hospital in Chattanooga, Tennessee, in the US fainted during a press briefing shortly after receiving the vaccine. Tiffany Dover had been talking about her team being among the first to receive the Covid vaccination. She later said she had an underlying health condition that causes her to faint when she experiences pain.
In a strange sequel, there were reports on social media and some websites that Tiffany Dover had died, but the CHI Memorial Hospital dismissed the rumour and posted a video on Facebook showing Dover with other members of staff.
In one case reported under the Yellow Card system in the UK, the person suffered a very severe epileptic seizure following the first dose of the Pfizer-BioNTech vaccine. She had been seizure free (on medication) for more than 15 years. The person tweeted that it took her nearly a week to recover. After a discussion with her doctor, she decided not to have the second dose.
There are defects in the VAERS and other reporting systems and these flaws are highlighted at length by those who consider that the reporting systems are of no use and rush to point out that anyone can report an adverse effect without evidence that there is a link with vaccination. Those labelled as “anti-vaxxers” are accused of hyping the adverse-event statistics, making fake reports, and fostering vaccine hesitancy.
While correlation does not equal causation, and reports on VAERS and similar databases needs to be treated with caution, the statistics can be an important warning signal about the risks associated with a particular drug or vaccine, particularly when numerous reports accumulate.
Knowingly filing a false VAERS report is a violation of US federal law, punishable by fine and imprisonment.
The CDC warns: “When evaluating data from VAERS, it is important to note that for any reported event, no cause-and-effect relationship has been established. VAERS receives reports on all potential associations between vaccines and adverse events.
“Therefore, VAERS collects data on any adverse event following vaccination, be it coincidental or truly caused by a vaccine. The report of an adverse event to VAERS is not documentation that vaccine caused the event.”
In the caveats noted on the VAERS website, it is stated: “The strengths of VAERS are that it is national in scope and can quickly provide an early warning of a safety problem with a vaccine.”
It is added, however: “While very important in monitoring vaccine safety, VAERS reports alone cannot be used to determine if a vaccine caused or contributed to an adverse event or illness. The reports may contain information that is incomplete, inaccurate, coincidental, or unverifiable.
“Most reports to VAERS are voluntary, which means they are subject to biases. This creates specific limitations on how the data can be used scientifically. Data from VAERS reports should always be interpreted with these limitations in mind.”
There is serious underreporting of adverse reactions to Covid vaccination.
While correlation does not equal causation, and reports on VAERS and similar databases needs to be treated with caution, the statistics can be an important warning signal about the risks associated with a particular drug or vaccine, particularly when numerous reports accumulate.
Knowingly filing a false VAERS report is a violation of US federal law, punishable by fine and imprisonment.
The CDC warns: “When evaluating data from VAERS, it is important to note that for any reported event, no cause-and-effect relationship has been established. VAERS receives reports on all potential associations between vaccines and adverse events.
“Therefore, VAERS collects data on any adverse event following vaccination, be it coincidental or truly caused by a vaccine. The report of an adverse event to VAERS is not documentation that vaccine caused the event.”
In the caveats noted on the VAERS website, it is stated: “The strengths of VAERS are that it is national in scope and can quickly provide an early warning of a safety problem with a vaccine.”
It is added, however: “While very important in monitoring vaccine safety, VAERS reports alone cannot be used to determine if a vaccine caused or contributed to an adverse event or illness. The reports may contain information that is incomplete, inaccurate, coincidental, or unverifiable.
“Most reports to VAERS are voluntary, which means they are subject to biases. This creates specific limitations on how the data can be used scientifically. Data from VAERS reports should always be interpreted with these limitations in mind.”
There is serious underreporting of adverse reactions to Covid vaccination.
The UK drugs regulator issued a tender request for the urgent development of an artificial intelligence software tool that can process “the expected high volume” of Covid-19 vaccine Adverse Drug Reactions (ADRs).
The MHRA said in its tender request that it was not possible to retrofit its legacy systems “to handle the volume of ADRs that will be generated by a Covid-19 vaccine”.
The UK government has granted Pfizer legal indemnity protecting the company from being sued by patients in the event of complications following vaccination with BNT162b2.
The new regulation prohibits civil liability against Pfizer or healthcare professionals distributing the vaccine for any damage that arises through use of the vaccine in accordance with specified recommendations.
It will be possible for people to claim a Vaccine Damage Payment. “If you’re severely disabled as a result of a vaccination against certain diseases, you could get a one-off tax-free payment of £120,000,” the UK government states on its website. However, this payment could affect the claimant’s entitlement to such benefits as income support, housing benefit, child tax and pension credits, and the employment and support allowance.
There has been concern in Germany about the lack of data about the efficacy of the AstraZeneca-Oxford vaccine in the older population and the authorities at one stage issued a draft recommendation that it should not be used for those aged 65 years and above.
In the trial of the AstraZeneca-Oxford vaccine, only 341 people aged over 65 received the vaccine, and 319 were given a placebo, the committee said.
However, on March 3, the German Chancellor, Angela Merkel, said the country’s authorities were changing their stance and would allow the vaccine to be administered to those aged 65 and above. Merkel said recent studies had now provided enough data for the vaccine to be approved for all ages.
Merkel also said the German authorities would extend the interval between vaccine doses to offer as many people as possible an initial shot.
Deutsche Welle reported on February 8 that 14 residents at a German nursing home tested positive for SARS-CoV-2 after receiving two doses of the Pfizer-BioNTech vaccine, with their last dose administered on January 25.
Officials in the district of Osnabruck said there was an outbreak of the UK variant of the virus at a nursing home in Belm, DW reported.
A local government spokesperson said the 14 residents tested positive at the end of the previous week. None of them showed serious Covid symptoms, officials said.
In August last year, five scientists from the WHO’s Solidarity Vaccines Trial Expert Group expressed their worries about Covid vaccine fast tracking.
The scientists said in a commentary published in The Lancet that deployment of a “weakly effective” vaccine could actually worsen the Covid-19 pandemic.
“There is a danger that political and economic pressures for rapid introduction of a Covid-19 vaccine could lead to widespread deployment of a vaccine that is in reality only weakly effective (e.g. reducing Covid-19 incidence by only 10–20%), perhaps because of a misleadingly promising result from an underpowered trial,” the scientists said.
“Deployment of a weakly effective vaccine could actually worsen the Covid-19 pandemic if authorities wrongly assume it causes a substantial reduction in risk, or if vaccinated individuals wrongly believe they are immune, hence reducing implementation of, or compliance with, other Covid-19 control measures.”
The five researchers said regulators should follow the WHO recommendation that “successful vaccines” should show an estimated risk reduction of at least one-half, with sufficient precision to conclude that the true vaccine efficacy is greater than 30%.
Reports from France
France’s National Agency for the Safety of Medicine and Health Products (the ANSM) says in its latest status report, which was published on August 27 and covers the period up to August 19, that, since Covid vaccination began in the country on December 26, 2020, there have been 78,639 reports of adverse reactions, 25% of which it considers to be serious.
The agency doesn’t provide a total figure for the number of reported deaths after Covid vaccination, but a tally of figures given in previous individual reports indicates that there have been at least 983.
The ANSM said there had been 761 deaths reported after administration of the Pfizer-BioNTech vaccine, 171 following administration of the AstraZeneca-Oxford vaccine, and 44 after administration of the Moderna vaccine.
The agency had earlier said that 87 of the deaths that occurred after administration of the AstraZeneca-Oxford vaccine occurred in the week following vaccination (41 within 48 hours).
Seven deaths have been reported after administration of the Janssen Biotech vaccine, which was first used in France on April 24 (for people aged over 55 years).
According to Worldometers.info, a total 114,083 people were reported to have died from Covid-19 in France as of August 28.
In its latest report, the ANSM said that more than 83,586,000 vaccine doses had been administered as of August 19. Of these, more than 66,445,000 were doses of the Pfizer-BioNTech vaccine, more than 7,766,000 were doses of the AstraZeneca-Oxford vaccine, more than 8,389,000 were Moderna doses, and more than 984,000 were Janssen Biotech doses.
A total 8,279 new adverse reaction reports were registered from July 30–August 19, the ANSM said, and 29% of these cases were considered to be serious. More than 10,833,000 vaccine doses had been administered during that period, the agency added.
The ANSM said 44,587 adverse reactions had been reported after vaccination with the Pfizer-BioNTech vaccine as of August 19, 28% of which were considered serious. A total 5,825 of the cases were reported from July 30–August 19 and 31% of these were considered serious.
The agency refers in its latest summary to the case in Denmark of an adolescent who developed paediatric inflammatory multisystem syndrome (PIMS) after being vaccinated with the Pfizer-BioNTech vaccine. The ANSM said the patient had recovered.
It said that, at this stage, no link with the vaccine and the syndrome had been established. “An analysis by the EMA of cases in Europe will take place shortly,” the ANSM said, adding that no PIMS cases had been reported in France.
The ANSM said that, as of August 19, it had received 24,384 adverse reaction reports relating to vaccination with the AstraZeneca-Oxford vaccine, of which 23% were considered serious. Most of the symptoms were flu-like, but were often intense (e.g. high fever, muscle pain, and headaches), the ANSM said. A total 912 of the cases were reported from July 30–August 19 and 25% of these were considered serious.
Since March 19, the AstraZeneca-Oxford vaccine has only been administered to people aged 55 years and above.
As of August 19, 9,167 adverse reactions had been reported after administration of the Moderna vaccine, 18% of which were considered serious, the ANSM said. A total 1,398 cases were reported from July 30–August 19 and 20% of these were considered serious.
The agency said it had received 501 reports of adverse reactions after administration of the Janssen Biotech vaccine, 38% of which were considered serious. A total 144 of the cases were reported from July 30–August 19 and 46% of these were considered serious.
In its latest summary, the ANSM said it had received 15 reports of Covid vaccine failure after administration of the Janssen vaccine and in one case the person died from Covid-19. The agency said the cases were the subject of further investigation.
The vaccine failures occurred in people whose median age was 75 years and the onset was a median of 71 days after administration of the one-dose vaccine, the ANSM said. In all of the cases, the agency said, the patients had comorbidities that carried a risk of developing severe Covid-19.
The ANSM also said that it had received two reports of atypical thrombosis after administration of the Janssen vaccine. In both cases, the patients were men in their fifties who suffered multiple thromboses with thrombocytopenia along with disseminated intravascular coagulation (DIC). In one case the patient had positive anti-PF4 antibodies.
In one of the cases, the patient was recovering well, the agency said, adding that the cases were the first two of their kind reported in France after administration of the Janssen vaccine.
The ANSM also said it had received two reports of idiopathic thrombocytopenic purpura. The agency said that in one of the cases it was unlikely that the vaccine was the cause as the patient had a history of the condition and a viral nasopharyngeal infection the previous week. The second case was being investigated, the ANSM said.
The agency said that, since June 15, when vaccination of 12- to 17-year-olds with the Pfizer-BioNTech vaccine began, more than five million young people in that age group had received at least one dose.
The ANSM said in an earlier summary that, as of July 29, it had received 86 reports of serious adverse reactions in 12- to 17-year-olds after administration of the vaccine, including 20 reports from July 23–29.
This data indicated that the overall rate of adverse reactions was similar among 12- to 17-year-olds to the rate among adults, the agency said.
The ANSM said that, as of July 30, it had received 11 reports of myocarditis in young people (two female and nine male) after administration of the Pfizer-BioNTech vaccine. Three of the cases were in individuals aged under 18 years.
Of the 11 cases, six occurred after the first vaccine dose and four after the second dose. In one case, this information was not available. Onset was between one and 14 days after vaccination (mostly between one and four days). In eight of the cases, the patient had recovered or was recovered at the time of reporting.
The ANSM also said in a previous summary that 64 cases of myocarditis and 111 cases of pericarditis after vaccination with the Pfizer-BioNTech vaccine had been reported since the start of the vaccination campaign. In most of the cases, the patients had recovered or were recovering, the ANSM said.
The agency also said previously that a preliminary analysis indicated that more cases of myocarditis were reported after administration of the Pfizer-BioNTech vaccine than would be expected in the general population aged under 50 years.
“The monitoring committee accepts the hypothesis that the Comirnaty [Pfizer-BioNTech] vaccine can have a role in cases of myocarditis and we are monitoring the myocarditis safety signal, particularly in the young population,” the agency said.
Myocarditis is a rare adverse reaction, the ANSM says, and the benefits of the vaccine still outweigh the risk.
The ANSM also said in its previous summary that it had received reports of ten cases of myocarditis after administration of the AstraZeneca-Oxford vaccine. The agency said that the time between vaccination and symptom onset was a median of five days. Nine of the cases occurred after the first vaccine dose and one after the second. Five of the patients were men and five were women and the median age was 67.
Thirty-eight cases of pericarditis had been reported after administration of the AstraZeneca-Oxford vaccine, the ANSM said. They included two cases in people aged under 30 years.
Thirty-four of the cases occurred after administration of the first dose and four after the second dose. The time between vaccination and symptom onset overall was a median of seven days. Twenty-seven of the patients were women and 11 were men and the median aged was 59 years.
On July 28, France’s National Health Authority (HAS) recommended administration of the Moderna vaccine to 12- to 17-year-olds. About 177,500 children and adolescents in that age group have received at least one dose, the ANSM says, and the agency said in an earlier summary that it had received 11 reports of adverse reactions.
As of July 30, seven cases of myocarditis had been reported in 18-year-olds (all male), the ANSM said earlier. No cases had been reported in children and adolescents aged under 18, the agency said.
One of the seven cases occurred after the first does of the Moderna vaccine, five occurred after the second dose and, in one case, this information was not available. Symptom onset was between one and 27 days after vaccination (mostly between one and four days). At the time of reporting, six of the patients had recovered or were recovering, the ANSM said.
The ANSM also said earlier that it had received reports of 13 cases of pericarditis after administration of the Moderna vaccine. These included three cases in people aged under thirty years, the agency said.
One case of pericarditis has been reported after administration of the Janssen Biotech vaccine. Its onset was five days after vaccination and the patient recovered well, the ANSM said.
In its previous summary the ANSM reported on a case of anaphylactic shock that led to the death of a person in their twenties ten hours after vaccination with the Pfizer-BioNTech vaccine. The agency said that no adverse effect had been observed immediately after vaccination.
The ANSM said that, at this time, and given that the person died ten hours after vaccination and was “very probably” exposed after vaccination to an allergen, and given that the person had a history of food allergies, it could not be concluded that the death was caused by the vaccine.
The agency said it had received 28 reports of severe anaphylactic reactions after administration of the Pfizer-BioNTech vaccine.
The ANSM has also reported on the death of a patient in their seventies who suffered anaphylactic shock ten minutes after receiving the Janssen Biotech vaccine. The patient, who had no history of allergies, died six days later after being taken into intensive care.
The agency said that the current information about the other deaths that occurred after administration of the Janssen Biotech vaccine did not lead to the conclusion that they were caused by the vaccine.
In its previous summary, the ANSM reported on one new case of “atypical thrombosis” after administration of the AstraZeneca-Oxford vaccine, bringing the total since the beginning of the vaccination campaign to 59. Thirteen of the patients died, the agency reported.
The new report concerned a case of multiple thromboses with thrombocytopenia in a man in his sixties.
The ANSM said it had received 48 cases of cerebral venous thrombosis and/or splanchnic vein thrombosis, one case of disseminated intravascular coagulation (DIC) alone, one case of DIC associated with deep venous thrombosis, two cases of DIC with a pulmonary embolism, four cases of thrombosis with thrombocytopenia, one case of thrombosis in multiple locations, one case of multiple thromboses with thrombocytopenia, and one case of venous thrombosis and pulmonary embolism “associated with positive anti-PF4 antibodies”.
The ANSM said earlier that it had received 18 reports of ischemic colitis after administration of the AstraZeneca-Oxford vaccine, mostly among women (16 of the patients were women and two were male). The patients’ median age was 63 and the median time between the onset of symptoms and vaccination was ten days.
The ANSM said in an earlier summary that there was a new potential safety signal after 229 cases of menstrual disorders had been reported as of July 27 after administration of the Pfizer-BioNTech vaccine.
The agency said in its summary published on August 6 that it had received 261 such reports, thirty of which related to serious adverse reactions. The median age of the women was 36.5 years (18 to 76 years).
The ANSM also said it had received 49 reports of menstrual disorders after administration of the Moderna vaccine. In six of the cases, the adverse reactions were considered to be serious. The median age of the women was 38 years. Most of the menstrual disorders occurred after the first dose (31 cases), the ANSM said. Eleven cases occurred after the second dose and six occurred after both doses.
In the case of both vaccines, the ANSM said that, in most of the cases, there was improvement in the women’s condition within a few days. “We cannot at this stage conclude that there is a link between vaccination and these menstrual disorders,” the ANSM said. “There could be multiple causes for these disorders.”
Reporting about the administration of the Pfizer-BioNTech and Moderna vaccines, the ANSM said the types of menstrual disorders reported were diverse and included delayed menstruation, intermenstrual bleeding, and heavy bleeding.
In the case of the Pfizer-BioNTech vaccine, most of the problems occurred after the first vaccine dose (177 cases). Fifty-eight cases occurred after the second dose and, in 11 cases, there were problems after both doses.
“These effects, mostly non-serious, but unexpected and occurring also in women after menopause, constitute a potential safety signal,” the ANSM had said earlier.
The agency said the monitoring committee considered there to be a potential safety signal for both the Moderna and Pfizer-BioNTech vaccines and that the ANSM would report that signal to the EMA.
The agency also said in an earlier summary that, as of July 1, it had received 52 reports of liver disorders after administration of the Pfizer-BioNTech and Moderna vaccines. Thirty-five of the cases occurred after the first vaccine dose and 15 after the second dose. In two cases, this information was not available to the agency.
Two of the patients died (one was in their nineties and one was in their seventies), and 11 were reported at that time to still be unwell.
Two of the patients (one in their seventies and one in their eighties) developed autoimmune hepatitis and, in the case of three patients, including one of the people who died, there was a resurgence of earlier autoimmune hepatitis. The three patients were in their forties, nineties, and seventies.
The ANSM said it could not be concluded that the vaccine caused the reported cases of liver disorders, which were mainly in elderly people.
The agency also said that, in the case of the fatalities reported after administration of the Pfizer-BioNTech vaccine, the information it had to date did not indicate that the vaccine was potentially to blame.
The ANSM said it had also received 52 reports of liver disorders after administration of the AstraZeneca-Oxford vaccine. In three of the cases the patient had hepatic thrombosis and in three cases the patient had infectious hepatitis. Three patients had autoimmune hepatitis. In one of those cases there appeared to be a resurgence of the disease in a patient in their seventies. In one of the other cases, the patient died.
In the 43 other cases (27 women and 16 men) onset was in a median of 9.5 days and the median age was 62. Twenty-three of the cases were serious, the ANSM said. In 22 cases, the patients’ condition was improving, the agency added.
The ANSM has also received one report of a case of hepatitis after administration of the Janssen Biotech vaccine. The patient was a woman in her sixties.
In an earlier summary, the ANSM said that 22 severe cases of rheumatoid arthritis had been reported among patients with an average age of 56.2 years. Twenty-one of the patients were women. In 15 of the cases, the patients had a history of rheumatoid arthritis. In two of the cases, there was a “positive rechallenge” (a reappearance of symptoms).
The cases indicated a potential safety signal for mRNA vaccines (Pfizer-BioNTech and Moderna) and would be reported at the European level, the agency said.
The agency also said earlier that it had received 12 reports of glomerulonephritis (a group of diseases that injure the part of the kidney that filters blood). In eight of the cases, there was a resurgence of the disease and the patients were aged between 20 and 60 years. Six of these cases occurred after the first vaccine dose and two after the second dose, and the onset interval was between one and thirty days.
In the four other cases, the patients were aged between 50 and 70 years and symptom onset was after the first vaccine dose, between two and 21 days after vaccination.
The ANSM said these cases also indicated a potential safety signal for mRNA vaccines (Pfizer-BioNTech and Moderna).
The agency has also received three reports of severe cases of rheumatoid arthritis and three reports of glomerulonephritis after administration of the Moderna vaccine. These cases would also be reported at the European level, the ANSM said.
The ANSM has also received reports of four cases of Guillain-Barré syndrome after administration of the Janssen vaccine. Two of the patients were woman and two were men, the agency said, and their average age was 61 years. Symptom onset was between eight and twenty days after vaccination. Three patients were recovering well, the ANSM said.
The ANSM also said earlier that it had received 30 reports of deafness or loss of hearing that occurred soon after administration of the AstraZeneca-Oxford vaccine and 22 of the cases were serious. The onset of the adverse reaction was a median of 6.5 days, the ANSM said, and the reactions occurred in 17 women and 13 men with a median age of 67 years.
The agency said the monitoring committee had concluded that these adverse reactions constituted a potential safety signal. Half of the patients had recovered well, the agency added.
In 17 cases (ten women and seven men, with a median age of 69), there was total deafness. In three of these cases (in people in their seventies, and on days 1,11, and 12 after vaccination) there was bilateral deafness. In two of the cases, the problem resolved itself within a few minutes.
Adverse reactions related to pregnancy
On August 6, the ANSM published its 4rd monthly pharmacovigilance report about Covid vaccination during pregnancy, which covers data up to July 22.
Seven foetal deaths in utero had been reported after Covid vaccination, the agency said. The ANSM said it was closely monitoring the situation, but added that, at this time, a link between the foetal deaths and Covid vaccination could not be established. Foetal deaths in utero occurred in one to three pregnancies in 1,000 in the general population, the agency said.
The ANSM said that no safety signals had emerged among pregnant and lactating women for the Covid-19 vaccines available in France. However, the agency added that certain adverse effects, such as thromboembolic effects, foetal deaths in utero, and cases of uterine contractions, needed to be monitored.
The agency said in its report published on August 27 that most of the adverse reactions reported in relation to pregnancy were miscarriages. “In light of the current data, we cannot conclude that these events are linked to the vaccine,” the ANSM said. “There were associated risk factors in several cases and miscarriages are relatively frequent in the general population (occurring in 12 to 20% of pregnancies, according to studies.”
In an earlier summary, the ANSM said that, in 30% of the cases of miscarriage after Covid vaccination, there were risk factors to be taken into consideration.
Most of the adverse reactions reported in relation to pregnancy occurred after administration of the Pfizer-BioNTech vaccine, which is the Covid vaccine most administered to pregnant women in France, the ANSM added.
Since April 3, pregnant women in France have, from the second trimester, had priority access to an mRNA vaccine (either Pfizer-BioNTech or Moderna).
On July 21, France’s advisory committee for vaccine strategy said that women who wished to receive a Covid vaccine in their first trimester should be able to do so.
The ANSM said in an earlier summary that it had received 150 reports of adverse reactions during pregnancy, 96 of which it considered serious.
A total 118 cases followed administration of the Pfizer-BioNTech vaccine. Forty-one of these cases were miscarriages, 22 of which occurred in the two weeks after vaccination, and four were foetal deaths in utero. The ANSM says that, in 14 of the 41 cases, there was a known risk of miscarriage. In 26 cases, the miscarriage occurred after the first vaccine dose and, in the other 15 cases, it occurred after the second dose.
The agency said it had received five reports of pulmonary embolism during pregnancy after administration of the Pfizer-BioNTech vaccine, and one case of venous thrombosis.
It said that in three of the six cases of thromboembolic events there were risk factors other than pregnancy, such as diabetes and obesity. In three of the cases of pulmonary embolism, the timing of symptom onset seemed to be incompatible with the vaccine being the cause (symptom onset the same or next day in two cases and 37 days after vaccination in one case).
The agency said it had also received reports of six cases of tachycardia during pregnancy, three of which it considered to be serious.
The ANSM also said it had received reports of nine cases of painful uterine contractions during pregnancy after administration of the Pfizer-BioNTech vaccine. “In seven of the nine cases, the chronology (onset between 30 minutes and 24 hours after vaccination, and symptom regression within 48 hours) strongly suggest that the vaccine was potentially the cause,” the agency added.
“The link between the onset of uterine contractions and Covid vaccination cannot be established at this stage, but this type of effect must be monitored,” the ANSM said.
Fourteen reports of adverse reactions followed administration of a first dose of the AstraZeneca-Oxford vaccine. They included nine miscarriages and one ectopic pregnancy. These reactions occurred before March 19, when it was recommended that the vaccine only be administered to people aged above 50 years.
On average, the miscarriages occurred 26.5 days after vaccination (from 13 to 43 days). In one case, there was a known risk factor (obesity).
One case of a thromboembolic adverse reaction during pregnancy has also been reported after administration of the AstraZeneca-Oxford vaccine.
Eighteen cases of adverse reactions during pregnancy followed administration of the Moderna vaccine, the ANSM reported. They included four miscarriages and three foetal deaths in utero.
The ANSM said it had received 27 reports related to breastfeeding, 19 of which followed administration of the Pfizer-BioNTech vaccine. Five followed administration of the AstraZeneca-Oxford vaccine and three followed administrations of the Moderna vaccine. Fourteen of the cases were medically confirmed and six were considered to be serious.
Five of the reports related to effects on lactation, 11 to effects experienced by the baby being breastfed, and 11 to effects experienced by the mother.
In its 2nd report about Covid vaccination during pregnancy, which covered data up to June 15, the ANSM said two of the reports of adverse reactions experienced by breastfeeding mothers were considered to be medically significant: a case of paresthesia (burning, prickling, or numbness) in the limbs and a case of vertigo.
In one case of adverse reactions after administration of the Pfizer-BioNTech vaccine, the breastfeeding baby had fever and asthenia (abnormal physical weakness or a lack of energy) the day after his/her mother received the Pfizer‐BioNTech vaccine. The mother had experienced injection-site pain, thirst, and muscle pain.
In another case, the baby had skin rashes 48 hours after his/her mother received the Pfizer‐BioNTech vaccine. The mother had experienced injection-site pain and digestive problems.
In one case, the baby had fever 72 hours after his/her mother received the AstraZeneca-Oxford vaccine. The mother had experienced flu-like symptoms, dyspnea (shortness of breath), pain in the extremities, and paresthesia.
In another case, a woman experienced an increase in lactation after receiving the AstraZeneca-Oxford vaccine. She also reported fever, fatigue, and pain at the injection site.
In two cases after administration of the Moderna vaccine, one woman experienced hyperlactation on the vaccination side of her body (her milk supply doubled) and, in another case, a woman who was vaccinated seven weeks after giving birth found her milk supply progressively diminishing over five days. By day six there was virtually zero lactation.
The ANSM said in the report published on August 6 that 11 children aged between two months and two years experienced adverse reactions after their mother received a Covid vaccination. These reactions ranged from skin rashes to gastrointestinal problems. The ANSM said a link had not been established with Covid vaccination.
According to media reports in France on May 1, the lawyer representing the family of a young medical student from Nantes who died ten days after receiving an AstraZeneca-Oxford vaccination says the postmortem “reinforces the hypothesis of a causality link” between the vaccination and the student’s death.
The student is reported to have died from abdominal thrombosis (in the spleen). The report of the postmortem makes no mention of any infection, virus, cancer, or tumour, the lawyer, Etienne Boittin, is quoted as saying.
Boittin is quoted as saying that the postmortem report does not say that the vaccination is the cause of the student’s death, but it eliminates a certain number of possible causes.
The student is reported to have been vaccinated on March 8 and died on March 18.
Two other cases of deaths in France after an AstraZeneca-Oxford vaccination are under investigation by the Paris public prosecutor.
Boittin is reported to be handling litigation in 15 cases of deaths after AstraZeneca-Oxford vaccination, “mostly of people aged under 60 years”.
Local media in France reported earlier that an investigation had been opened into the death of a man in Arles who had received the AstraZeneca-Oxford vaccine the week before he died on March 11. The man’s wife submitted a complaint to the police and a postmortem is reported to have been carried out.
It was also reported that, on February 11, several hospitals in western France suspended their vaccination campaigns because so many of their staff had to take leave because of adverse reactions after receiving the AstraZeneca vaccine.
At the request of the regional health agency, vaccination resumed at the hospitals the next day, but in a staggered manner.
According to the news website Le Télégramme, between 20 and 25% of the vaccinated hospital staff in Brest had to take time off work because they suffered from high fever and headaches after Covid vaccination and the situation was the same in the hospital at Quimper.
Agence France Presse (AFP) reported that about fifty staff at the Saint-Lô hospital in Normandy were vaccinated on February 10 and, the next day, a proportion of them were ill with fever and nausea.
“It puts us in difficulty when we have whole teams being vaccinated on the same day and 15% of the team has post-vaccination symptoms,” the hospital’s communications officer, Mélanie Cotigny, told AFP.
Vaccinating children and adolescents
On September 14, Pfizer’s chief financial officer, Frank D’Amelio, said the company expected to apply in November for FDA emergency use authorisation for its Covid-19 vaccine for children aged between six months and five years.
On September 20, Pfizer and BioNTech announced results of a phase 2/3 trial of use of their Covid vaccine for children aged five to 11 years. The companies said the vaccine was “safe, well tolerated and showed robust neutralising antibody responses”.
They said they would submit the data to the FDA, the EMA and other regulatory agencies around the world as soon as possible.
In the trial, two doses of 10 µg were administered 21 days apart (30 µg doses are administered to people aged 12 and above).
“The 10 µg dose was carefully selected as the preferred dose for safety, tolerability and immunogenicity in children five to 11 years of age.”
The data provided from the study, which is enrolling children aged between six months and 11 years, related to 2,268 participants aged between five and 11 years.
Side effects from the vaccine were generally comparable to those observed in participants 16 to 25 years of age, the companies said.
Pfizer and BioNTech said that the SARS-CoV-2–neutralising antibody geometric mean titer (GMT) was 1,197.6 (95% confidence interval [CI, 1106.1, 1296.6]), “demonstrating strong immune response in this cohort of children one month after the second dose”.
This, the companies said, compared well (was non-inferior) to the GMT of 1146.5 (95% CI: 1045.5, 1257.2) from participants aged 16 to 25 years old, who were used as the control group for the analysis and who were administered a two-dose, 30 µg regimen.
While there is a 4% difference between the GMTs for the age groups, the fact that the GMT for the younger age group lies within the confidence interval of the GMT of the 16- to 25-year-olds studied means that, statistically, there is a possibility that both groups could have the same GMT.
The phase 1/2/3 trial initially enrolled up to 4,500 children, aged between six months and 11 years, in the US, Finland, Poland, and Spain. It was designed to evaluate the safety, tolerability, and immunogenicity of the Pfizer-BioNTech vaccine in three age groups: five to 11 years; two to five years, and six months to two years. Children aged under five received two 3 µg doses.
Reporting for STAT news, Matthew Herper pointed out that Pfizer and BioNTech provided only an average antibody level. “That could mean that some kids would have lower levels – and less protection,” he wrote.
Herper quoted William Gruber, a senior vice-president of vaccine clinical research and development at Pfizer, as saying that antibody levels were high throughout the group studied.
“Pfizer’s press release did not include any data on the extent to which the vaccine reduced the chances that children would become sick,” Herper added.
“Gruber said that there were not enough cases of illness to tell. But outside experts said it was reasonable to assume that similar levels of antibodies would mean similar protection from disease.”
Outside experts viewed the data as positive, but limited, Herper wrote.
Pfizer and BioNTech said that, for the US, they expect to include the new data in a near-term submission for emergency use authorisation as they continue to accumulate the safety and efficacy data required to file for full FDA approval for use of their vaccine for five- to 11-year-olds.
A request to the EMA to update the EU’s conditional marketing authorisation was also planned, the companies said.
“Topline readouts” for the other two age cohorts from the trial – children aged two to five years and children aged six months to two years – were expected as soon as the fourth quarter of this year, they added.
On July 23, the EMA announced that its human medicines committee had recommended authorisation of use of the Moderna vaccine (Spikevax) for children and adolescents aged 12 to 17 years. The vaccination would be given in two doses, four weeks apart.
The EMA said effects of the vaccine had been investigated in an ongoing study involving 3,732 children and adolescents aged 12 to 17 years.
The agency said the study showed that the vaccine produced a comparable antibody response in 12- to 17-year-olds to that seen in young adults aged 18 to 25 years (as measured by the level of antibodies against SARS-CoV-2).
“In addition, none of 2,163 children receiving the vaccine developed Covid-19 compared with four of 1,073 children given a dummy injection,” the EMA said.
The CHMP said that, given the limited number of children and adolescents included in the study, the trial could not have detected new uncommon side effects or estimated the risk of known side effects such as myocarditis and pericarditis.
“However, the overall safety profile of Spikevax determined in adults was confirmed in the adolescent study,” the EMA said. “The CHMP therefore considered that the benefits of Spikevax in children aged 12 to 17 outweigh the risks, in particular in those with conditions that increase the risk of severe Covid-19.”
The most common adverse effects in 12- to 17-year-olds were similar to those experienced by people aged 18 and above, the EMA said.
“They include pain and swelling at the injection site, tiredness, headache, muscle and joint pain, enlarged lymph nodes, chills, nausea, vomiting, and fever,” the agency added.
These effects were usually mild or moderate and improved within a few days, the EMA said.
On August 17, the MHRA extended its conditional marketing authorisation for the Moderna vaccine to allow its use in Britain for 12- to 17-year-olds.
June Raine said it was now for the JCVI to advise on whether that age group should be vaccinated with the Moderna vaccine.
The Moderna vaccine was already authorised for use for 12- to 17-year-olds in Northern Ireland under the CMA extension granted by the EMA on July 23.
On May 10, the FDA expanded the emergency use authorisation for the Pfizer-BioNTech vaccine to include adolescents aged 12 to 15 years. It was the first authorisation in the US for use of a Covid vaccine for this age group.
The FDA said it had determined that the vaccine had met the statutory criteria to amend the EUA, and that “the known and potential benefits of this vaccine in individuals 12 years of age and older outweigh the known and potential risks, supporting the vaccine’s use in this population”.
The administration said that from March 1, 2020 to April 30, 2021, approximately 1.5 million Covid-19 cases in individuals aged 11 to 17 years had been reported to the CDC.
“Children and adolescents generally have a milder Covid-19 disease course as compared to adults,” the FDA said.
The Pfizer-BioNTech vaccine would be administered to 12- to 15-year-olds as a series of two doses, three weeks apart as in the case of people aged 16 years and above, the FDA said.
The FDA said that immune response to the vaccine in 190 participants aged between 12 and 15 was compared to the immune response of 170 participants aged between 16 and 25 years.
“In this analysis, the immune response of adolescents was non-inferior to (at least as good as) the immune response of the older participants,” the FDA said.
The FDA said it conducted an analysis of cases of Covid-19 occurring seven days after the second vaccine dose among participants aged between 12 and 15 years.
“In this analysis, among participants without evidence of prior infection with SARS-CoV-2, no cases of Covid-19 occurred among 1,005 vaccine recipients and 16 cases of Covid-19 occurred among 978 placebo recipients,” the FDA said.
Pfizer said the FDA based its decision on data from a Phase 3 clinical trial in which 2,260 participants aged 12 to 15 years were enrolled.
Results from the trial were were published in The New England Journal of Medicine on May 27.
A total 2,260 children aged 12 to 15 years of age received two injections, 21 days apart, of 30 μg of BNT162b2 or a placebo (1,131 children received BNT162b2 and 1,129 received a placebo).
Robert W. Frenck, Jr et al. said that BNT162b2 had a “favourable safety and side-effect profile”, with mainly transient mild-to-moderate reactogenicity. The side effects were predominantly injection-site pain (in 79 to 86% of participants), fatigue (in 60 to 66% of participants), and headache (in 55 to 65% of participants). There were no vaccine-related serious adverse events and few overall severe adverse events, the researchers said.
Among the 1,983 trial participants who could be evaluated, and did not have evidence of previous SARS-CoV-2 infection, no cases of Covid-19 with an onset of seven or more days after the second dose were observed among BNT162b2 recipients (1,005 children) and 16 cases were observed among placebo recipients (978 children).
In the group that included all 2,229 participants in the cohort who could be evaluated, regardless of whether they had evidence of previous SARS-CoV-2 infection, no Covid-19 cases were observed among BNT162b2 recipients from seven days after the second vaccine dose and 18 cases were observed among placebo recipients.
After dose 1 and before dose 2, three Covid-19 cases were noted (within 11 days after dose 1) among BNT162b2 recipients, as compared with 12 cases among placebo recipients. No cases of severe Covid-19 were observed in the age cohort studied.
Pfizer had announced on March 25 that the first children in the paediatric trial of the Pfizer-BioNTech Covid vaccine had received their initial vaccine doses. The first doses were given to the cohort aged five to 11 years.
Pfizer said that Phase 1 of the trial was an “open-label, dose-finding study” to identify the preferred dose level(s) of BNT162b2 from up to three different levels (10 µg, 20 µg, and 30 µg) with an option for 3 µg, in three age groups (five to 11 years, two to five years, and six months to two years.
The trial started with 144 participants. “Once tolerability is confirmed with the 10 µg within the five- to 11-year-old group, we will progressively move to the next higher dose in the age group, while also starting the following age group (two- to five-year-olds) at the lowest dose (10 µg),” Pfizer said. “This escalation approach will be followed for all doses and age groups.”
In the US, at Stanford Medicine in California, which includes the Stanford University School of Medicine and Stanford Health Care, researchers have started to vaccinate children aged two to five years.
Pfizer said the Phase 2/3 part of the trial would evaluate the safety, tolerability, and immunogenicity of the selected dose level in each age group. Participants would be randomised in a 2:1 ratio to receive the vaccine or a placebo. The vaccine will be administered in a two-dose schedule, with the doses given about 21 days apart.
Throughout the full trial, about 4,644 children would be enrolled in the US and Europe, Pfizer said.
At the six-month follow-up visit, all participants would be unblinded and those who originally received a placebo would be given the opportunity to receive BNT162b2.
The primary endpoints of the study were to evaluate the safety and immunogenicity of the vaccine, Pfizer said. “Vaccine effectiveness in the study will be inferred through immunobridging to the 16- to 25-year-old population from the pivotal Phase 3 trial,” the company added.
Pfizer said that children younger than six months of age might subsequently be evaluated once an “acceptable safety profile” had been established.
If safety and immunogenicity was confirmed, and pending agreement with and endorsement from regulators, Pfizer and BioNTech said they hoped to receive authorisation for vaccination of younger children by early 2022.
“Pfizer and BioNTech expect to have definitive readouts and, subject to the data generated, submit for an EUA or a variation to Conditional Marketing Authorisations for two cohorts, including children two–five years of age and five–11 years of age, in September,” Pfizer said on May 10. “The readout and submission for the cohort of children 6 months to 2 years of age are expected in the fourth quarter.”
On May 28, the European Commission announced that its CMA for the Pfizer-BioNTech vaccine had been expanded to include children aged 12 to 15. This followed a recommendation by the CHMP to authorise use for the 12–15 age group. The extended authorisation is valid in all 27 EU member states. The vaccine had already been approved for use in adults and adolescents aged 16 years and above.
The EC’s decision was also based on data from the Phase 3 trial involving 2,260 children.
Each EU member state can decide whether or not to administer the vaccine to individuals in the 12-15 age group, the EMA said.
The Pfizer-BioNTech vaccine was the first Covid-19 vaccine to receive authorisation in the EU and is the first to have its CMA extended to adolescents.
In Germany, the Standing Committee on Vaccination (STIKO) has decided that only children and adolescents with certain pre-existing conditions should be given the Pfizer-BioNTech vaccine.
The committee said on May 10 that it was only recommending the vaccine for children and adolescents with a condition that raises their risk of a developing a serious case of Covid-19. It cited obesity, immunosuppression, heart defects, chronic lung disease or kidney failure, and diabetes, and children and adolescents with trisomy 21
The STIKO, which is an independent advisory group, also recommends vaccinating children and adolescents who are in close contact with relatives or other people who are at high risk of severe Covid-19 but cannot be vaccinated themselves.
The committee said it was not currently recommending use of the Pfizer-BioNTech vaccine for 12- to 17-year-olds without pre-existing conditions, but advised that the vaccine could be administered after medical advice and with “individual risk acceptance”.
In the UK the JCVI has recommended Covid-19 vaccination for some children and adolescents. The committee said on July 19: “From today, the JCVI is advising that children at increased risk of serious Covid-19 disease are offered the Pfizer-BioNTech vaccine.
“That includes children aged 12 to 15 with severe neurodisabilities, Down’s syndrome, immunosuppression, and multiple or severe learning disabilities.”
The Pfizer-BioNTech vaccine is the only vaccine that has been authorised for children in the UK, for those aged 12 years or older.
The JCVI said it was also recommending that children and young people aged 12 to 17 who live with an immunosuppressed person should be offered the vaccine.
“Under existing advice, young people aged 16 to 17 with underlying health conditions which put them at higher risk of serious Covid-19 should have already been offered vaccination,” the JCVI said.
The committee said that, based on the current evidence, it was not currently advising routine vaccination of children outside of these specified groups.
“As evidence shows that Covid-19 rarely causes severe disease in children without underlying health conditions, at this time the JCVI’s view is that the minimal health benefits of offering universal Covid-19 vaccination to children do not outweigh the potential risks,” the committee said.
The committee has since reiterated this viewpoint, stating on September 3 that, while the health benefits from Covid vaccination for healthy children aged 12 to 15 years were “marginally greater than the potential known harms”, the margin of benefit was considered too small to support universal vaccination of healthy 12- to 15-year-olds at this time.
“Given the very low risk of serious Covid-19 disease in otherwise healthy 12- to 15-year-olds, considerations on the potential harms and benefits of vaccination are very finely balanced and a precautionary approach was agreed,” the JCVI said.
Wei Shen Lim said: “Children aged 12 to 15 years with underlying health conditions that put them at higher risk of severe Covid-19 should be offered Covid-19 vaccination. The range of underlying health conditions that apply has recently been expanded.”
Previously, the JCVI advised that children with severe neurodisabilities, Down syndrome, immunosuppression, profound and multiple learning disabilities, and severe learning disabilities, or who were on the learning disability register, should be offered Covid-19 vaccination.
The committee said that, following consideration of updated data on hospital admissions and deaths, it now advised that 12- to 15-year-olds with the following conditions should also be offered the vaccination:
- haematological malignancy;
- sickle cell disease;
- type 1 diabetes;
- congenital heart disease;
- chronic respiratory disease;
- chronic heart conditions;
- chronic conditions of the kidney, liver, or digestive system;
- chronic neurological disease;
- endocrine disorders;
- immunosuppression;
- asplenia (the absence of a spleen) or dysfunction of the spleen, and
- serious genetic abnormalities that affect a number of systems.
“Children with poorly controlled asthma and less common conditions, often due to congenital or metabolic defects where respiratory infections can result in severe illness, should also be offered Covid-19 vaccination,” the JCVI added.
On September 13, the chief medical officers (CMOs) in the UK’s four nations recommended that the Covid vaccination programme be extended to 12- to 15-year-olds. The UK’s Health Secretary, Sajid Javid, said he accepted the CMOs’ recommendation.
The CMOs said that healthy children should be offered a single dose of the Pfizer-BioNTech vaccine and the rollout should begin as soon as possible.
The CMO for England, Chris Whitty, said that vaccination of 12- to 15-year-olds would “reduce education disruption”. It was for ministers to decide whether to accept the CMOs’ recommendation that Covid vaccination be offered to that age group, he added.
He said the CMOs thought it was “an important and potentially useful additional tool to help reduce the public health impacts that come through educational disruption”.
Pfizer and BioNTech are also planning studies to further evaluate their vaccine in people with compromised immune systems.
On July 23, the TGA in Australia announced that it was extending its provisional approval of the Pfizer-BioNTech vaccine to include children and adolescents aged 12 to 15 years.
The ATAGI has recommended that the following groups of children among those aged 12–15 years be prioritised for vaccination:
- children who are immuno-compromised and those with specified medical conditions that increase their risk of severe Covid-19 (including severe asthma, diabetes, obesity, cardiac and circulatory congenital anomalies, neuro developmental disorders, epilepsy, and trisomy 21 (Down syndrome),
- Aboriginal and Torres Strait Islander children, and
- all children aged 12–15 years in remote communities.
The ATAGI said on August 2 that it would make recommendations to the government about the use of the Pfizer-BioNTech vaccine for all other children in the 12–15 years age group in the coming months after a review of emerging information.
It will be assessing the following:
- the safety and effectiveness of Covid-19 vaccines in adolescents vaccinated in overseas vaccination programmes,
- the incidence, risk factors, and outcomes of cases of myocarditis reported overseas after the vaccination of adolescents and young adults,
- the results of mathematical modelling about the overall benefits at population level of vaccinating adolescents, and
- evidence about the optimal timing and schedule of vaccination in adolescents in terms of the number of doses and dose spacing.
The ATAGI said preliminary evidence suggested that children and adolescents had a lower susceptibility to
SARS-CoV-2 compared to adults, and played a lesser role in transmission at a population level.
“Healthy children also have a much lower risk of severe illness from Covid-19 than adults, and typically exhibit a mild course of illness,” the ATAGI said.
“Several publications have reported, however, that children, adolescents and young adults with underlying medical conditions have an increased likelihood of developing severe disease and complications when infected with SARS-CoV-2.”
Only a limited number of studies provided data on these risk associations stratified by selected specific medical conditions, the ATAGI added. Most other published studies reported only by broad disease groups, it said.
A trial in Britain in which the AstraZeneca-Oxford vaccine was being tested on children was halted because of the reports of blood clotting in adults who received the vaccine.
“Parents and children should continue to attend all scheduled visits and can contact the trial sites if they have any questions.”
Children and teenagers aged 6–17 years had been enrolled in the trial, which was set to involve 300 children (up to 150 participants aged 6–11 years and up to 150 aged 12–17 years). Those placed in the control group were being given a meningococcal vaccine, not a saline placebo.
The Oxford researchers argue that, because a saline placebo has no adverse effects, participants who had adverse reactions would know that they had received the AstraZeneca-Oxford vaccine.
“It is critical for this study that participants remain blinded to whether or not they have received the vaccine, as, if they knew, this could affect their health behaviour in the community following vaccination, and may lead to a bias in the results of the study,” the researchers said.
The same vaccine dose was being given as in the trials involving adults. The first doses were given to children aged 12–17 years. Data was to be reviewed before the vaccine was given to younger children.
The researchers said that, because this was the first time the AstraZeneca-Oxford vaccine had been tested on children, only healthy children were being enrolled. “It is likely that, in future studies, children with pre-existing conditions will be enrolled,” they said.
The Oxford researchers say a small number of children have developed serious Covid-19 symptoms and required hospital admission (more than 700 in the first wave in the UK).
“Many of these children had pre-existing medical conditions which made them more susceptible to the effects of a virus which affects the lungs,” the researchers said.
They added that paediatricians have also seen a new inflammatory syndrome emerge, called PIMS-TS, which appears to be associated with Covid-19 disease and often occurs a few weeks after SARS-CoV-2 infection.
The syndrome can make children very unwell and some have suffered multi-organ failure, the researchers say, adding that the number of children affected by the syndrome in the first wave of Covid -19 was fewer than one hundred.
On March 16, Moderna announced that the first participants in a trial to test its vaccine on children had received their initial doses. The company says it expected to enrol 6,750 children aged between six months and 11 years in the “KidCOVE” study in Canada and the US.
The company stated: “In Part 1, each participant ages two years to less than 12 years may receive one of two dose levels (50 μg or 100 μg). Also in Part 1, each participant ages six months to less than 2 years may receive one of three dose levels (25 μg, 50 μg and 100 μg).
“An interim analysis will be conducted to determine which dose will be used in Part 2, the placebo-controlled expansion portion of the study.
“Participants will be followed through 12 months after the second vaccination. Vaccine effectiveness will either be inferred through achieving a correlate of protection, if established, or through immunobridging to the young adult (ages 18-25) population. Evaluation of vaccine safety and reactogenicity is also a primary endpoint of the study.”
Moderna announced on June 10 that it had asked the FDA to grant the company an EUA for use of its Covid-19 vaccine for adolescents.
The company said it had also filed for authorisation with Health Canada and would make similar applications to other regulatory agencies around the world.
On May 25, Moderna issued a statement about its ‘TeenCOVE’ Phase 2/3 study, in which more than 3,700 participants aged 12 to 17 years inclusive were enrolled in the US.
The company said there were no symptomatic cases of Covid-19 among those who received two doses of the vaccine and no significant safety concerns were identified. There were four Covid-19 cases in the placebo group.
Vaccine efficacy of 93% in seronegative participants was observed starting 14 days after the first dose, Moderna said.
“Because the incidence rate of Covid-19 is lower in adolescents, a secondary case definition based on the CDC definition of Covid-19 was also evaluated to include cases presenting with milder symptoms,” the company added.
“Using the CDC definition, which requires only one Covid-19 symptom and a nasopharyngeal swab or saliva sample positive for SARS-CoV-2 by RT-PCR, a vaccine efficacy of 93% after the first dose was observed.”
Moderna said most adverse events were mild or moderate in severity. The most common local adverse event was injection site pain and the most common systemic adverse events after the second vaccine dose were headache, fatigue, myalgia, and chills.
Vaccination certificates
Countries are increasingly introducing regulations that allow those who have received Covid vaccination access to certain places and facilities, such as indoor dining in restaurants, and deny such access to those who have not been vaccinated or cannot show proof of recovery from Covid-19 or a recent negative SARS-CoV-2 test.
There have been demonstrations against such regulations in several European countries, including France, Britain, Switzerland, Italy, and Ireland.
On August 3, the mayor of New York, Bill de Blasio, announced that access to indoor dining, indoor fitness facilities, and indoor entertainment facilities is to be restricted – in the case of workers and customers – to those who have received at least one dose of a Covid vaccine.
De Blasio said the new policy would be phased in over the coming weeks and the final details would be announced and implemented in the week of August 16. Inspection and enforcement would start in the week of September 13. “We’ll be issuing a mayoral executive order and a health commissioner’s order,” De Blasio said.
He said that if people in New York wanted to participate fully in society, they had to get vaccinated.
“ … I want you to imagine the notion that, because someone’s vaccinated, they can do all the amazing things that are available in this city,” De Blasio said.
“This is a miraculous place, literally full of wonders and, if you’re vaccinated, all that’s gonna open up to you. You’ll have the key; you can open the door.
De Blasio argues that the new policy will guarantee a much higher level of vaccination in New York City. “And that is the key to protecting people and the key to our recovery,” he said.
On July 21, police in Athens used tear gas and water cannons to disperse protesters demonstrating against the Greek government’s plans to make Covid vaccination mandatory for staff in nursing homes and other care facilities.
There has been widespread outrage in France over the country’s new ‘pass sanitaire’. There are plans, for example, to limit hospital visiting to those who have received Covid vaccination, have recovered from Covid-19, or have recently tested SARS-CoV-2 negative.
People in France wanting to go to events or places where there are more than fifty people already have to present a ‘pass sanitaire’ (there is an exemption for 12- to 17-year-olds), and the regulation is due to be extended in August to restaurants, cafés, trade shows, long-distance travel on public transportation, and entry to medical establishments, except for emergencies. It may also be required in large shopping centres.
In Montelimar, hospital staff began an indefinite strike in protest against compulsory Covid-19 vaccination.
In Israel, the ‘Corona Cabinet’ decided that, as of August 8, only those who could show proof of Covid vaccination or a negative PCR test would be able to go to the cinema, the theatre, the synagogue, or an amusement park or join in any activity that involves more than 100 people indoors or outdoors.
The prime minister, Naftali Bennett, accused those who are eligible to get vaccinated but had not done so of endangering those around them and the freedom of every Israeli citizen.
He said people who had been vaccinated would be able to fly to “clean” countries and, on their return to Israel, if their PCR test was negative, they would be exempt from quarantine. The non-vaccinated would have to quarantine for a week, no matter which country they were returning from, and they would have to cover the cost of any PCR tests, he said.
Bennett urged people to persuade others to get vaccinated.
He said that there were still more than 600,000 young people aged up to 30 years who had not yet received a Covid vaccination.
In February, Israel introduced a certificate that was used to verify that people had either been vaccinated against, or recovered from, Covid-19 or had proof of a recent negative PCR test. Having a ‘green pass’ became a requirement for entering certain businesses and events, but the system expired on June 1. It has now been reinstated. It is required in the following indoor venues where there is an occupancy of more than 100 people:
- event venues,
- clubs, and
- gathering halls where food is served as well as in certain other places such as restaurants or hotels where a celebration is held with more than 100 people in attendance.
An event that is held partly outdoors and partly indoors is subject to the same regulations as a purely indoor event.
The health ministry announced on August 29 that, as of October 1, the ‘green pass’ would expire six months after the holder received their second or third Covid vaccine dose.
The ministry also announced that, as of September 3, there would be an exemption from a week-long quarantine for people who had received a third Covid vaccine dose a week earlier if they were returning to Israel from countries considered to have a low or moderate risk of Covid infection.
The exemption also applied to those who had received a second vaccine dose within the previous six months, the ministry said.
IBM has developed a Digital Health Pass, using blockchain technology, that stores details about people’s vaccination status and the results of PCR tests.
The pass is designed “to enable organisations to verify health credentials for employees, customers and visitors entering their site based on criteria specified by the organisation”, IBM says.
The World Economic Forum and the Swiss nonprofit public trust the Commons Project have been testing CommonPass, a platform for documenting people’s Covid-19 status, including information about PCR tests and Covid vaccination.
Denmark’s government has said that it plans to introduce a digital passport that will indicate citizens’ Covid vaccination status.
In Spain the Tourism Minister, Reyes Maroto, announced that the government was working to introduce a Covid vaccination certificate.
On January 21, Iceland became the first country in the Schengen area to issue Covid-19 vaccination certificates, which are given to citizens who have received the full number of vaccine doses.
The country has also launched an electronic system that enables people to obtain a vaccination certificate online.
“The aim is to facilitate the movement of people between countries so that individuals can present a vaccine certificate at the border and are then exempt from Covid-19 disease control measures in accordance with the rules of the country concerned,” the Ministry of Health said.
Iceland says it will recognise all Covid-19 vaccination certificates that will be issued by EEA/EFTA countries.
According to Schengenvisainfo.com travellers who hold a document that proves they have received a Covid vaccination in any of these countries will be exempt from official border control measures when entering Iceland and will therefore not be obliged to go through border screening procedures.
On June 1, the European Commission said the technical gateway for use of the new EU Digital Covid Certificate had gone live, one month ahead of deadline, and seven member states had already started to issue the certificates.
The EC said the system should facilitate free movement inside the EU. “It will not be a pre-condition to free movement, which is a fundamental right in the EU,” the commission said. “Being vaccinated will not be a pre-condition to travel. All EU citizens have a fundamental right to free movement in the EU and this applies regardless of whether they are vaccinated or not.”
Available in digital format or on paper, the certificate records whether people have been vaccinated against Covid-19, recovered from the disease, or recently tested negative for SARS-CoV-2. The Commission has proposed that the validity period for tests should be 72 hours for PCR tests and, where accepted by a member state, 48 hours for rapid antigen tests.
“The EU certificate was proposed by the Commission to resume safe travelling this summer,” the EC said. “It will be free of charge, secure, and accessible to all.
“The certificate can be used across all EU member states as well as in Iceland, Liechtenstein and Norway. Contacts are also ongoing to enable its use with Switzerland.”
The EC says the gateway provides for the verification of the security features contained in the QR codes of all certificates. “This will allow citizens and authorities to be sure that the certificates are authentic. During this process, no personal data is exchanged or retained.”
Certificates will be issued to any person who received a Covid-19 vaccination in an EU member state, irrespective of the number of doses. “The number of doses will be clearly stated in the EU Digital Covid certificate to indicate whether the vaccination course has been completed,” the EC said.
The EC added: “National authorities are in charge of issuing the certificate. It could, for example, be issued by test centres or health authorities, or directly via an eHealth portal.
“The digital version can be stored on a mobile device. Citizens can also request a paper version. Both will have a QR code that contains essential information, as well as a digital signature to make sure the certificate is authentic.
Member states have agreed on a common design that can be used for the electronic and paper versions to facilitate the recognition.”
The EC says the certificate contains necessary key information such as name, date of birth, date of issuance, relevant information about vaccination, test, or recovery from Covid-19, “and a unique identifier”.
The commission says the data remains on the certificate and is not stored or retained when a certificate is verified in another member state.
“The certificates will only include a limited set of information that is necessary. This cannot be retained by visited countries,” the EC stated. “For verification purposes, only the validity and authenticity of the certificate is checked by verifying who issued and signed it. All health data remains with the member state that issued an EU Digital Covid Certificate.”
On January 27, the Council of Europe’s parliamentary assembly adopted Resolution 2361, which states that Covid vaccination in EU member states is not mandatory, that no one should be pressured to get themselves vaccinated, and that there should be no discrimination against anyone for not being vaccinated.
Excerpt from the text of Resolution 2361 about Covid-19 vaccines adopted by the Council of Europe’s parliamentary assembly.
WHO spokesperson Margaret Harris said on April 6 that the WHO was saying it would not like to see vaccination passports as a requirement for entry or exit “because we are not sure at this stage that the vaccine prevents transmission”.
Harris added that vaccine passports might not be an effective strategy as not everyone had access to vaccines and there were groups in society that were excluded.
The business magnate and self-appointed expert on pandemics Bill Gates (pictured below) wants digital certificates contained in quantum-dot tattoos to be introduced to identify who has been tested for SARS-CoV-2, who has been vaccinated against it, and who has recovered from Covid-19.
Researchers at the Massachusetts Institute of Technology (MIT) have shown that their new dye, which consists of nanocrystals called quantum dots, can remain for at least five years under the skin. The dye emits near-infrared light that can be detected by a specially equipped smartphone.
The dots are only about 4 nanometers in diameter, but they are encapsulated in microparticles that form spheres about 20 microns in diameter. This encapsulation allows the dye to remain in place, under the skin, after it is delivered by a microneedle patch.
Bill Gates
Several airlines, including Etihad Airways, Emirates, Saudia, and Gulf Air have been trialling a digital travel pass developed by the International Air Transport Association (IATA), which shows whether passengers have been vaccinated and/or have tested negative for SARS-CoV-2.
Writing in the Weekend Australian published on February 7, Christine Kellett quoted the Minister for Government Services, Stuart Robert, as saying it is “highly likely” that vaccination certificates will be required for international travel.
The CEO of the Australian airline Qantas, Alan Joyce, said that proof of Covid vaccination would be compulsory for international air travel on board his aircraft.
The CEO of the International Air Transport Association (IATA), Alexandre de Juniac, said at the time of Joyce’s comment that his stance was a “bit premature” and that testing was more critical than vaccines.
There is a petition on change.org against mandatory vaccination for international travel, which has been signed by more than 34,000 people.
The UK-based independent tour operator Tradewinds Travel said it would no longer do business with Qantas. “We are not anti-vaccination, but we are pro-choice,” the company said in a statement. “There is a huge difference between coercion and making a free choice.”
The British cruise firm Saga said it would not accept any guest who had not received a Covid vaccination.
“We have taken the decision to introduce the requirement that all guests must be fully vaccinated,” Saga stated on its website. “This means that guests must have received their full two doses of the Covid‑19 vaccination at least 14 days before travelling with us.”
Cruise passengers would be required to bring evidence of vaccination with them at the time of boarding, Saga said. No one who was exempt from vaccination would be accepted on a Saga cruise.
SARS-CoV-2 variants present new challenges
On May 1, the WHO announced that it had assigned labels for key variants of SARS-CoV-2, using letters of the Greek alphabet. Labels are being assigned to variants that the WHO has designated Variants of Interest (VOIs) or Variants of Concern (VOCs).
The labels do not replace existing scientific names (e.g. those assigned by the global repository GISAID, Nextstrain, and PANGO), which convey important scientific information and will continue to be used in research, the WHO said.
“While they have their advantages, these scientific names can be difficult to say and recall, and are prone to misreporting. As a result, people often resort to calling variants by the places where they are detected, which is stigmatising and discriminatory,” the organisation added.
“To avoid this and to simplify public communications, WHO encourages national authorities, media outlets and others to adopt these new labels.”
The variant that was most recently designated as a VOI is the Mu variant, B.1.621, that was first detected in Colombia in January 2021 and was classifed as a VOI on August 30.
The WHO said in its weekly epidemiological Covid-19 update published on August 31 that the Mu variant had a “constellation of mutations that indicate potential properties of immune escape”.
Preliminary data presented to the Virus Evolution Working Group showed a reduction in neutralisation capacity of convalescent and vaccinee sera similar to that seen for the Beta variant, the WHO said, but this needed to be confirmed by further studies.
As of August 29, more than 4,500 sequences (3,794 sequences of B.1.621 and 856 sequences of B.1.621.1) had been uploaded to GISAID from 39 countries, it added.
The WHO said that more studies were required to understand the phenotypic and clinical characteristics of the variant. “The epidemiology of the Mu variant in South America, particularly with the co-circulation of the Delta variant, will be monitored for changes,” the organisation added.
The Mu variant has the same mutations as several VOCs, including Delta. It has some of the mutations present in the Beta variant’s receptor binding domain (RBD).
Image courtesy of https://covariants.org/.
Variants of Concern
Variants of Interest
Alerts for further monitoring
There are concerns that a SARS-CoV-2 variant, C.1.2, which was first detected in South Africa, could be more infectious than other variants and have an effect on antibody neutralisation following SARS-CoV-2 infection or Covid vaccination.
The variant has been detected in England, China, the Democratic Republic of the Congo, Mauritius, New Zealand, Portugal, and Switzerland,
A team of South African researchers said in a preprint published on medRxiv on August 26 that their findings suggested that the emergence of the C.1.2 lineage resulted from a rate of about 41.8 mutations per year.
This was about 1.7-fold faster than the current global rate of mutations and 1.8-fold faster than the initial estimate of SARS-CoV-2 evolution, they said.
They say that more than half of the C.1.2 sequences have 14 mutations, but additional mutations have been observed in some of the sequences, suggesting ongoing intra-lineage evolution.
Cathrine Scheepers et al. said the C.1.2 lineage was first identified in May 2021 and evolved from C.1, one of the lineages that dominated the first wave of SARS-CoV-2 infections in South Africa and was last detected in January 2021.
They said that, like several VOCs, C.1.2 had accumulated a number of substitutions beyond what would be expected from the background SARS-CoV-2 evolutionary rate.
Scheepers et al. said C.1.2 contained multiple substitutions (R190S, D215G, N484K, N501Y, H655Y and T859N) and deletions (Y144del, L242-A243del) within the spike protein, which had been observed in other VOCs “and were associated with increased transmissibility and reduced neutralisation sensitivity”.
They said the accumulation of additional mutations (C136F, Y449H and N679K) was of greater concern and was likely to impact neutralisation sensitivity or furin cleavage “and therefore replicative fitness”.
The researchers said that C.1.2 contains many mutations that had been identified in all four VOCs (Alpha, Beta, Delta and Gamma) and three VOIs (Kappa, Eta, and Lambda) as well as additional mutations within the N-terminal domain (C136F), the RBD (Y449H), and adjacent to the furin cleavage site (N679K).
The spike mutations that have previously been identified in other VOIs and VOCs include D614G, common to all variants, and E484K and N501Y, which are shared with Beta and Gamma. E484K has also been seen in Eta and N501Y in Alpha.
N440K, which can be seen in some of the smaller clusters from more recent sequences, and Y449H are not characteristic of current VOCs or VOIs, the researchers say, but they have been associated with escape from certain class 3 neutralising antibodies.
“Many of the shared mutations have been associated with improved ACE2 binding (N501Y) or furin cleavage (H655Y and P681H/R), and reduced neutralisation activity (particularly Y144del, 242-244del, and E484K), providing sufficient cause for concern of continued transmission of this variant,” Scheepers et al. wrote.
“Future work aims to determine the functional impact of these mutations, which likely include neutralising antibody escape, and to investigate whether their combination confers a replicative fitness advantage over the Delta variant.”
The researchers, who included scientists from the National Institute for Communicable Diseases (NICD) and the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), said that the number of available sequences of C.1.2 is most likely an underrepresentation of the spread and frequency of the variant within South Africa and globally.
They said they were seeing consistent increases in the number of C.1.2 genomes in South Africa on a monthly basis.
“In May C.1.2 accounted for 0.2% (2/1054) of genomes sequenced, in June 1.6% (25/2177) and in July 2.0% (26/1326), similar to the increases seen in Beta and Delta in South Africa during early detection,” they wrote.
“The C.1.2 lineage is continuing to grow. At the time of submission (20 August 2021) there were 80 C.1.2 sequences in GISAID with it now having been detected in Botswana and in the Northern Cape of South Africa.”
Scheepers et al. said they were currently assessing the impact of the C.1.2 variant on antibody neutralisation following SARS-CoV-2 infection or vaccination against SARS-CoV-2 in South Africa.
Three SARS-CoV-2 variants – initially discovered in the UK, South Africa, and in travellers from Brazil – spread rapidly around the world.
The B.1.1.7 variant, which was initially discovered in the UK, has 17 mutations in the viral genome and eight mutations located in the spike protein.
The South Africa variant, B.1.351, also known as 20H/501Y.V2, contains ten mutations in the spike protein. There are critical mutations in the virus’s RBD and multiple mutations outside the RBD.
A combination of the N501Y, K417N, and E484K mutations has been found in B.1.351 and in the P.1 variant, which was first identified in Brazil. The N501Y mutation is also present in the B1.1.7 variant.
Researchers at the University of British Colombia in Canada were the first in the world to publish structural images of the N501Y mutation.
They say that the pictures, taken at near-atomic resolution, and unveiled on May 3, provide critical insight as to why the B.1.1.7 variant is more infectious.
Sriram Subramaniam, who is a professor in the UBC faculty of medicine’s department of biochemistry and molecular biology, says the images show that the changes resulting from the mutation are localised.
British government researchers discovered that the B1.1.7 variant had acquired the E484K mutation, which was identified in 11 patients.
The researchers said in a report published in January 2021 by Public Health England: “The COG-UK dataset (total sequences 214,159) was analysed on 26/01/2021. The spike protein mutation E484K (found in VOC [Variant of Concern] 202012/02 B1.351 and VOC 202101/02 P1) has been detected in 11 B1.1.7 sequences. Preliminary information suggests more than one acquisition event.”
Virologist Björn Meyer thinks E484K might enhance another mutation seen in B1.1.7, thereby letting SARS-CoV-2 “grip” the human ACE2 receptor more strongly and in a more stable way.
Researchers have seen E484K show a tenfold reduction of neutralisation by various antibodies in some patients compared with the neutralisation of SARS-CoV-2 without the mutation.
Allison J. Greaney et al. reported in a preprint published on bioRxiv on January 4 this year that the mutations that most reduce antibody binding usually occur at just a few sites in the RBD’s receptor binding motif.
The National Institute for Communicable Diseases (NICD) stated on its website that the N501Y and K417N mutations in the spike protein of SARS-CoV-2 had allowed the virus “to become resistant to antibody neutralisation”.
In a study in South Africa by Constantinos Kurt Wibmer et al., the researchers examined sera from 44 people previously infected with SARS-CoV-2. In 48% of the cases, there was no detectable neutralisation activity against E484K and, in more than 90% of the cases, there was reduced immunity.
In a preprint published on bioRxiv on January 13, Gard Nelson et al. reported: “Molecular dynamic simulation reveals E484K mutation enhances spike RBD-ACE2 affinity and the combination of E484K, K417N and N501Y mutations (501Y.V2 variant) induces conformational change greater than N501Y mutant alone, potentially resulting in an escape mutant.”
In a separate study, researchers in South Africa found that antibodies from six recovered patients were six to 200 times less effective at neutralizing B.1.351.
In a paper published in the New England Journal of Medicine on March 16, Shabir A. Madhi et al. from South Africa reported that two doses of the AstraZeneca-Oxford vaccine did not provide protection against mild-to-moderate Covid-19 caused by the B.1.351 variant.
Madhi et al. said that overall efficacy of the vaccine against mild-to-moderate Covid-19 in South Africa was 21.9% and efficacy against the B.1.351 variant was 10.4%.
The researchers were reporting on a study that involved HIV-negative adults aged 18 to 64 who received either two standard doses of the vaccine or a placebo 21 to 35 days apart from June 24 to November 9, 2020. The participants’ median age was thirty.
Of the 750 participants who received the vaccine, 19 developed mild to moderate Covid-19 more than 14 days after the second dose as compared with 23 of the 717 people who were given a placebo.
Of the 42 total cases of Covid-19, 39 were caused by B1351. None of the patients were hospitalised.
“The lack of efficacy against the B.1.351 variant should be considered in the context of the 75% efficacy … in preventing mild-to-moderate Covid-19 with onset at least 14 days after even a single dose of ChAdOx1 nCoV-19 vaccine that was observed before the B.1.351 variant emerged in South Africa.”
The researchers said that the demographic and clinical profile of the enrolled participants contributed to the absence of severe Covid-19 cases, hence the trial findings were “inconclusive with respect to whether the ChAdOx1 nCov-19 vaccine may protect against severe Covid-19 caused by infection with the B.1.351 variant”.
In a preprint published on bioRxiv on December 31, 2020, Bulgarian researcher Filip Fratev states: “The K417N mutation had much more pronounced effect and in a combination with N501Y fully abolished the antibody effect.”
Speaking in December 2020, Andre Watson said that, in the case of the newly discovered mutated variants, antibody binding was not likely to be tremendously different, so vaccines were still likely to confer similar protection as they would against other strains identified previously.
He tweeted on December 23, 2020, however: “The current South Africa/UK/other locale mutant seems to bind more strongly to ACE2 – up to 3x more if consistent with prior N501T substitution (vs. the N501Y substitution in this newer spreading mutant). This would increase competition with neutralising antibodies.”
He added that clinical evidence suggested that the antibody response was six times weaker against the new South Africa strain.
In an article published in Science Direct on March 12, Wilfredo F. Garcia-Beltran et al. said their study findings highlighted the potential for virus variants to escape from neutralising humoral immunity.
The 15 researchers from the US, South Africa, and Germany assessed the potential of neutralisation against SARS-CoV-2 pseudoviruses bearing spike proteins found on circulating strains. They studied sera from 99 people who had received one or two doses of the BNT162b2 (Pfizer-BioNTech) vaccine or the mRNA-1273 (Moderna) vaccine.
The pseudoviruses represented ten globally circulating strains of SARS-CoV-2. “Five of the ten pseudoviruses, harbouring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralisation,” Garcia-Beltran et al. said.
The researchers said that cross-neutralisation of strains with RBD mutations was poor and both RBD and non-RBD mutations mediated escape from vaccine-induced humoral immunity. They said their findings suggested that a relatively small number of mutations could mediate potent escape from vaccine responses.
Garcia-Beltran et al. used high-throughput pseudovirus neutralisation assay to quantify neutralisation against variants first arising in the UK (B.1.1.7), Denmark (B.1.1.298), the US (B.1.429), Brazil, and Japan (P.2 and P.1), and South Africa (three variants of the B.1.351 lineage), as well as SARS-CoV from the 2002 Hong Kong outbreak and the pre-emergent bat coronavirus WIV1-CoV.
The researchers added: “Taken together, our results highlight that BNT162b2 and mRNA-1273 vaccines achieve only partial cross-neutralisation of novel variants and support the reformulation of existing vaccines to include diverse spike sequences.
The researchers pointed out that their studies relied on pseudoviruses that are only capable of modelling the ACE2-dependent entry step of the SARS-CoV-2 life cycle.
“While numerous studies have now demonstrated a close correlation between neutralisation titers measured against pseudovirus and live SARS-CoV-2 cultures … it is unclear what impact additional mutations located outside of the spike may have on immunological escape, virulence, infectivity, or pathogenesis,” they wrote.
In a paper published on the medRxiv preprint server on April 9 Timothy A. Bates et al. said there was evidence of reduced immunity to the UK and South Africa variants after vaccination with the Pfizer-BioNTech vaccine and after natural SARS-CoV-2 infection.
The researchers from Portland, Oregon, in the US said: “In this study we provide evidence of reduced antibody-mediated immunity to newly emerging SARS-CoV-2 variants B.1.1.7 and B.1.351 after immunisation with the Pfizer-BioNTech Covid-19 vaccine or following natural infection.”
Bates et al. noted that the B.1.1.7 and B.1.351 variants had been associated with increases in infections and hospitalisations in their countries of origin and all had increased in frequency in other regions, “suggesting a competitive fitness advantage over existing lineages”.
Many VOCs encode residues in the spike protein, which interacts with ACE2 via its RBD, the researchers noted. RBD mutations, they said, could potentially increase transmissibility by enhancing binding to ACE2, or promote immune escape by altering epitopes that are the primary target of potently neutralising antibodies.
Bates et al. tested human sera from large, demographically balanced cohorts of BNT162b2 vaccine recipients (51 participants) and Covid-19 patients (44 participants) for neutralising antibodies against the B.1.1.7 and B.1.351 variants.
Age was negatively correlated with neutralisation in vaccinees, the researchers said.
Bates et al. say the risk of reinfection by VOCs may be driven by generally low serological responses in most Covid-19 patients rather than the presence of RBD mutations that allow immune escape.
Researchers in Israel said in a report also published on medRxiv on April 9 that the South Africa variant caused breakthrough infection among people who received the Pfizer-BioNTech vaccine.
The researchers noted, however, that the variant’s prevalence in Israel was low, so the sample size was small, and the research had not been peer reviewed.
“When examining the results, it became evident that B.1.1.7 was the predominant strain of virus in Israel over the entire sampling period, increasing in frequency over time. Conversely, the B.1.351 strain was at an overall frequency of less than 1% in our sample, confirming previous reports,” Talia Kustin et al. said.
Talia Kustin et al. performed a case-control study that examined whether those vaccinated with BNT162b2 and had documented SARS-CoV-2 infection were more likely than unvaccinated individuals to become infected with the UK or South Africa variants.
They found that, in the case of vaccinees infected at least a week after the second dose, the prevalence of the South Africa variant was eight times higher than in those who were not vaccinated.
The researchers said their results overall suggested that vaccine breakthrough infection was more frequent with both VOCs, yet a combination of mass vaccination with two doses coupled with non-pharmaceutical interventions controlled and contained their spread.
They said their results generally aligned with those from in vitro neutralisation assays that have shown a large reduction in neutralisation against B.1.351, and little to no reduction against B.1.1.7 in fully vaccinated individuals.
From a biological point of view, the breakthrough cases observed in their study might either be due to immune evasion of both strains, or the ability of B.1.1.7 to create higher viral loads, they added.
On April 29, Sriram Subramaniam and 12 other researchers from the University of British Colombia and the University of Pittsburgh Medical School published an article in PLOS Biology.
They said that the N501Y mutation did not result in large structural changes and this enabled important neutralisation epitopes to be retained in the spike receptor binding domain.
“This is an important observation and adds to the growing body of evidence that the majority of antibodies elicited in our immune system by existing vaccines are likely to remain effective in protecting us against the B1.1.7 variant.”
Researchers from the Philippines have reported that samples containing the SARS-CoV-2 variant emerging in that country have all been found to contain spike mutations found in the South African, Brazilian, and UK variants.
Neil Andrew D. Bascos et al. said in a paper published on the preprint server bioRxiv on March 8: “A SARS-CoV-2 emergent lineage with multiple signature mutations in the spike protein region was reported with cases centred in Cebu Island, Philippines.
The researchers said their analysis suggested that the mutations could significantly impact the possible interactions of the spike protein monomer with the ACE2 receptor and neutralising antibodies and warranted further clinical investigation.
(A monomer is a molecule that forms the basic unit for polymers, which are the building blocks of proteins.)
A: Position of signature mutations for the Philippine variant. Mutations are coloured based on their predicted functional effect.
B. Position of signature mutations in several reported SARS-CoV-2 variants.
According to news reports in Sri Lanka and India, a new variant of SARS-CoV-2 is circulating in Sri Lanka.
News media have quoted Professor Neelika Malavige from the Department of Immunology and Molecular Medicine at the Faculty of Medical Sciences of the University of Sri Jayewardenepura as saying the new variant is spreading faster than the original SARS-CoV-2 strain.
Malavige was quoted as saying that droplets of the new strain could remain airborne for nearly an hour.
A variant, known as Delta Plus or the ‘Nepal variant’, which contains the K417N mutation, has been observed in numerous countries, including the UK, the US, and India.
Public Health England (PHE) said in a briefing published on June 18 that available information suggested that there were at least two separate clades of Delta with K417N.
PHE said that, as of June 16, 161 genomes of Delta-AY.1 had been identified on GISAID. They were from Canada (1), India (8), Japan (15), Nepal (3), Poland (9), Portugal (22), Russia (1), Switzerland (18), Turkey (1), and the US (83).
There were 38 cases of Delta-AY.1 in England (36 confirmed sequencing and two probable genotyping), PHE said. Cases had been detected in six different regions in England. Delta-AY.2 had not been detected in England, PHE said.
“Delta with K417N can be detected by genotyping assay, which means that rapid case identification and response activities can be undertaken,” PHE added.
The director of the Covid-19 Genomics Initiative at the Wellcome Sanger Institute, Jeff Barrett, said of the K417N mutation: “This mutation is present in B.1.351/Beta and is believed to be part of why that variant is less well neutralised by vaccines,” Barrett said. “Because of this possibility, and because Delta appears more transmissible than Beta, scientists are monitoring it carefully.”
Barrett said 13 of the samples of the Delta+K417N variant identified in Japan were taken during airport quarantine from travellers arriving from Nepal.
India’s Ministry of Health and Family Welfare said on June 16 that the Delta Plus variant had not yet been classified as a Variant of Concern and remained a Variant of Interest, but, in a statment on June 22, the ministry described it as a Variant of Concern, saying it showed increased transmissibility and states should increase testing.
The health ministry cited two other characteristics of AY.1: “stronger binding to receptors of lung cells” and “potential reduction in monoclonal antibody response”.
Delta Plus was first identified in the states of Maharashtra, Kerala, and Madhya Pradesh, but has since also been detected in Tamil Nadu, Punjab, Gujarat, Andhra Pradesh, Odisha, Rajasthan, Jammu, and Karnataka.
Member of the NITI Aayog public policy think tank Dr V.K. Paul has said “… there is no way that we can shoot these variants away, to use any precision weapon to ensure that they don’t appear in future”. The appropriate response included containment measures and Covid-appropriate behaviour, Paul said.
India’s Ministry of Health and Family Welfare said on March 24 that 771 VOCs had been detected in 10,787 positive samples from 18 different states in the country.
A total 736 samples tested positive for the viruses of the UK variant, 34 tested positive for the South Africa variant, and one sample was found to be positive for the Brazilian variant.
The ministry also said a new “double-mutant” variant, which has now been classified as B.1.617, had been found in India. The new variant was found by the Indian SARS-CoV-2 Consortium on Genomics (INSACOG), which is a grouping of ten national laboratories.
Virologist Shahid Jameel told the BBC that “there may be a separate lineage developing in India with the L452R and E484Q mutations coming together”.
In the E484Q mutation, glutamic acid is replaced by glutamine at the 484th position on the virus’s spike protein. In the L452R mutation, leucine is replaced by arginine at the 452nd position.
The variants identified in India had not been detected in numbers that were sufficient to either establish a direct relationship or explain the rapid increase in cases in some states, the Indian health and family welfare ministry added.
According to later local media reports, on April 1, B.1.617 accounted for 80% of all analysed genome sequences of mutant variants sent by India to GISAID.
The ministry’s announcement came on the day when India reported 47,262 new Covid-19 cases, which, at that moment, was the highest reported increase in a single day in 2021. (On April 22 India recorded 314,835 new cases, the world’s highest ever single-day Covid tally.)
Other variants of SARS-CoV-2, including N440K and E484Q, had already been detected in India.
Writing in GenomeConnect on April 22, Samatha Mathew said: “First detected as a rising variant in Maharashtra in March, the B.1.617 variant has been reported in at least ten states until mid-April.
Mathew writes that there are a total of 15 new mutations in B.1.617, six of them leading to alterations in the spike protein, “which can increase its capability to infect and multiply faster”.
The changes have increased the virus’s infectivity, Mathew says; “that is, its ability to jump from one human host to the next has become much easier”.
A change in the B.1.617 RNA sequence causes an alteration in the virus’s spike protein that enables it to evade antibodies, Mathew explains.
“The second change (called E484Q) is at a site in the RNA sequence known to accommodate changes in already documented virus variants of concern. This second change also confers ability of immune evasion to the virus and a better fit or binding of the spike protein to human cells, making this variant probably more capable of immune escape than variants with only L452R change.”
On May 11, the WHO said that the B.1.617 variant had been detected in sequences uploaded from 44 countries in all six WHO regions.
“As of 11 May, over 4,500 sequences have been uploaded to GISAID and assigned to B.1.617 from 44 countries in all six WHO regions, and WHO has received reports of detections from five additional countries,” the organisation said in its weekly epidemiological update about Covid-19.
B.1.617 has three sub-lineages.
Public Health England said that, as of May 19, B.1.617.2 had been detected in 43 countries across six continents.
The WHO said it had designated B.1.617 as a VOC “based on early evidence of phenotypic impacts compared to other circulating virus variants”.
The organisation cited the following impacts:
- B.1.617 sublineages appear to have higher rates of transmission, including observed rapid increases in prevalence in multiple countries (moderate evidence available for B.1.617.1 and B.1.617.2), and
- preliminary evidence suggests potential reduced effectiveness of Bamlanivimab, a monoclonal antibody used for Covid-19 treatment, and potentially slightly reduced susceptibility to neutralisation antibodies (limited evidence available for B.1.617.1).
The WHO added that preliminary laboratory studies awaiting peer review suggest that, with the B.1.617 lineage, there was a limited reduction in neutralisation by antibodies. “However, real-world impacts may be limited,” it added.
One study found a seven-fold reduction in neutralisation effectiveness against B.1.617.1 of antibodies generated by vaccination with the Moderna and Pfizer-BioNTech vaccines, the WHO said.
Another study showed that B.1.617.1 (with additional spike mutations R21T and Q218H) mediates increased entry into certain human and intestinal cell lines, and was resistant to the monoclonal antibody bamlanivimab. However, it was efficiently inhibited by imdevimab and by a cocktail of casirivimab and imdevimab.
The WHO said that, outside of India, the UK had reported the largest number of cases sequenced as B.1.617 sub-lineages.
“This follows a recent steep increase in the number of cases sequenced as B.1.617 sublineages, and a national assessment that characterized B.1.617.2 as at least equivalent in terms of transmissibility as VOC B.1.1.7,” the WHO said. “However, they noted insufficient data to assess the potential for immune escape.”
Public Health England (PHE) has reclassified B.1.617.2 as a ‘Variant of Concern’. On May 19, it reported 3,424 cases of the variant in the UK.
PHE said B.1.617.2 was at least as transmissible as B.1.1.7 (the Kent variant). The other characteristics of B.1.617.2 were still being investigated, the PHE said.On May 7, PHE said that, following a rise in cases in the UK and evidence of community transmission, it had reclassified B.1.617.2, which was classified as a Variant Under Investigation (VUI) on April 28, as a Variant of Concern, now known as VOC-21APR-02.
The health authority said there was currently insufficient evidence to indicate that any of the variants recently detected in India caused more severe disease or rendered the vaccines currently being administered any less effective.
“PHE is carrying out laboratory testing, in collaboration with academic and international partners to better understand the impact of the mutations on the behaviour of the virus,” PHE added.
Another variant that has been found in several countries, but mainly in India, has been dubbed the ‘Bengal strain’ or the ‘triple-mutant variant’ and is classified as B.1.618. It contains the E484K mutation.
Vinod Scaria, who is a researcher at the Council of Scientific and Industrial Research’s Institute of Genomic and Integrative Biology in New Delhi, tweeted on April 20: “E484K is a major immune escape variant – also found in a number of emerging lineages across the world.
“E484K can escape multiple mAbs as well as panels of convalescent plasma.”
The three mutations in B.1.618 are a deletion and two changes in the spike protein. H146 and Y145 have been deleted and, in addition to E484K, there is also a D614G mutation.
While E484K is in the RBD, Y145 and H146 are not part of the residues interacting with the human ACE2 receptor, Scaria explains. “The structural impact of the 2AA deletion causes to spike protein is yet to be understood completely,” he tweeted.
B.1.618 was first sequenced on October 25, 2020, from samples collected from a patient in West Bengal, Scaria says. Members of the lineage had also been found in other parts of the world, but they didn’t have the full complement of variants as found in India, he said.
Presence of B.1.618 in ten countries:
The presence of B.1.618 has been growing significantly in recent months in West Bengal.
Scaria added: “At this moment, there is no conclusive evidence that the lineage drives the epidemic in West Bengal, apart from the fact that the nos and proportions have been significantly increasing in recent months. More focused epidemiological investigations would address these questions.
“There are many unknowns for this lineage at this moment including its capability to cause reinfections as well as vaccine breakthrough infections. Additional experimental data is also required to assess the efficacy of vaccines against this variant.”
Vaccine efficacy studies
Pfizer and BioNTech said in January that their Covid-19 vaccine was effective against virus variants detected in the UK and South Africa but there was reduced efficacy against the South Africa variant.
In March, the companies said that BNT162b2 was 100% effective in preventing Covid-19 in South Africa.
Much has been made of a study conducted by researchers in the UK and published as a preprint by Public Health England on May 20. The researchers say the study indicates effectiveness of the Pfizer-BioNTech (BNT162b2) and AstraZeneca-Oxford (ChAdOx1) vaccines against symptomatic disease from the B.1.617.2 variant.
According to Jamie Lopez Bernal et al. the protection after two vaccine doses is similar to that provided against the B.1.1.7 (Kent) variant, which is the dominant variant in the UK.
Bernal et al. say that, for the period from April 5 to May 16, the Pfizer-BioNTech vaccine was 88% effective against symptomatic disease from the B.1.617.2 variant two weeks after the second dose, as compared to 93% effectiveness against the B.1.1.7 variant.
They said that two doses of the AstraZeneca-Oxford vaccine were 60% effective against symptomatic disease from the B.1.617.2 variant as compared to 66% effectiveness against the B.1.1.7 variant.
Both vaccines were 33% effective against symptomatic disease from B.1.617.2 three weeks after the first dose as compared to about 50% effectiveness against the B.1.1.7 variant, they said.
“After two doses of either vaccine there were only modest differences in vaccine effectiveness with the B.1.617.2 variant,” they added. “Absolute differences in vaccine effectiveness were more marked with dose one. This would support maximising vaccine uptake with two doses among vulnerable groups.”
The researchers wrote: “Effectiveness was notably lower after 1 dose of vaccine with B.1.617.2 cases 33.5% (95%CI: 20.6 to 44.3) compared to B.1.1.7 cases 51.1% (95%CI: 47.3 to 54.7) with similar results for both vaccines.”
They said that, with BNT162b2, two-dose effectiveness reduced from 93.4% (95%CI: 90.4 to 95.5), with B.1.1.7 to 87.9% (95%CI: 78.2 to 93.2), with B.1.617.2.
With ChAdOx1, two-dose effectiveness reduced from 66.1% (95% CI: 54.0 to 75.0) with B.1.1.7 to 59.8% (95%CI: 28.9 to 77.3) with B.1.617.2, they added.
“Sequenced cases detected after 1 or 2 doses of vaccination had higher odds of infection with B.1.617.2 compared to unvaccinated cases (OR 1.40; 95%CI: 1.13-1.75),” they wrote.
A total of 12,675 sequenced cases were included in the analysis of which 11,621 had B.1.1.7 detected and 1,054 had B.1.617.2 detected.
Bernal et al. note that their findings are observational and should be interpreted with caution.
“There may be factors that could increase the risk of Covid-19 in vaccinated individuals, for example if they adopt more risky behaviours following vaccination, however, this would be likely to affect analysis of both variants,” they wrote.
“Low sensitivity or specificity of PCR testing could also result in cases and controls being misclassified which would attenuate vaccine effectiveness estimates. This could affect one variant more than another though this might be expected to affect B.1.1.7 more than B.1.617.2 …”
The researchers said that the difference in effectiveness between the vaccines after two doses may be explained by the fact that rollout of second doses of the AstraZeneca-Oxford vaccine was later than for the Pfizer-BioNTech vaccine, “and other data on antibody profiles show it takes longer to reach maximum effectiveness with the AstraZeneca vaccine”.
Professor of Primary Care Health Sciences at the University of Oxford Patricia Greenhalgh tweeted that the study had a weak design.
Indian data scientist Vijay Gupta adds that the time period used to calculate the efficacy of the first vaccine dose was too long (“symptom onset 21 days or more after the first dose”).
He said: “It should be ten to 14 days with the Indian variant. I am guessing that if they made it ten days the efficacy would drop sharply. They should also present the data for five to nine days. This would help determine if the vaccine is causing an initial drop in immunity.”
Gupta also says that no Oxford researchers should be involved in such a study about the AstraZeneca-Oxford vaccine as the university makes a great deal of money from the vaccine via Vaccitech.
Director of the Clinical Operational Research Unit at University College London Christina Pagel tweeted the following:
Pagel added on Twitter: “Essentially – YES two doses work almost as well against B.1.617.2 as they do against B.1.1.7. And in a country that had 3 weeks between doses, this would be less of an issue. But we are not that country.”
“We are doing 10–12 weeks between doses – now being reduced to 8 weeks for over 50s. In the context of a rapidly growing variant against which vax is only 33% after 1 dose, 8 weeks is a LONG time.
Moderna said it was examining two strategies to deal with the new virus variants and was planning to test an additional dose of mRNA-127 to see if it would increase neutralising titers against emerging strains and was also planning preclinical and Phase 1 studies of a new booster (mRNA-1273.351) that would specifically target the South Africa variant.
Pfizer and BioNTech said on January 27 that sera from individuals vaccinated with their Covid vaccine neutralised samples of SARS-CoV-2 that contained the E484K and N501Y mutations.
The results of the in vitro studies were published on the preprint server bioRxiv. Xuping Xie et al. said that SARS-CoV-2 mutations identified in the UK and South Africa had only small effects on the virus neutralisation generated by two doses of the companies’ BNT162b2 vaccine.
The companies said that three engineered viruses with key mutations were tested against sera from twenty participants in the Phase 3 trial who had received the Pfizer-BioNTech vaccine.
Of the three recombinant variants, one had a mutation common to both the UK and South Africa variants (N501Y), one had mutations common to the UK variant (Δ69/70+N501Y+D614G), and the third had mutations common to the South Africa variant (E484K+N501Y+D614G).
“The sera from individuals vaccinated with the Pfizer-BioNTech Covid-19 vaccine neutralised all the SARS-CoV-2 strains tested,” the companies said.
“However, the companies believe the small differences in viral neutralisation observed in these studies are unlikely to lead to a significant reduction in the effectiveness of the vaccine.”
The companies said they were encouraged by the early in vitro findings and were evaluating the full set of mutations in the spike protein of the South African variant.
“While these findings do not indicate the need for a new vaccine to address the emerging variants, the companies are prepared to respond if a variant of SARS-CoV-2 demonstrates evidence of escaping immunity by the Covid-19 vaccine,” they added.
“Pfizer and BioNTech will continue to monitor emerging SARS-CoV-2 strains and continue to conduct studies to monitor the vaccine’s real-world effectiveness.”
Xuping Xie et al. said one limitation of the study was that the engineered viruses did not include the full set of spike mutations found in the UK or South Africa variants.
Also, they said, no serological correlate of protection against Covid-19 had been defined. “Therefore, predictions about vaccine efficacy based on neutralisation titers require assumptions about the levels of neutralisation and roles of humoral and cell-mediated immunity in vaccine-mediated protection.
The researchers said the ongoing evolution of SARS-CoV-2 necessitated continuous monitoring of the significance of changes for vaccine efficacy.
The CEO of BioNTech, Ugur Sahin, said in an interview with CNBC on January 11 that his company was talking to regulators around the world about what types of clinical trials and safety reviews would be required to authorise a new version of the Pfizer-BioNTech vaccine that would be better able to work against B.1.351.
“We can change the sequence of the vaccine within a few days and we could deliver a new vaccine within six weeks in principle,” Sahin said.
On April 1, Pfizer and BioNTech announced updated results from their Phase 3 study of BNT162b2, saying that the vaccine had been shown to be 91.3% effective against Covid-19 when efficacy was measured between seven days and six months after the second dose.
The results are based on an analysis of 927 confirmed symptomatic cases of Covid-19 observed during the trial up to March 13.
“Safety data from the Phase 3 study has also been collected from more than 12,000 vaccinated participants who have a follow-up time of at least six months after the second dose, demonstrating a favourable safety and tolerability profile.”
A total 46,307 people were enrolled in the Phase 3 trial. Of the 927 confirmed symptomatic cases of Covid-19, 850 cases occurred in the placebo group and 77 were in the vaccinated group.
Thirty-two cases of severe Covid-19 disease, as defined by the CDC, were observed in the placebo group versus none in the vaccinated group. Twenty-one severe cases, as defined by the FDA, were observed in the placebo group versus one case in the vaccinated group.
“Efficacy was generally consistent across age, gender, race and ethnicity demographics, and across participants with a variety of underlying conditions,” the companies said.
In South Africa, where 800 trial participants were enrolled, nine cases of Covid-19 were observed, all in the placebo group.
In an exploratory analysis, the nine strains were sequenced and six of the nine were confirmed to be of the B.1.351 lineage.
Pfizer’s CEO, Albert Bourla, said the results positioned the company to submit a biologics licence application to the FDA.
The company said that vaccine safety had now been evaluated in more than 44,000 participants aged 16 years and above, with more than 12,000 vaccinated participants having had at least six months follow-up after their second dose.
Novavax
In a trial conducted in South Africa, researchers analysed the efficacy of NVX-CoV2373, produced by the American company Novavax. They found that the vaccine had an efficacy rate of only 49.4% in South Africa compared with 89.3% in a trial in the UK.
The efficacy rates relate to the prevention of mild, moderate and severe Covid-19 disease.
Almost all the cases of infection analysed in South Africa were caused by B.1.351. Twenty-seven of 44 cases of Covid-19 were analysed and 25 of them were caused by the B.1.351 variant. (Twenty-nine cases were observed in the placebo group and 15 in the vaccinated cohort.)
Sixty percent efficacy was observed in the 94% of the studied population who were HIV-negative.
NVX-CoV2373 is a subunit vaccine in which a purified protein is encoded by the genetic sequence of the SARS-CoV-2 spike protein. The gene is inserted into a baculovirus that is then introduced into cells of the fall armyworm moth. The spike proteins are harvested from the moth cells and are assembled into nanoparticles. The vaccine contains a saponin-based adjuvant.
Subunit vaccines can be manufactured quickly, but generally don’t produce as strong an immune response as some other vaccines.
Like inactivated whole-cell vaccines, subunit vaccines do not contain live components of the pathogen, but they differ from inactivated whole-cell vaccines in that they contain only the antigenic parts of the pathogen.
Novavax announced on August 31 that it had reached an agreement in principle with the Canadian government to supply the country with 76 million doses of its NVX-CoV2373 vaccine. The company is reported to have also signed SARS-CoV-2 vaccine deals with India, the UK, the Czech Republic, South Africa, and Japan.
The Serum Institute of India’s CEO, Adar Poonawalla, had been hopeful that Novavax’s vaccine would be launched in India by June 2021, but there have been licensing delays in the US. The SII is manufacturing the vaccine under the local brand name Covovax.
Novavax has twice delayed its timeline for seeking emergency use authorisation in the US for its Covid vaccine. It is now expected to file for authorisation in the fourth quarter of 2021. There are reported to be “documentation issues”.
Approval for use of the vaccine is also being sought in Indonesia and the Philippines.
Adar Poonawalla said he was now hopeful that Covovax would be launched in India in October for adults and by the first quarter of 2022 for children.
The SII is set to start trials of Covovax for children and adolescents aged 12 to 17 years later in August.
Moderna
Moderna has also said that its vaccine has reduced efficacy against the South Africa variant.
The company announced on January 25 that it still expected its Covid vaccine to be protective against the South Africa variant, but added that antibodies triggered by the vaccine appeared to be less potent against the B.1.351 variant than original SARS-CoV-2.
Researchers from Moderna and the Vaccine Research Center at the US National Institutes of Health studied sera from individuals vaccinated with mRNA-1273 and found that the vaccine produced neutralising titers against all the key emerging variants tested, including B.1.1.7 and B.1.351.
However, a six-fold reduction in neutralising titers was observed in the case of the B.1.351 variant compared with previous variants.
Pengfei Wang et al. analysed the serum of 12 people who received the Moderna vaccine and ten who received the Pfizer-BioNTech vaccine and reported in a preprint on bioRxiv that every sample lost activity against the B.1.351 variant, “ranging from slight to substantial”. Overall, the mean loss of neutralising activity against the B.1.1.7 variant appeared to be small, the researchers said.
The approximately twofold loss of neutralising activity of vaccinee sera against the B.1.1.7 variant was unlikely to have an adverse impact due to the large “cushion” of residual neutralising antibody titer, Wang et al. said.
However, they added, the 6.5- to 8.6-fold loss in activity against B.1.351 was “more worrisome”.
The researchers also noted that convalescent plasma from patients infected with SARS-CoV-2 early on in the pandemic show slightly decreased neutralising activity against B.1.1.7, but the diminution against the South Africa variant was “remarkable”.
This relative resistance was largely due to E484K, the researchers said. “Again, in areas where such viruses are common, one would have heightened concerns about re-infection, which has already been well documented even in the absence of antigenic changes.”
In an email to Science, Pfizer wrote that it was “laying the groundwork to respond quickly if a future variant of SARS-CoV-2 is unresponsive to existing vaccines”.
Johnson & Johnson
Johnson & Johnson said on January 29 that the efficacy of its JNJ-78436735 vaccine was higher against moderate to severe Covid-19 disease in the US (72%) than in South Africa (57%) and Latin America (66%).
The company said that its vaccine was 66% effective overall at preventing moderate to severe Covid illness, and 85% protective against the most serious symptoms.
Efficacy against severe Covid disease increased over time, Johnson & Johnson added. (There were no cases in vaccinees after day 49.)
After day 28, none of those vaccinated were hospitalised or died.
Johnson & Johnson said more serious adverse events were reported among participants who received a placebo than those who received the vaccine, and no anaphylaxis was observed.
About one-third of participants in Johnson & Johnson’s ENSEMBLE trial, which was conducted in eight countries across three continents, were aged over 60 years and more than 40% had conditions that increased their risk of suffering severe Covid-19 disease, including obesity and diabetes.
Forty-one percent of participants in the study had comorbidities associated with an increased risk for progression to severe Covid-19.
Johnson & Johnson has initiated rolling submissions with several health agencies outside the US. The company says it expects to supply 100 million vaccine doses to the US in the first half of 2021.
Research in China
In a preprint published on bioRxiv on February 2, 2021, Chinese researchers Baoying Huang et al. report on the capacities of the BBIBP-CorV inactivated virus vaccine and the protein subunit vaccine ZF2001 to neutralise the 501Y.V2 variant.
BBIBP-CorV was developed by the Beijing Bio-Institute Biological Products Co. Ltd (BBIBP). ZF2001, trade-named RBD-Dimer, was developed by Anhui Zhifei Longcom in collaboration with the Institute of Microbiology at the Chinese Academy of Sciences.
The Beijing institute is a unit of the China National Biotec Group, which is the vaccine and bioscience arm of the company Sinopharm.
Baoying Huang et al. said that both vaccines largely preserved neutralising titres against 501Y.V2 with only a slight reduction compared with their titres against original SARS-CoV-2 and the D614G variant.
Variants containing the D614G mutation in the SARS-CoV-2 spike protein were first reported from the middle of 2020 and significantly increased the transmission rate and had become dominant in circulating strains ever since, Baoying Huang et al. note.
“These data indicated that 501Y.V2 variant will not escape the immunity induced by vaccines targeting whole virus or RBD,” they report.
They add that the potential 1.6-fold reduction of neutralising geometric mean titres (GMTs) should be taken into account for its impact for the clinical efficacy of these vaccines.
“For both vaccines, antisera neutralise both variant 501Y.V2 and D614G, the one currently circulating globally, without statistical significances.”
A spike protein of SARS-CoV-2 in ‘closed’ form (ACE2 shown in red). Photo courtesy of Andre Watson.
A spike protein of SARS-CoV-2 in ‘open’ form, in which it binds to ACE2. (Photo courtesy of Andre Watson.)
The German chancellor Angela Merkel said that if vaccines did not work on variants of SARS-CoV-2, then “we start all over again”. Covid vaccines might be needed for many years to come, she said. “It’s similar to the flu vaccine, where you re-vaccinate against the new mutation of the virus every time,” she said on February 1.
The South African government put use of AstraZeneca’s vaccine on hold then sold one million doses, which had been received from the Serum Institute of India, to other African countries. South Africa’s Health Minister, Zweli Mkhize, said research had indicated that the vaccine did not significantly reduce the risk of Covid-19 disease resulting from infection with the 501Y.V2 variant.
COVAX said on February 8: “In light of recent news stories regarding the preliminary data on minimal effectiveness of the AstraZeneca-Oxford vaccine at preventing mild to moderate Covid-19 disease caused by the viral variant B.1.351, it is important to note that primary analysis of data from Phase 3 trials has so far shown – in the context of viral settings without this variant – that the AstraZeneca-Oxford vaccine offers protection against severe disease, hospitalisation, and death.
This meant it was vitally important “to determine the vaccine’s effectiveness in preventing more severe illness caused by the B.1.351 variant”, COVAX added.
CEPI had announced funding for additional clinical research “to optimise and extend the use of existing vaccines”, COVAX said, and this could include mix-and-match studies of different vaccines.
COVAX has signed advance purchase agreements with AstraZeneca and the SII, which is responsible for testing and manufacturing Covishield, and says it plans to distribute nearly 350 million doses of the vaccine in the first half of this year.
On February 15, the WHO granted an emergency use listing (EUL) to two versions of the AstraZeneca-Oxford vaccine (one produced by AstraZeneca-SKBio in the Republic of Korea and one manufactured by the SII).
This gives the green light for the vaccines to be rolled out globally via COVAX and for it to be used for individuals aged 18 years and above.
The EUL allows for two doses of the vaccine to be administered with an interval between doses of four to 12 weeks.
The WHO’s Strategic Advisory Group of Experts on Immunisation (SAGE) recommended a dosing interval of eight to 12 weeks. The group also recommended use of the vaccine in countries where new variants, including the South African B1.351 variant, are prevalent.
On March 12, the WHO listed the Janssen Biotech vaccine for emergency use in all countries and for COVAX roll-out. It was the first single-dose Covid vaccine to be granted an EUL by the WHO.
To expedite listing of the vaccine, the WHO and a team of assessors from all regions adopted an “abbreviated assessment” based on outcomes of the review by the European Medicines Agency “and evaluation of quality, safety, and efficacy data focused on low- and middle-income country needs”.
The WHO said its assessment also considered suitability requirements such as cold chain storage and risk management plans to be implemented in different countries.
“While the vaccine needs to be stored at -20 degrees, which may prove challenging in some environments, it can be kept for three months at 2-8°C and it has a long shelf life of two years,” the WHO said.
The organisation said it would convene SAGE to formulate recommendations on use of the Janssen Biotech vaccine. “In the meantime, the WHO continues to work with countries and COVAX partners to prepare for roll-out and safety monitoring,” the WHO added. COVAX has booked 500 million doses of the vaccine.
The WHO gave the Pfizer-BioNTech vaccine an EUL on December 31, 2020. On April 30, the organisation listed Moderna’s Covid vaccine for emergency use for people aged 18 years and above.
On May 7, the WHO listed the Sinopharm Covid-19 vaccine for emergency use and, on June 1, it granted CoronaVac an EUL. The WHO recommends CoronaVac for use in adults aged 18 years and above, in a two-dose schedule with an interval of two to four weeks between doses.
The WHO said: “Few older adults (over 60 years) were enrolled in clinical trials, so efficacy could not be estimated in this age group. Nevertheless, WHO is not recommending an upper age limit for the vaccine because data collected during subsequent use in multiple countries and supportive immunogenicity data suggest the vaccine is likely to have a protective effect in older persons.
“There is no reason to believe that the vaccine has a different safety profile in older and younger populations. WHO recommends that countries using the vaccine in older age groups conduct safety and effectiveness monitoring to verify the expected impact and contribute to making the recommendation more robust for all countries.”
Deaths after Covid vaccination
The doctor and researcher who uses the Twitter handle @AMcA32449832 tweeted that she was alarmed when she reviewed the first one hundred deaths reported in VAERS after Covid vaccine administration.
The results of a study of 100 deaths after Covid vaccination in nursing homes in Norway were published on July 7.
Between December 27, 2020, and February 15, 2021, about 29,400 of approximately 35,000 patients in nursing homes in Norway were vaccinated with the Pfizer-BioNTech vaccine.
During the same period, the Norwegian Medicines Agency received 100 reports of suspected fatal adverse reactions to the vaccine. (As of 12 May 12, 2021, the number of such reports had risen to 142.)
An expert group examined the 100 reports. The mean age of the patients was 87.7 years (range 61–103 years).
Reporting on their findings, Torgeir Bruun Wyller et al. said they concluded that a causal link to the vaccine was probable in ten of the cases, possible in 26, and unlikely in 59. They considered five of the cases as unclassifiable.
“Nursing home patients should still be given priority for vaccination, but the benefits versus risk must be carefully weighed up for the frailest patients.”
The researchers said it must be emphasised that their estimates were very uncertain.
They said the categories ‘probable’ and ‘unlikely’ were used in cases where the expert group considered there to be a clear likelihood one way or the other, and the category ‘possible’ was used where a causal link between vaccination and death was just as likely as unlikely.
“Many of the cases classified as ‘possible’ are therefore very uncertain, and some of them could perhaps also have been categorised as unclassifiable,” Wyller et al. said.
“The group considered far more cases to be either probable or unlikely than the Norwegian Institute of Public Health in its initial assessment. This is probably due to access to more information as well as knowledge of typical clinical courses in frail elderly people.”
Wyller et al. wrote: “The extremely high mortality rate in nursing homes means that random factors will lead to a certain number of deaths shortly after vaccination anyway. It cannot be ruled out that some of the deaths that were classified as probable are in fact due to such random factors.
“Nevertheless, we find it reasonable to assume that adverse effects from the vaccine in very frail patients can trigger a cascade of new complications which, in the worst case, end up expediting death.”
They added: “The adverse reaction reports were submitted within a period of approximately 50 days, during which it can be assumed that 2,000–2,500 nursing home patients died in Norway.
“Whether ten or 36 of these deaths were accelerated by the vaccine, the proportion is still low. In the same period, almost 30,000 nursing home patients were vaccinated, which means that there will most likely have been far more than 100 deaths in nursing homes in a close temporal relationship to vaccination in the relevant time period. Our findings cannot therefore be used to estimate the incidence of vaccine-related deaths.”
One death that made international headlines is that of the British model Stephanie Dubois who died in Cyprus after receiving an AstraZeneca-Oxford vaccination.
Dubois, aged 39, posted on Facebook after she received her first vaccine dose on May 6 that she felt horrendous and on May 14 she was taken to hospital with breathing problems.
Dubois wrote on her Facebook page on May 14 that her white blood cell count was high and doctors didn’t know what was causing it.
“Maybe I’m having a prolonged reaction to my Covid jab last week, or maybe those side effects affected my immune system and I’ve caught something else in the process,” Dubois wrote.
“I am completely drained, no energy and my whole body hurts with sore and weak joints … but it is better than it was this morning. This morning really scared me to be honest.”
Earlier in the day she had written: “Woke up feeling fine and then within an hour I had fully (sic) body shakes, all my joints seized and I was struggling to breathe and was cold to the bone with a persistent headache and dizziness. I was convinced I’d come down with Covid!
“Mum and dad came to look after me and took me for a covid test, which thankfully was negative … but it still doesn’t explain what the problem is.”
According to media reports, by May 19 Dubois had gone into a coma. Local media reported that she had suffered a brain haemorrhage and died on May 22.
A Cypriot health service spokesman has been quoted as saying said that Dubois’ death would be investigated by the EMA.
Another death that made headlines is that on May 21 of a BBC presenter, Lisa Shaw, who died, aged 44, after receiving the AstraZeneca-Oxford vaccine. A coroner concluded that her death was due to complications of the vaccination.
The coroner said that Shaw was previously fit and well. He said it was clearly established that her death was due to a very rare vaccine-induced thrombotic thrombocytopenia.
Shaw, who was a presenter at BBC Radio Newcastle, received her first dose of the vaccine on April 29 and, on May 13, was taken to hospital after suffering headaches for several days.
Her family said: “She was treated by the RVI’s [Royal Victoria Infirmary] intensive care team for blood clots and bleeding in her head.
“Tragically she passed away, surrounded by her family … We are devastated and there is a Lisa-shaped hole in our lives that can never be filled. We will love and miss her always.
A 64-year-old surgeon who was working at the Pieve di Coriano hospital in Mantua, Italy, died a few days after receiving the Pfizer-BioNTech Covid vaccination. A postmortem has been carried out.
According to local media reports, the doctor, Enrico Patuzo, suffered from several chronic conditions, including cardiac problems.
In Genoa, Italy, an 89-year-old woman died after suffering a cerebral haemorrhage. She had received a Covid vaccination. Investigators said they had found no direct causal link between the haemorrhage and the vaccination.
Obstetrician Gregory Michael, aged 56, from Miami in the US died on the night of January 3/4, just over two weeks after receiving a dose of the Pfizer-BioNTech vaccine. Health officials from Florida and the CDC are conducting an investigation.
According to a Facebook post written by his wife, Heidi Neckelmann, Michael died from the complications of idiopathic thrombocytopenic purpura (immune thrombocytopenia).
“He was vaccinated with the Pfizer vaccine … on December 18, three days later he saw a strong set of petechiae on his feet and hands which made him seek attention at the emergency room at MSMC [the Mount Sinai Medical Centre],” Neckelmann wrote.
“The CBC [complete blood count] that was done at his arrival showed his platelet count to be 0 (a normal platelet count ranges from 150,000 to 450,000 platelets per microliter of blood.) He was admitted in the ICU with a diagnosis of acute ITP … .
Neckelmann points out that Michael was a pro vaccine advocate. “That is why he got it himself,” she said. She is convinced that the vaccine caused her husband’s death.
She described Michael as “a very healthy 56 year old, loved by everyone in the community”.He delivered hundreds of healthy babies and worked tireless through the pandemic, she wrote.
In a statement to the South Florida Sun Sentinel, a spokesman for Pfizer said the company was aware of Michael’s death and said it was a “highly unusual clinical case”.
A spokesperson for Pfizer told CBS12 News: “We are actively investigating this case, but we don’t believe at this time that there is any direct connection to the vaccine. There have been no related safety signals identified in our clinical trials, the post-marketing experience thus far or with the mRNA vaccine platform.”
A Johns Hopkins scientist told the New York Times it was a “medical certainty” that Pfizer’s vaccine caused Michael’s death.
In an article for Case Reports in Hematology published in 2016, Joji Nagasaki et al. report on cases of ITP in three elderly patients that they say was caused by influenza vaccination.
“Influenza vaccination is an underlying etiology of ITP in elderly patients,” the researchers said. “Clinicians should be aware of the association between ITP and influenza vaccinations.”
Post-influenza vaccination ITP in elderly patients may occur within several days or two to three weeks after vaccination, Nagasaki et al. wrote.
ITP is associated with several types of vaccinations, Nagasaki et al. say.
Vaccine adjuvants have been implicated in autoimmune/inflammatory syndrome induced by adjuvants (ASIA), the researchers add.
“The Berlin Case-Control Surveillance Study of drug-associated ITP concluded that influenza vaccinations increase the risk of ITP. Twelve cases of postinfluenza vaccination ITP, including our three, have been reported. Features common to most reported cases include PAIgG elevation, time from vaccination to development of ITP, and treatment response.”
Case of ITP have also been linked with HPV vaccination. The manufacturer of Gardasil, Merck, has admitted that it seems “biologically plausible” that non-specific immune stimuli, including vaccinations, could precede cases of ITP in susceptible individuals, but insists that there is insufficient evidence to infer that HPV vaccination can cause the condition.
A large section of Merck’s June–to–December 2018 Periodic Safety Update Report (PSUR) is devoted to reports about people who, after HPV vaccination, developed ITP. There were 94 reports (76 for quadrivalent Gardasil and 18 for Gardasil 9).
Officials in Orange County, California, are meanwhile investigating the death of a 60-year-old healthcare worker who died four days after receiving his second injection of the Pfizer-BioNTech vaccine.
X-ray technologist Tim Zook was hospitalised on January 5 just hours after being vaccinated.
Zook’s wife Rochelle told the Orange County Register that her husband’s health rapidly deteriorated over the next few days. He died on January 9.
The Register reported that, a couple of hours after vaccination, Zook had an upset stomach and trouble breathing. He was taken to hospital and was put on oxygen, then, four hours later, a BiPAP machine was used to help push air into his lungs. Multiple tests came back negative for SARS-CoV-2.
Zook had to be put into in a medically induced coma and was placed on a ventilator, but his blood pressure dropped. His kidneys then started to fail and his condition became critical.
Rochelle Zook told the Register that her husband believed in vaccines, and that she didn’t blame “any pharmaceutical company” for his death, but she added: “When someone gets symptoms two and a half hours after a vaccine, that’s a reaction.”
She said Zook was “quite healthy”, but was slightly overweight and took medication for high blood pressure.
In an email to the Orange County Register, Pfizer said it was aware of Zook’s death and added: “We closely monitor all such events and collect relevant information to share with global regulatory authorities.
The company said that, based on ongoing safety reviews performed by Pfizer, BioNTech and health authorities, the vaccine retained a positive benefit-risk profile for the prevention of Covid-19 infections.
“Serious adverse events, including deaths that are unrelated to the vaccine, are unfortunately likely to occur at a similar rate as they would in the general population,” the company added.
Media in the US reported on February 8 that health officials in New York had confirmed that a man died shortly after getting the Covid-19 vaccine on February 7.
The man was reported to have collapsed as he was leaving the Hudson Yards vaccination site and died at in hospital a short time later.
New York State health commissioner Howard Zucker was quoted as saying: “Initial indications are that the man did not have any allergic reaction to the vaccine.”
The Los Angeles Times reported on January 26 that multiple agencies were investigating the death of a person on January 21 in Placer County.
Officials from the Placer County public health department and the Placer County Sheriff’s Office said that the deceased had tested positive for SARS-CoV-2 in late December and had been given a Covid vaccination several hours before he died.
A nurse, Sonia Azevedo, died in Portugal on January 1 after receiving the Pfizer-BioNTech vaccine on December 30. On January 5, the Portuguese Ministry of justice said that preliminary autopsy results did not establish a direct correlation between the administration of the vaccine and Azevedo’s death.
A 58-year-old doctor died at a private hospital in Karnataka, India, on January 20, just two days after he received a Covishield vaccination.
The Union Health Ministry said the death of T. A. Jayaprakash was due to cardiac arrest and was unrelated to the vaccination.
There have been numerous media reports about the number of deaths that occurred in Gibraltar in the ten days after vaccination with the Pfizer-BioNTech vaccine began.
It is reported that up until January 9, when the vaccination drive started, only 12 people had died from Covid-19 in Gibraltar since the beginning of the pandemic. However, from January 10 to 19, 53 deaths were attributed to the disease.
According to local media, there were 27 deaths attributed to Covid-19 in the first week after the vaccine rollout. Within a day of the vaccination drive starting, there were four deaths, all of elderly people.
The government of Gibraltar said on January 10: “It is with deep regret that the government confirms the deaths of four residents of Gibraltar from Covid-19. This brings the total number of deaths related to Covid-19 in Gibraltar to 16.
“The first was a male resident of Elderly Residential Services, aged 90–95 years old, who died last night of Covid-19 pneumonia with septicemia.
“The second was a man, aged 70–75 years old, who was also a cancer patient at the time of their death. The patient died today of Covid-19 pneumonitis.
“The third was a female resident of Elderly Residential Services, aged 90–95 years old, who died today from septicemia due to Covid-19.
“The fourth was a woman aged 95–100 years old, who died today of Covid-19 pneumonitis.”
The government continued to commend Covid vaccination, saying the vaccine’s rollout “brings us genuine relief and hope for a brighter tomorrow” and urged everyone to register their interest in being vaccinated.
VAERS lists the deaths of four elderly women that occurred in Kentucky nursing homes on the same day within hours of the women receiving the Pfizer-BioNTech vaccine.
Another VAERS report relates to the death on January 13 in Arizona of an 88-year-old woman who had arthritis and high blood pressure. She died the day after she received the Pfizer-BioNTech vaccine. The report states that the woman suffered initial pain in the back of her head, then “extreme headache” and vomiting. The report continued “At emergency, went into coma and was intubated. Hole drilled in skull to relieve pressure. MRI taken. Lot of bleeding in brain …” An aneurism lead to the woman’s death approximately 14 hours after her initial symptoms.
Another report relates to the death of a 28-year-old man with no pre-existing conditions or listed medications, who was “found unresponsive at work” in New Jersey 19 days after receiving a first dose of the Pfizer-BioNTech vaccine. It was the day he was due to receive his second dose. He died on January 11, 2021, after being intubated and suffering cardiac arrest.
Another relates to the death of an 88-year-old man in Florida who had no pre-existing conditions and had an adverse reaction on the day he received the Pfizer-BioNTech vaccine (January 16).
The report states that, within five to ten seconds after vaccination, the man patient started clenching his hands tightly and became unresponsive. He was lowered to the floor and did not exhibit a pulse.
“CPR was initiated and 911 was called,” the report continued. “An AED [automated external defibrillator] was used and healthcare professionals onsite continued compressions until the paramedics arrived.”
Another elderly man in Florida (aged 75). “became sick three hours after the vaccine and was found deceased one day after his vaccination”.
The website https://vaxpain.us/ also lists VAERS reports relating to Covid vaccination. On August 29, there were 443,046 total reports about adverse effects after Covid vaccination listed on the website.
There are 5,745 records of deaths after Covid vaccination. There are 252 records of death occurring on the same day as vaccination, 764 of death occurring within one day of vaccination, 2,011 records of death occurring within seven days of vaccination, 2,720 of death occurring within 14 days, and 3,776 of death occurring within 30 days.
Arutz Sheva (Israel National News), reported that a 75-year-old man from Beit Shean died from cardiac arrest on December 28 about two hours after being vaccinated with the Pfizer-BioNTech vaccine. Israel’s health ministry said initial investigation of the case showed no link between the man’s death and his vaccination.
The man received the vaccine at 8:30 a.m, and waited for the customary time at the health clinic before he was released to his home feeling well, Arutz Sheva reported, adding that, some time later, the man lost consciousness and was later confirmed dead from heart failure.
Arutz Sheva quoted the health ministry as saying the man suffered from heart disease and had had several heart attacks.
The publication also reported on the death of an 88-year-old man who collapsed in his home on December 29 a few hours after receiving a Covid vaccination and died later in hospital.
The man “suffered from prolonged, complex, and severe background illnesses”, Arutz Sheva quoted a hospital spokesperson as saying.
In an article published in The BMJ on January 15, Ingrid Torjesen reports that doctors in Norway have been told to conduct more thorough evaluations of very frail elderly patients in line to receive the Pfizer-BioNTech vaccine following the deaths of 23 patients shortly after receiving the vaccine.
Torjesen quotes the medical director of the Norwegian Medicines Agency (NOMA), Steinar Madsen, as saying: “It may be a coincidence, but we aren’t sure. There is no certain connection between these deaths and the vaccine.”
The agency has investigated 13 of the deaths so far and concluded that common adverse reactions of mRNA vaccines, such as fever, nausea, and diarrhoea, may have contributed to fatal outcomes in some of the frail patients, Torjesen reported.
“There is a possibility that these common adverse reactions, that are not dangerous in fitter, younger patients and are not unusual with vaccines, may aggravate underlying disease in the elderly,” Torjesen quotes Madsen as saying.
“We are now asking for doctors to continue with the vaccination, but to carry out extra evaluation of very sick people whose underlying condition might be aggravated by it,” Madsen is further quoted as saying.
This evaluation includes discussing the risks and benefits of vaccination with the patient and their families to decide whether or not vaccination is the best course, Torjesen wrote.
Pfizer said that Pfizer and BioNTech were working with NOMA to gather all the relevant information and all reported deaths would be thoroughly evaluated by NOMA to determine if they were related to the vaccine.
“The Norwegian government will also consider adjusting their vaccination instructions to take the patients’ health into more consideration,” Pfizer added.
In the briefing document the FDA released on December 8 it reports that two trial participants who received the Pfizer-BioNTech vaccine died. They were both more than 55 years of age.
The document was released ahead of the Vaccines and Related Biological Products Advisory Committee Meeting held on December 10.
It states: “A total of six (two vaccine, four placebo) of 43,448 enrolled participants (0.01%) died during the reporting period from April 29, 2020 (first participant, first visit) to November 14, 2020 (cutoff date). Both vaccine recipients were >55 years of age; one experienced a cardiac arrest 62 days after vaccination #2 and died three days later, and the other died from arteriosclerosis three days after vaccination #1.
“The placebo recipients died from myocardial infarction (n=1), hemorrhagic stroke (n=1) or unknown causes (n=2); three of the four deaths occurred in the older group (>55 years of age). All deaths represent events that occur in the general population of the age groups where they occurred, at a similar rate.”
Pfizer and BioNTech did not mention the deaths referred to in the FDA document in their own announcements in November and December.
Warnings over allergic reactions
In its information about safety precautions Pfizer states: “Severe allergic reactions have been reported following the Pfizer-BioNTech Covid-19 vaccine during mass vaccination outside of clinical trials. Additional adverse reactions, some of which may be serious, may become apparent with more widespread use of the Pfizer-BioNTech Covid-19 vaccine.”
A health care worker in Alaska developed a severe allergic reaction shortly after receiving the Pfizer-BioNTech vaccine on December 15 and had to be hospitalised overnight.
Health officials said the woman had no history of allergies and had never previously experienced anaphylaxis.
After two healthcare workers in the UK experienced an anaphylactoid reaction shortly after receiving the BNT162b2 vaccine, also known as tozinameran, the MHRA stated that any person with a history of anaphylaxis to a vaccine, medicine, or food should not receive it.
In an article published in the BMJ on 18 January 2021 Rebecca E. Glover et al. noted that the MHRA revised its position on December 30 “after careful consideration based on enhanced surveillance of over one million doses of the vaccine in the UK and North America –including in jurisdictions where people with serious allergies were never barred from receiving the vaccine”.
The MHRA found no evidence of an increased risk of anaphylaxis to the Pfizer-BioNTech vaccine among people with serious but unrelated allergy histories and advised that only people who had an allergic reaction to the first dose of this vaccine, or who previously had reactions to any of its components, should not receive it, Glover et al. noted.
The UK’s Commission on Human Medicines now recommends that “anyone with a previous history of allergic reactions to the ingredients of the vaccine should not receive it, but those with any other allergies such as a food allergy can now have the vaccine”.
The MHRA stated: “Widespread use of the vaccine now suggests that severe allergic reactions to the Pfizer/BioNTech vaccine are very rare (less than 1 in 10,000 people receiving this vaccine), and have been reported at a rate between 1 and 2 cases per 100,000 doses administered.”
The agency said on September 23 that, as of September 15, it had received 818 reports of “spontaneous adverse reactions associated with anaphylaxis or anaphylactoid reactions” after administration of the AstraZeneca-Oxford vaccine.
The MHRA said that these reactions were rare, but added that an update to the product information had been made “to reflect the fact that reports of anaphylaxis have been received for the Covid-19 Vaccine AstraZeneca”.
The agency said it had received 484 reports of “spontaneous adverse reactions associated with anaphylaxis or anaphylactoid reactions” after administration of the Pfizer-BioNTech vaccine.
“The nature and frequency of these reports is in line with that reported in previous updates, and severe allergic reactions to the Pfizer-BioNTech vaccine remain very rare,” the agency said. “The MHRA’s guidance remains that those with a previous history of allergic reactions to the ingredients of the vaccine should not receive it.”
Thirty-nine reports of anaphylaxis had been reported in association with the Moderna vaccine, the MHRA said. “Anaphylaxis is a potential side effect of the vaccine, and it is recommended that those with known hypersensitivity to the ingredients of the vaccine should not receive it,” the agency added.
The CDC says that anaphylaxis has occurred after Covid vaccination in approximately two to five people per million vaccinated in the US.
On VAERS, updated on September 24 with data up to September 17, 5,552 reports of anaphylactic reaction are listed.
Polyethylene glycol (PEG 2000) is the only excipient in the Pfizer-BioNTech vaccine that is a known potential allergen, Glover et al. wrote.
“The Oxford-AstraZeneca vaccine does not contain PEG 2000 so remains an alternative for people with a history of allergy to this ingredient. However, there is some cross-reactivity between PEG and polysorbate 80, an ingredient in the Oxford-AstraZeneca vaccine, so evaluation by an allergy specialist may be advisable before vaccination in anyone with a suspected PEG allergy history,” they added.
“Allergists can assess patients who report allergy to a vaccine, injectable medication, or PEG and triage them into those able to go ahead with vaccination with the routine 15 minutes of observation, those requiring 30 minutes of observation, and those who require skin testing to PEG and polysorbate before vaccination.”
Andre Watson has doubts about PEG being the culprit in people’s allergic reactions to Covid vaccination.
Watson says that, in the case of SARS-CoV-2, there are about 100 spikes per virus. “Each of the spikes is pointing in a very specific direction and only the very tip of the spike sticks to the ACE2 receptor and should be bound by neutralising antibodies.
“If you cut off the spike and just throw it into circulation, it will face random directions and you may develop many of the wrong antibodies preferentially. The neutralising ones may decline disproportionately to other epitopic, or immune binding, sites.
Watson cites the example of someone who already has a history of allergies, and perhaps has a relative ratio of too many Th2 cells versus Th1 cells.
“If the Th2 cells generate a stronger response to portions of the spike protein or other parts of the virus – and perhaps the vaccine creates this in a way that isn’t seen as much with the virus itself – then the person can get an allergic reaction that cross reacts with some other similar sequence in their body.”
Watson says that old-fashioned vaccines would be more effective than the ones developed in the US.
In Watson’s view, it is the live attenuated and virus-like particle approaches that are most likely to be successful, “or whatever presents the spike protein on the surface facing the right way, just like the virus does”.
In the case of live attenuated vaccines against SARS-CoV-2, the virus is grown in cells and is genetically weakened using targeted mutations so that it can’t infect cells and reproduce effectively.
No potential live attenuated vaccine against SARS-CoV-2 has yet made it to the stage of human trials.
Disease enhancement
Atomic-level structure of the spike protein of SARS-CoV-2. Credit: McLellan Lab, University of Texas at Austin.
Andre Watson is concerned about possible antibody-dependent enhancement (ADE), in which a person’s body pumps out antibodies that bind to the virus but don’t neutralise it, and vaccine-associated enhanced respiratory disease (VAERD).
“This has been observed before with spike protein vaccines and SARS-CoV-1 and MERS-CoV, in the sense of vaccine-associated enhanced respiratory distress.”
There is a real possibility that some or many vaccines, especially spike protein vaccines, may make infection worse, especially if neutralising antibody titers decline while off-target antibodies remain highly produced, Watson (pictured left) says.
“This would be made possible by the burying of the spike protein neutralising antibody binding site by ACE2, which binds extremely strongly and we have demonstrated in our lab is capable of inhibiting antibody binding to this site.”
Research scientist James Lyons-Weiler wrote in an article published in March: “In SARS, a type of ‘pathogenic priming’ of the immune system was observed during animal studies of SARS spike protein-based vaccines.
“The exposure of vaccinated animals to the SARS virus led to increased morbidity and mortality. The problem, highlighted in two studies, only became obvious following post-vaccination challenge with the SARS virus.”
Lyons-Weiler added: “SARS-CoV-2 is the sister taxon of SARS-CoV. If pathogenic priming is to occur in humans given spike-protein based SARS-CoV-2 vaccine, as is expected given the SARS spike protein animal studies, the 20% mortality rate expected in the elderly could raise to 40% – and the rest of the population could be sensitised and we could see mortality rates worldwide of the next coronavirus higher than 20%.”
In an article published in the International Journal of Clinical Practice on October 28, 2020, Timothy Cardozo, from the Department of Biochemistry and Molecular Pharmacology at the NYU Langone Health academic medical centre in New York and Ronald Veazey from the Department of Pathology and Laboratory Medicine at the Tulane University School of Medicine, Covington, Louisiana, warn about ADE and call for improved informed consent procedures for Covid vaccination.
They say the risk of ADE in Covid‐19 vaccination is “non‐theoretical and compelling”.
“Vaccines for SARS, MERS and RSV have never been approved, and the data generated in the development and testing of these vaccines suggest a serious mechanistic concern: that vaccines designed empirically using the traditional approach (consisting of the unmodified or minimally modified coronavirus viral spike to elicit neutralising antibodies), be they composed of protein, viral vector, DNA or RNA and irrespective of delivery method, may worsen Covid‐19 disease via antibody‐dependent enhancement (ADE).”
Cardozo and Veazey reviewed published literature to identify preclinical and clinical evidence that Covid‐19 vaccines could worsen disease upon exposure to challenge or circulating virus. Clinical trial protocols for Covid‐19 vaccines were reviewed to determine if risks were properly disclosed.
“Given the strong evidence that ADE is a non‐theoretical and compelling risk for Covid‐19 vaccines and the ‘laundry list’ nature of informed consents, disclosure of the specific risk of worsened Covid‐19 disease from vaccination calls for a specific, separate, informed consent form and demonstration of patient comprehension in order to meet medical ethics standards.”
Vaccine‐elicited enhancement of disease was previously observed in human subjects with vaccines for respiratory syncytial virus (RSV), dengue virus and measles, Cardozo and Veazey point out. Vaccine‐elicited enhancement of disease was also observed with the SARS and MERS viruses and with feline coronavirus.
A prophylactic and a therapeutic
Andre Watson’s company is developing peptides that mimic just the very tip of the spike protein and are showing early results of being able to inhibit viral binding to the ACE2 receptor while stimulating an immune response.
Watson and his colleagues published a pre-print paper on bioRxiv on August 6, 2020, about Ligandal’s peptide antidotes.
They said that their peptide scaffolds demonstrated promise for future studies evaluating the specificity and sensitivity of immune responses to their antidote-vaccine.
Watson et al. said that Ligandal’s peptides were able to “potently and competitively” inhibit the SARS-CoV-2 spike protein receptor binding domain (RBD) binding to ACE2, which is the main cellular entry pathway for SARS-CoV-2, “while also binding to neutralising antibodies against SARS-CoV-2”.
They added: “In summary, SARS-BLOCK™ peptides are a promising Covid-19 antidote designed to combine the benefits of a therapeutic and vaccine, effectively creating a new generation of prophylactic and reactive antiviral therapeutics whereby immune responses can be enhanced rather than blunted.”
Watson says the spike protein vaccines are of concern to him because of the issue of immune shielding (the ability of the virus to shield itself from a person’s immune system).
“All five of the vaccines that the US has put more than $2 billion into through BARDA [the Biomedical Advanced Research and Development Authority], which are the Moderna RNA vaccines and also some viral-based vaccines, they all produce a spike protein; they’re all going to have the same issue. I have a little bit more hope for Novavax because at least their spike protein is presenting the right way.
With the approach that’s being taken by the big pharmaceutical companies, Watson says, the strongest antibody responses are likely being generated against the sides of the spike protein, not against the tip, because these spike proteins exhibit the same ACE2 binding and immune-shielding effect.
“With our approach, the virus can be seen by your antibodies and your B cells and you can get a neutralising response. You can actually generate that response preferentially as opposed to generating a response against parts of the spike protein you don’t want to be targeted.
This transmission electron microscope image shows SARS-CoV-2, isolated from a patient in the US, emerging from the surface of cells cultured in the lab. Photo courtesy of NIAID.
Watson says he is particularly concerned about viral-based vaccines. Citing AstraZeneca’s Covid vaccine he said: “If you already have antibodies against a particular viral vector, your body will clear that virus out. When you receive a second vaccine dose, you’ll generate an immune response to the viral vector that encodes the SARS-CoV-2 DNA.
The potential problem with immune reactions to the viral vector is the reason AstraZeneca is testing a combination of its vaccine with Sputnik V, Watson says. “They have realised that they need to give a second dose and those vaccinated will be immune to the viral vector used for the first dose.”
There have been reports that Russia is set to launch the ‘Sputnik Light’ version of Sputnik V for export.
The Reuters news agency quoted Kirill Dmitriev, who is the head of the RDIF, as saying that the two-dose vaccine would remain the main version used within Russia. The fund is responsible for marketing Sputnik V abroad,
According to Reuters, some Russian manufacturers are finding the second vector less stable to produce, leading to a surplus of the first component.
Russia’s TASS news agency has quoted the director of the Gamaleya National Research Center for Epidemiology and Microbiology, Alexander Gintsburg, as saying that protective immunity after just the first dose of Sputnik V lasts about three to four months.
Reuters reported that, in December, Russia shipped 300,000 vials of the Sputnik V vaccine to Argentina. The shipment was made up only of the first component, drawn from this surplus batch, the agency reported.
Brazil postpones Sputnik V importation approval
On April 26, the National Health Surveillance Agency (Anvisa) in Brazil decided not to approve the importation of Sputnik V, which has been requested by ten states.
Anvisa said that replication-competent adenovirus (RCA) was found in batches of the vaccine.
Replication-competent virus particles are capable of infecting cells and replicating to produce additional infectious particles.
The RDIF and the Gamaleya research centre said Anvisa’s decision was “of a political nature and has nothing to do with the regulator’s access to information or science”.
The Sputnik V team said the existing quality controls ensured that no RCA could exist in its vaccine.
On April 30, the Gamaleya institute issued a statement to clarify issues related to what it describes as “the ongoing disinformation campaign against Sputnik V”.
The institute described allegations by Anvisa that it had detected RCA in Sputnik V as “inaccurate and misleading”.
The Gamaleya institute says Anvisa has now admitted that it did not undertake any tests of the Sputnik V vaccine “and was referring to a regulatory limit in Russia on potential RCA presence”.
It said that no RCA was detected in any of the batches of the Sputnik V vaccine and add that this information was sent to Anvisa on March 26.
The institute sent an official letter dated March 26, 2021, that stated: “In addition, we would like to inform you that during the release of the vaccine product at the centre site and at the contract site of JBC Generium, not a single batch containing RCA was recorded.”
The institute said it had clarified to Anvisa that the limit used for quality control of the Sputnik V vaccine was much stricter than the allowed regulatory limit in Russia and corresponded to the strictest standards of world regulators.
“That strict limit has been confirmed by 64 of the world’s regulators that authorised Sputnik V,” the institute said.
The institute says that Anvisa did not attempt to clarify any of these issues after its visit “and their inaccurate statements could have been avoided simply by asking for the Gamaleya institute to comment”.
It added: “The Gamaleya Institute regrets that unethical forces continuously attack the Sputnik V vaccine for competitive and political reasons costing lives and undermining the world vaccination programme.”
Anvisa said that that the presence of RCA could lead to infections in humans and “can cause damage and death, especially in people with low immunity and respiratory problems, among other health problems”.
The agency said that consistent and reliable data about Sputnik V was lacking and the evaluation of available data pointed to “flaws in the development and production of the vaccine”.
Anvisa added: “There is an absence or insufficiency of data on quality control, safety, and efficacy of the product.”
According to Brazil’s General Management of Medicines and Biological Products (GGMED), flaws in the development of Sputnik V were identified in all stages of the clinical studies (phases 1, 2, and 3), Anvisa said.
“Inadequate characterisation studies of the vaccine were detected, including with regard to the analysis of impurities and contaminating viruses during the manufacturing process,” the agency said.
Anvisa also said that there was a lack of toxicity testing to see if the vaccine might be harmful to reproductive cells.
The agency also says too little is known about short-, medium-, and long- term adverse effects resulting from use of the Sputnik V vaccine.
To date, 14 states have sent import orders for the Sputnik V vaccine to Anvisa.
The Sputnik V team said the Brazilian regulator’s decision contradicted a previous decision by the Ministry of Science, Technology and Innovation, “which recognised the Sputnik V vaccine as safe and allowed its production in Brazil”.
The Sputnik V team said: “The quality and safety of Sputnik V are, among other things, guaranteed by the fact that, unlike other vaccines, it uses a four-stage purification technology that includes two chromatography stages and two tangential flow filtration stages.
The Federal Supreme Court in Brazil will review Anvisa’s decision and hear a motion from seven Brazilian states whose governments want to accelerate their vaccination programmes.
It’s been reported that Anvisa’s decision doesn’t affect a separate request from the Brazilian company União Química for emergency use authorisation of Sputnik V that is produced locally.
On March 29, Brazil’s General Manager of Sanitary Inspection and Inspection denied a request from the Indian company Bharat Biotech for certification of good manufacturing practices for its vaccine Covaxin.
The step is a prerequisite for drug manufacturers to receive authorisation for the emergency use of a vaccine, or for definitive registration. Anvisa carried out an inspection of Bharat Biotech’s factory in India in early March.
Dangers of vaccinating SARS-CoV-2 carriers
On January 26, 2021, Hooman 
Noorchashm wrote a ‘letter of warning’ to the FDA And Pfizer about “the immunological danger of Covid-19 vaccination in the recently convalescent and asymptomatic carriers”.
He had earlier written a ‘public letter of warning’ to the medical director of The Massachusetts Department of Public Health, Larry Madoff, about what he described as “a potentially high immunological risk to asymptomatic SARS-CoV-2 carriers who non-selectively receive the 2020 influenza vaccine (or any other vaccine)”.
Noorchashm, who makes clear that he is not taking an anti-vaccination stance, says no one who has has natural immunity from a prior SARS-CoV-2 infection should receive a Covid vaccination. He has described the vaccination of already immune children as an “intolerable act of public health negligence”.
He says it is his sincere hope that his most recent emailed letter “might stimulate FDA, Pfizer and Moderna leaders to think critically and quickly about the immunological danger the Covid-19 vaccine might pose to the recently convalescent or asymptomatic carriers of SARS-CoV-2 –most especially to those who are elderly, frail or have significant cardiovascular risk factors”.
He says he wants to make clear that his warning is based on a “near definitive scientific immunological prognostication” that he has put forth “in the absence of clear ‘evidence’ of it being a material risk”. He says he is “an ardent supporter of President Biden’s plan to vaccinate 150 million Americans in 100 days”.
Noorchashm points out that the SARS-CoV-2 virus has tropism for the vascular endothelium, among other tissues and organs.
It seems that endothelial injury from the virus or from the inflammatory reaction it incites is the reason why many Covid-19 patients experience thromboembolic complications, Noorchashm writes.
“So it is a matter of certainty that viral antigens are present in the endothelial lining of blood vessels in all persons with active or recent SARS-CoV-2 infection – irrespective of whether they are symptomatic or convalescent.”
Noorchashm warns that “it is an almost certain immunological prognostication that, if viral antigens are present in the tissues of subjects who undergo vaccination, the antigen-specific immune response triggered by the vaccine will target those tissues and cause tissue inflammation and damage”.
When viral antigens are present in the vascular endothelium, and especially in elderly and frail people with cardiovascular disease, the antigen-specific immune response incited by the vaccine is almost certain to do damage to the vascular endothelium, Noorchashm says.
“Such vaccine-directed endothelial inflammation is certain to cause blood clot formation with the potential for major thromboembolic complications, at least in a subset of such patients.
Noorchashm asks the FDA, in collaboration with Pfizer and Moderna, to immediately, “and at the very minimum”, issue clear recommendations to clinicians to delay vaccinating any recently convalescent Covid patients as well as any known symptomatic or asymptomatic carriers and to actively screen as many patients with high cardiovascular risk as is reasonably possible in order to detect the presence of SARS-CoV-2 prior to vaccinating them.
Noorchashm also highlights the case of Hank Aaron, “a giant in the black American struggle and a hero to America’s civil rights movement”, who died, aged 86, of a massive stroke on January 22 this year, 17 days after receiving the Moderna Covid vaccine.
Aaron (pictured left), who is regarded as one of the greatest baseball players of all time, had medical co-morbidities and likely met the medical definition of “frailty”, Noorchashm wrote in an article on Medium.
Noorchashm says he doesn’t personally believe that the Moderna vaccine caused Aaron’s death. “It is entirely likely that Hank Aaron’s death from a massive stroke has nothing to do with his vaccine dose,” he said. “86-year-olds with his health profile have massive strokes every day across the country.”
He adds, however: “I do believe that we ought to take Mr Aaron’s death following Covid-19 vaccination very seriously – and to do our best to help the public make sense of it.
“We do this through logical, respectful and scientifically based discourse – not just with experts, but even more importantly, with the general public. And in the case of Mr Aaron’s death, with the black community in America.”
It is an immunological possibility, Noorchashm says, that Aaron was an asymptomatic carrier of SARS-CoV-2, and that the vaccine may have exacerbated a local vasculitis that led to an acute thrombotic event, i.e. a blood clot in the blood vessels to or in his brain that led to his stroke.
It would be reasonable for Aaron’s family and community to ask his local health authorities, the FDA and Moderna to perform assays on his remaining tissues and see if he was a carrier of SARS-CoV-2, Noorchashm says.
“In general, I believe that it is logical and safest to delay vaccination in any known asymptomatic carriers of the virus by a few months, especially if they are found to have antibodies – and, certainly, I would screen all frail patients or those with cardiovascular co-morbidities for Covid-19, before vaccinating them.
Frequency of grade 3 adverse events ‘higher than for most vaccines’
Peter Doshi noted in an article published in the New York Times on January 7, 2021, that, with the Moderna vaccine, the frequency of grade 3 adverse events – those severe enough to prevent daily activity – was higher than it was for most vaccines: 17.4 percent, or nearly one in five 18-to-64-year-olds who received two doses of the vaccine in the company’s trial.
FDA briefing document about the Moderna vaccine
Cell signalling
On January 11, Yuichiro J. Suzuki from the Georgetown University Medical Centre, Washington, DC, in the US and Sergiy G. Gychka from Bogomolets National Medical University, Kiev, in Ukraine published an article entitled ‘SARS-CoV-2 Spike Protein Elicits Cell Signalling in Human Host Cells: Implications for Possible Consequences of Covid-19 Vaccines’.
They proposed that the SARS-CoV-2 spike protein (without the rest of the viral components) triggers cell signalling events “that may promote pulmonary vascular remodelling and PAH [pulmonary arterial hypertension] as well as possibly other cardiovascular complications”.
The two researchers said the advancement in spike protein-based Covid-19 vaccine development was exciting and had “shed light on how to end the current pandemic” and the vaccines “should benefit elderly people with underlying conditions if they do not exhibit any acute adverse events”.
Suzuki and Gychka cite research by Kuba et al. that showed that the injection of mice with recombinant SARS-CoV-1 spike protein reduced ACE2 expression and worsened acid-induced lung injury.
“In mice with an acid-induced lung injury, the recombinant SARS-CoV-1 spike protein dramatically increased angiotensin II, and the angiotensin receptor inhibitor losartan attenuated the spike protein-induced enhancement of lung injury,” Suzuki and Gychka wrote.
Suzuki and Gychka also refer to research by Patra et al. who show that the SARS-CoV-2 spike protein without the rest of the viral components activates cell signalling.
“This cell signalling cascade was found to be triggered by the SARS-CoV-2 spike protein downregulating the ACE2 protein expression, subsequently activating the angiotensin II type 1 receptor,” Suzuki and Gychka wrote.
The two researchers say their results “collectively reinforce the idea that human cells are sensitively affected by the extracellular and/or intracellular spike proteins though the activation of cell signal transduction”.
They said they found that, in contrast to the full-length spike protein or the full-length SARS-CoV-2 spike protein S1 subunit, protein that only contained the RBD did not promote cell signalling.
“It is generally thought that the sole function of viral membrane fusion proteins is to allow the viruses to bind to the host cells for the purpose of viral entry into the cells, so that the genetic materials can be released and the viral replication and amplification can take place,” Suzuki and Gychka wrote.
Suzuki and Gychka only tested the effects of the SARS-CoV-2 spike protein in lung vascular cells and those implicated in the development of PAH. However, they said, the spike protein may also affect the cells of systemic and coronary vasculatures, eliciting other cardiovascular diseases such as coronary artery disease, systemic hypertension, and stroke.
“Thus, it is important to consider the possibility that the SARS-CoV-2 spike protein produced by the new Covid-19 vaccines triggers cell signalling events that promote PAH, other cardiovascular complications, and/or complications in other tissues/organs in certain individuals.”
Researchers at the Old Dominion University in Norfolk, Virginia, in the US have meanwhile discovered that the SARS-CoV-2 spike protein alone is enough to induce Covid-like symptoms in mice, including severe inflammation of the lungs.
Pavel Solopov, who is an assistant professor at the Frank Reidy Research Center for Bioelectrics at the university, said the researchers’ findings showed that the SARS-CoV-2 spike protein caused lung injury even without the presence of the intact virus
Solopov is presenting the new research at the annual meeting of the American Society for Pharmacology and Experimental Therapeutics during the virtual Experimental Biology 2021 meeting, being held from April 27–30.
Solopov explained that studying SARS-CoV-2 could be challenging because experiments involving the intact virus requires a Biosafety Level 3 laboratory. The researchers therefore used transgenic mice that expressed the human receptor for SARS-CoV-2 in their lungs.
“Our mouse model dramatically reduces the danger of doing this type of research by allowing Covid-19 lung injury to be studied without using the intact, live virus,” Solopov said.
The researchers injected the genetically modified mice with a segment of the spike protein and analysed their response 72 hours later. Another group of mice received only saline as as a control.
The scientists found that the genetically modified mice injected with the spike protein exhibited Covid-19-like symptoms that included severe inflammation, an influx of white blood cells into their lungs, and evidence of a cytokine storm. The mice that only received saline remained normal.
The left image shows healthy mouse lung tissue and the right one shows tissue from mouse lungs exposed to the spike protein. Photo credit: Pavel Solopov.
Vaccination during pregnancy
On January 25, the WHO issued interim guidance for use of the Moderna mRNA-1273 vaccine. It recommended that mRNA-1273 not be used during pregnancy, “unless the benefit of vaccinating a pregnant woman outweighs the potential vaccine risks, such as in health workers at high risk of exposure and pregnant women with comorbidities placing them in a high-risk group for severe Covid-19”.
On November 29 it did an about-turn and said that, while very little data are available to assess vaccine safety in pregnancy. “based on what we know about this kind of vaccine, we don’t have any specific reason to believe there will be specific risks that would outweigh the benefits of vaccination for pregnant women”.
The WHO now says that those pregnant women at high risk of exposure to SARS-CoV-2 (e.g. health workers) or who have comorbidities that add to their risk of severe disease “may be vaccinated in consultation with their health care provider”.
In the guidance it issued on January 25, the WHO said: “The available data on mRNA-1273 vaccination of pregnant women are insufficient to assess vaccine efficacy or vaccine-associated risks in pregnancy.
However, it should be noted that the mRNA-1273 vaccine is not a live virus vaccine, and the mRNA does not enter the nucleus of the cell and is degraded quickly. Developmental and reproductive toxicology (DART) studies in animals have not shown harmful effects in pregnancy. Further studies are planned in pregnant women in the coming months.”
The EMA states: “There is limited experience with use of Covid-19 Vaccine Moderna in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or post-natal development. Administration of Covid-19 Vaccine Moderna in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and foetus.”
Neither Moderna nor Pfizer enrolled pregnant women in their Covid-19 vaccine trials. Moderna says it plans to establish a registry to study pregnancy outcomes in mothers and infants.
Pfizer and BioNTech announced on February 18 that the first participants in a Phase 2/3 study to evaluate the safety, tolerability, and immunogenicity of their Covid vaccine for pregnant women had received their initial vaccine dose.
Participants are being vaccinated when they are 24 to 34 weeks pregnant. They will receive two doses of BNT162b2 or a placebo, administered 21 days apart.
About 4,000 participants will be enrolled at more than 130 sites in the US, Canada, Brazil, Chile, Mozambique, South Africa, the UK, and Spain.
Each woman will participate in the study for approximately seven to ten months, depending on whether she was randomised to receive the vaccine or a placebo.
The infants of the vaccinated women will be studied to assess vaccine safety and examine whether the women transferred antibodies to their babies.
The infants will be monitored until they are about six months old. After a trial participant’s infant is born, she will be unblinded and those who were in the placebo group will be offered the vaccine.
Pfizer and BioNTech say that, prior to conducting their trial involving pregnant women, they completed a developmental and reproductive toxicity (DART) study of BNT162b2, which they say “showed no evidence of fertility or reproductive toxicity in animals”.
Pfizer says that, currently, available data “are insufficient to inform vaccine-associated risks in pregnancy”.
Outcry over delayed 2nd dose
In Britain there has been an outcry over the government’s decision to delay administration of second doses of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines. There are fears that this could create a favourable terrain for further virus mutations and spread.
The British government followed the advice of the JCVI that the priority should be to give as many people in at-risk groups their first dose, rather than providing the required two doses in as short a time as possible.
The UK’s four chief medical officers said they agreed with the JCVI’s recommendation. “Operationally this will mean that second doses of both vaccines will be administered towards the end of the recommended vaccine dosing schedule of 12 weeks,” they said. This would maximise the number of people getting vaccinated.
The non-profit advocacy group, the Doctors’ Association UK, tweeted: “We have real and grave concerns about these sudden changes to the Pfizer vaccine regime. It undermines the consent process, as well as completely failing to follow the science.”
The association wrote to the Health Secretary Matt Hancock, NHS England, and the JCVI, saying that frontline staff that were concerned about the change, which the doctors’ association described as an “untested strategy” that is not based on the evidence published so far by the pharmaceutical companies who have produced these vaccines.
Pfizer said on December 31 that the Phase 3 trial for its Covid vaccine was designed to evaluate the vaccine’s safety and efficacy following a two-dose schedule, separated by 21 days.
“The safety and efficacy of the vaccine has not been evaluated on different dosing schedules as the majority of trial participants received the second dose within the window specified in the study design,” the company said.
“Data from the Phase 3 study demonstrated that, although partial protection from the vaccine appears to begin as early as 12 days after the first dose, two doses of the vaccine are required to provide the maximum protection against the disease, a vaccine efficacy of 95%. There are no data to demonstrate that protection after the first dose is sustained after 21 days.”
The BMA, which represents general practitioners across the UK tweeted. “The decision to delay follow-up dose of Pfizer vaccine is grossly unfair to thousands of at-risk patients in England, as appointments are rescheduled. It will have a terrible emotional impact on many patients.”
AstraZeneca published data on February 3, 2021, suggesting that longer gaps between the 1st and 2nd vaccine doses may be associated with higher efficacy.
In a preprint published in The Lancet, a group of researchers from Britain, Brazil, and South Africa, including 15 from the Oxford Vaccine Group and the co-founder of Vaccitech, Sarah C. Gilbert, said that vaccine efficacy from day 22 to day 90 after a first single standard dose was 76%, with protection maintained until administration of the second dose.
“These analyses show that higher vaccine efficacy is obtained with a longer interval between the first and second dose, and that a single dose of vaccine is highly efficacious in the first 90 days,” the researchers said.
“Antibody levels were maintained during this period with minimal waning by day 90.”
Reporting on the Phase 3 clinical trials in the UK and Brazil and phase 1/2 trials in the UK and South Africa the researchers said efficacy after the 2nd dose was higher when there was a longer gap between doses.
Efficacy with an inter-dose interval of 12 weeks or more was 82.4% compared with 54.9% if the gap was less than six weeks.
In people aged between 18 and 55 years there was reported to be double the antibody binding response after the longer gap.
The primary analysis was based on 17,177 participants and a total of 332 symptomatic cases of Covid-19 that occurred more than 14 days after the second vaccine dose in the three trials.
The standard dose in the AZD1222 trials was approximately 5×1010 viral particles, but a subset (1,367 people) in the UK received a half dose as their first dose, followed by a full second dose.
“This was because of differences in the results of quantification methods between batches of the vaccine,” researchers stated in a report on December 8.
“The low-dose/standard-dose group did not include adults over the age of 55 years as the low-dose was given in an early stage of the trial before recruitment of older adults had commenced.”
AstraZeneca announced on November 23 that its vaccine was 90% effective when given as a half dose followed by a full dose at least one month later.
The company said the vaccine was 62% effective when given as two full doses at least one month apart.
The combined analysis from both dosing regimens resulted in an average efficacy of 70%, AstraZeneca said. The evaluation relates to a total of 131 cases of Covid-19 that were confirmed during the trial and an analysis of how many of those cases occurred among those vaccinated and how many occurred among those given the meningococcal conjugate vaccine MenACWY or a saline placebo.
The company said there were no hospitalisations or severe cases of Covid-19 in participants treated with its vaccine.
In the latest report, overall vaccine efficacy more than 14 days after the second dose is put at 66.7%. (This calculation relates to all cohorts in the trials, including participants in the UK who received a reduced dose.)
In the cohort that received a standard dose, 74 Covid-19 cases occurred in the vaccinated group and 197 in the control group, and there were 61 cases among those who received a reduced first dose.
There were 130 cases of asymptomatic infection occurring more than 14 days after the second vaccine dose (UK cohort only). In the cohort that received standard doses there was no evidence of protection (41 cases in the vaccinated group versus 42 in the control group).
In the cohort in which vaccinees received a reduced first dose, there were 47 cases (16 in the vaccinated group versus 31 in the control group).
The researchers said there were no severe cases of Covid-19 during the trials, and no hospitalisations in the vaccinated group after 21 days following the first dose.
From the day of the first vaccination, there were two hospitalisations in the vaccinated cohort and 22 in the control group.
AstraZeneca says researchers have seen a first indication that its vaccine reduces virus transmission by up to 67%.
“The analysis also showed the potential for the vaccine to reduce asymptomatic transmission of the virus, based on weekly swabs obtained from volunteers in the UK trial,” the researchers reported.
“The data showed that PCR positive readings were reduced by 67% … after a single dose, and 50% … after the two-dose regimen.”
There was an overall reduction in PCR positive readings of 54.1%, indicating the potential for a reduction of transmission with a regimen of two standard doses, the researchers said.
The researchers concluded that vaccinating a large proportion of the population with a single dose, with a second dose given after three months was “an effective strategy for reducing disease, and may be the optimal for rollout of a pandemic vaccine when supplies are limited in the short term”.
The chief investigator of the Oxford Vaccine Trial, Andrew Pollard, who is a co-author of the paper in The Lancet, said the new data supported the JCVI’s recommendation that there should be a 12-week interval between vaccine doses.
Israeli researchers from the Clalit Research Institute found that one dose of the Pfizer-BioNTech vaccine appeared to be less effective than expected.
The researchers compared infection data relating to 200,000 people people aged 60 and above who were not vaccinated with that of 200,000 people of the same age group who received one dose of the vaccine and were monitored for at least 11 days from the date of vaccination.
On day 14 post vaccination there was a “significant decrease” of about 33% in the number of positive tests for SARS-CoV-2 among those who had been vaccinated, the researchers found. This decrease remained the same between days 15 and 17.
“The report has raised concerns, as published results have suggested that the efficacy of the Pfizer vaccine was 52.4% between the first and second dose (spaced 21 days apart), and data assessed by Public Health England indicated it could be as much as 89% protective from day 15 to 21,” Elisabeth Mahase wrote in The BMJ on January 22.
She added that the Clalit Research Institute’s results included only people aged 60 and over, whereas the Pfizer trials also included younger people. Also, she said, the institute’s findings had not yet been peer reviewed.
“Additionally, the Clalit study identified those infected according to laboratory tests of those who chose to be tested, while Pfizer’s studies only referred to the appearance of symptomatic disease.”
Data from Israel
Israel’s vaccination drive began on December 19, 2020. While researchers reported indications of decreased SARS-CoV-2 infection and fewer Covid-19 cases after vaccination, the number of severe Covid-19 cases, daily SARS-CoV-2 infections, and total active Covid-19 cases reached all-time peaks in Israel in January.
Vaccinations with the Pfizer-BioNTech vaccine began amid a surge of infections that led to a national lockdown on December 27, 2020. Daily infections peaked at 10,213 cases on January 20, 2021, and lockdown was lifted on March 7.
By April 3, 72% of people aged over 16 years (4,714,932 of 6,538,911) and 90% of those over 65 years (1,015,620 of 1,127,965) had received two doses of the Pfizer-BioNTech vaccine.
In a report published in The Lancet on May 5, Eric J. Haas et al. said nationwide data in Israel showed that two doses of the Pfizer-BioNTech vaccine were more than 95% effective against infection, hospitalisation, and death from Covid-19, including among the elderly, at a time when the B.1.1.7 variant was the dominant strain.
Israel is the country with the second highest proportion of its population vaccinated in the world. According to the Bloomberg vaccine tracker, 57.9% of the vaccine-eligible population in Israel has been vaccinated, as compared with 66.5% in the Seychelles. (Bloomberg calculates vaccine coverage by dividing the number of doses administered for each vaccine type by the number of doses required for full vaccination.)
The researchers’ analysis indicated that the vaccine provided 95.3% protection against infection and 96.7% protection against death seven days after the second dose. Protection against symptomatic and asymptomatic infection was 97.0% and 91.5%, respectively, they said.
The vaccine was shown to provide 97.2% protection against hospitalisation overall and 97.5% protection against severe and critical hospitalisation, they added.
By 14 days after vaccination, the protection conferred by a second dose increased to 96.5% against infection, 98.0% against hospitalisation, and 98.1% against death, Eric J. Haas et al. reported.
Eric J. Haas et al. reported that protection was considerably lower between seven and 14 days after administration of the first vaccine dose: 57.7% protection against infection, 75.7% protection against hospitalisation, and 77.0% protection against death.
The observational study was conducted by researchers from Israel’s Ministry of Health, Pfizer Pharmaceuticals Israel, and Pfizer USA.
Eight of the 15 authors of the report declared that they held stock and stock options in Pfizer.
Haas et al. said that, while their findings were encouraging, challenges to controlling the Covid-19 pandemic remained.
They said that, despite indications of at least partial effectiveness after one dose of BNT162b2, relying on protection against Covid-19 from a single dose might not be prudent.
“BNT162b2 was developed and evaluated in the RCT [randomised controlled trial] as a two-dose schedule, and substantially lower levels of neutralising antibodies were observed after one dose compared with after two doses,” the researchers wrote.
“Additionally, little is known about the duration of protection of one dose and how it compares with the durability after two doses. It is possible that one dose will provide a shorter duration of protection than two doses, particularly in an environment where new SARS-CoV-2 variants continue to emerge.”
Haas et al. used national pandemic surveillance data recorded by Israel’s Ministry of Health to calculate adjusted vaccine effectiveness.
Data was analysed in groups based on age. The average follow-up time for people who received two vaccine doses was 48 days.
During the analysis period, there were 232,268 confirmed SARS-CoV-2 infections in the country. B.1.1.7 accounted for 94.5% of specimens tested (8,006 of 8,472 specimens).
A total 66.6% of the infections were in people aged over 16 years. There were 7,694 hospitalisations (in 4,481cases, the illness was severe and, in 188 cases, the patient’s condition was critical). There were 1,113 deaths.
Haas et al. say that protection among the elderly was as strong as that for younger people, with analysis indicating that people aged over 85 years had 94.1% protection against infection, 96.9% protection against hospitalisation, and 97% protection against death seven days after the second vaccine dose.
They said that people aged between 16 and 44 years had 96.1% protection against infection, 98.1% protection against hospitalisation, and 100% protection against death.
Haas et al. say that declines in SARS-CoV-2 infections for each age group corresponded with achieving high vaccine coverage in that age group rather than initiation of the nationwide lockdown.
“These findings suggest that the primary driver of reductions in the incidence of SARS-CoV-2 infections was high vaccine coverage, not implementation of the lockdown,” they wrote. “Furthermore, even after reopenings occurred, SARS-CoV-2 incidence remained low, suggesting that high vaccine coverage might provide a sustainable path towards resuming normal activity.”
The report’s authors say that, given the differences in the way vaccines are rolled out in different countries, and how the pandemic evolves, caution should be used in extrapolating their findings to other nations.
They say their study has some limitations. “In the absence of randomisation, there could have been unmeasured differences between vaccinated and unvaccinated persons (e.g. different test-seeking behaviours or levels of adherence to non-pharmaceutical interventions) which might have confounded our vaccine effectiveness estimates,” they wrote.
“Although we adjusted our estimates for age, sex, and calendar week, the effect of additional covariates such as location, comorbidities, race or ethnicity, socioeconomic status, and likelihood of seeking SARS-CoV-2 testing should be evaluated in future studies.
“Preliminary findings from a study in Israel, for example, indicate that neighbourhood might be an important confounder.”
The researchers also note the possibility that some people who had SARS-CoV-2 infection and reported being asymptomatic at the time they were interviewed may in fact have been presymptomatic.
“Further studies are needed to confirm the magnitude of BNT162b2 protection against asymptomatic infection that we observed,” they wrote. “Specifically, studies are needed to evaluate testing behaviour of vaccinated and unvaccinated people and to determine the extent to which prevention of asymptomatic infection leads to interruption of transmission.”
In a linked comment, Eyal Leshem from the Chaim Sheba Medical Centre in Israel and Annelies Wilder-Smith from the London School of Hygiene and Tropical Medicine, who were not involved in the study, wrote: “Haas and colleagues’ findings from Israel suggest that high vaccine coverage rates could offer a way out of the pandemic. Regrettably, rapid population-level coverage cannot be easily replicated in many other countries. The global use of BNT162b2 vaccine is limited by supply issues, high costs, and ultra-cold chain storage requirements.”
Haas et al. said that, among 154,648 SARS-CoV-2 infections in those aged 16 years and older, 109,876 (71%) were unvaccinated and 6,266 (4.1%) were fully vaccinated (with ≥7 days after the second dose).
Among the 54,677 people aged 16 years and older who had symptomatic Covid-19, 39,065 (71.4%) were unvaccinated and 1,692 (3.1%) received two doses (with ≥7 days after the second dose).
Among the 7,694 people aged 16 years and older who were hospitalised with Covid-19, 5,526 (71.8%) were unvaccinated and 596 (7.7%) received two vaccine doses with ≥7 days after the second dose.
Of the 4,481 severe or critical hospitalisations related to Covid-19 that occurred in people aged 16 years and above, 3,201 (71.4%) people were unvaccinated and 364 (8.1%) were fully vaccinated.
Of the 1,113 people aged 16 years and older who died from Covid-19, 715 (64.2%) were unvaccinated and 138 (12.4%) were fully vaccinated.
In a blog post entitled ‘Is the Pfizer vaccine as effective as claimed?’, published on May 17, professor in risk information management Norman Fenton and professor in computer science and statistics Martin Neil gave their analysis of the report by Haas et al..
They said that the 95% effectiveness measure was exaggerated. They referred to an article by Will Jones, who stated that Haas et al. did not adjust for the declining infection rate during the study period. When this adjustment was made, Jones said, effectiveness dropped to 74% in the over 65s.
Fenton and Neil noted that Haas et al. stated the following; “Israel’s SARS-CoV-2 testing policy was different for unvaccinated and vaccinated individuals during the study period. At seven days after the second dose, vaccinated individuals were exempt from the SARS-CoV-2 testing required of individuals who either had contact with a laboratory-confirmed case or returned from travel abroad.
Fenton and Neil explained: “What this is saying is that, whereas unvaccinated people continued to be regularly and routinely subject to PCR tests, vaccinated people no longer had to be.”
They added: “If you stop testing vaccinated people then you are not going to find any ‘cases’ among them.”
Haas et al. stated that 19% of the 4.4 million PCR tests conducted during the study period were done on exempted (vaccinated) individuals.
However, Fenton and Neil say, “this still means unvaccinated people were much more likely to be tested than vaccinated people, so we have to take account of the absolute number of tests performed on both vaccinated and unvaccinated”.
Fenton and Neil noted that the number of ‘cases’ per 1,000 tests was as follows:
- 30.8 for unvaccinated people (109,876 divided by 3,564,000 times 1,000), and
- 7.5 for vaccinated people (6,266 divided by 836,000 times 1000).
They based this calculation on the conclusion that there 836,000 tests on vaccinated people and 3,564,000 tests on unvaccinated people.
“Using the simple ‘cases per 1,000 tests’ (rather than the biased ‘incident rate per 100,000 person days’) results in an approximate ‘vaccine effectiveness’ measure of 75.7%,” Fenton and Neil said.
Hilla De-Leon et al. had reported in a preprint published on medRxivon February 3 that the Pfizer-BioNTech vaccine might curb cases of Covid-19 by about 50 percent 14 days after the first of two doses is administered.
The researchers admitted, however, that their study had numerous limitations. They used data analysis tools and simulations to model epidemic dynamics in Israel, comparing different scenarios of lockdown duration and effectiveness. Each scenario was modelled with and without up-to-date vaccine coverage.
“While our study cannot accurately estimate the effectiveness of the Pfizer-BioNTech vaccine, it suggests that the effectiveness is greater than 50% and that there is a considerable level of prevention of transmission following vaccinations,” Hilla De-Leon et al. said.
Statistics reported by the Maccabi health fund indicated that vaccination with the Pfizer-BioNTech vaccine led to a 51% drop in SARS-CoV-2 infection two weeks after an initial vaccine dose.
Researchers from the Maccabi research and innovation centre, the KSM, and Tel Aviv University conducted a retrospective study using data from all Maccabi members aged 16 years or above who were vaccinated with BNT162b2 between December 19, 2020, and January 15, 2021. Daily and cumulative infection rates on days 13–24 after the first dose were compared with those on days 1–12.
Data from 503,875 individuals, of whom 351,897 had 13–24 days of follow-up after the first dose, were analysed.
“Our findings showed that the first dose of the vaccine is associated with an approximately 51% reduction in the incidence of PCR-confirmed SARS-CoV-2 infections at 13 to 24 days after immunisation compared to the rate during the first 12 days,” Gabriel Chodick et al. said. “Similar levels of effectiveness were found across age groups …
“Our findings … might be an underestimation of the vaccine effectiveness against Covid-19. Nonetheless, our study provides critically needed evidence on the early performance of BNT162b2 vaccine in real life.”
Maccabi said that when researchers analysed the first 430,000 Covid vaccinations received by its members the rate of SARS-CoV-2 infection dropped by 60% after the 12th day post-vaccination.
“The rate of infection decreased from about 40 per 100,000 persons per day in the first 12 days to about 15 per 100,000 persons on days 13 to 21, indicating an efficiency of about 60% in reducing the infection,” Maccabi said.
“Despite the encouraging findings, there were still cases of people being infected after 13 days had already passed since the first dose. The researchers emphasise that, even after receiving the first dose, the rules of social distancing must be maintained.”
In a separate analysis, Maccabi researchers, in collaboration with scientists from the KI Institute, studied a group of 50,777 over-60s vaccinated in late December and mid-January. They found that, two days after the second dose, the number of new infections and hospitalisations were both down about 60% from their peak.
The researchers found that the rate of hospitalisation started to fall sharply from Day 18 after the first dose.
Until Day 13, the vaccinated cohort had similar infection rates as the overall population of over-60s. By Day 23, there were 18 daily infections among the total cohort of 50,777 people, but just six among those vaccinated.
The head of infectious diseases at the Sheba Medical Centre, Galia Rahav, told The Times of Israel that some of the decrease might be due to a tendency of newly vaccinated people to adhere to lockdown rules, which caused a drop in infection and hospitalisation.
On February 1, Maccabi published data about 132,015 of its members over the age of 60 who received the first dose of BNT162b2 between December 20 and 29, 2020.
Day 10 represented the peak of confirmed SARS-CoV-2 infections and a slight decrease began at day 11. There was a peak in Covid-19 related hospitalisations on day 14.
A 55% decrease in average daily infections was seen between the peak point and day 21. In a similar timeframe, a 14% increase in SARS-CoV-2 infections was seen in the general population.
An additional 25% decrease in the number of newly infected members was seen between days 21 and 28 whereas an 18% decrease was seen in the general population.
“The decrease in daily hospitalisation numbers is more significant, though we draw attention to the fact that the numbers are small – and therefore must be cautiously interpreted,” Maccabi said.
“Compared to the peak number of newly vaccinated hospitalised patients on day 14, an 80% decrease is seen on days 27-28.”
Tal Patalon, who is the head of KSM, said: “Though the trend is encouraging, those vaccinated still need to be cautious. We still do not have enough data about hospitalisations among vaccinated individuals – as well as their potential to infect – and not merely be infected.”
In a separate study, reported on in a preprint published on medRxiv on February 8, researchers from Maccabi and the Israel Institute of Technology found that, after vaccination with the Pfizer-BioNTech vaccine, viral load was reduced fourfold in infections occurring 12–28 days after the first vaccine dose.
“These reduced viral loads hint to lower infectiousness, further contributing to vaccine impact on virus spread,” the researchers said.
The study was based on an analysis of positive post-vaccination samples obtained between December 23, 2020, and January 25. Patients who had a positive test prior to vaccination were excluded as well as patients aged 90 and above.
The researchers pointed to several limitations of their study, which was observational, not a randomised, controlled trial:
- The group of vaccinees may have differed from the demographically matched control group in ways that could affect the observed viral load, such as behaviour, tendency to get tested, and general health status.
- Different viral variants, which could be associated with different viral loads, may affect different parts of the population.
- The oro-nasopharyngeal test does not distinguish the viral load in the nose from the one in the oral cavity, which may be more representative of viral shedding and infectiousness.
The researchers also said that post-vaccination positive tests “may be enriched for long-term, low viral load infections lasting from pre-immunisation transmission events”.
They added: “With the accumulation of additional and longer-term datasets, it will also be important to see how these results vary for other vaccines as well as among viral variants.”
On January 28, The Times of Israel reported that the Pfizer-BioNTech vaccine had been shown to be 92 percent effective.
Thirty-one out of 163,000 Israelis vaccinated by Maccabi Healthcare Services were diagnosed with Covid-19 in the first ten days after the second dose, Maccabi’s top vaccine statistics analyst, Anat Ekka Zohar, told The Times of Israel.
Israel’s health ministry said in January that just 0.04 per cent of Israelis (317 out of 715,425) who had received two doses of the Pfizer/BioNTech vaccine had tested positive for SARS-CoV-2.
Clalit Health Services said on January 14 that a study involving 600,000 people who received two doses of the Pfizer/BioNTech vaccine and 600,000 people who had not been vaccinated indicated that the vaccine provided more than 90% protection against Covid disease.
In the vaccinated group, there was 94% less symptomatic infection and about 92% (between 91 and 99%) fewer cases of serious Covid illness, compared to the non-vaccinated group, Clalit said.
The rate of “efficacy” was the same across all age groups, including those aged 70 years and above, Clalit said.
Those vaccinated were tested at least seven days after their second vaccine dose. The founding director of the Clalit Research Institute, Ran Balicer, said that a preliminary examination of results indicated that the vaccine had even higher efficacy in preventing symptomatic and severe Covid disease 14 days or more post-vaccination.
Each vaccinated person was “paired” for study with a unvaccinated person of a similar age, with a similar health and risk profile.
A limitation of the study is that it is observational research, not a randomised controlled trial.
In a report, published in the New England Journal of Medicine on February 24, Israeli and American researchers said their study, conducted in Israel, suggested that effectiveness of the Pfizer-BioNTech vaccine was high in preventing hospitalisation, severe illness, and death from Covid-19 and the “estimated benefit” benefit increased in magnitude as time passed.
Noa Dagan et al. assessed estimated vaccine effectiveness in the period from day 14 to day 20 after the first dose and seven or more days after the second dose.
They said that estimated effectiveness in combatting documented infection was 46% and 92% respectively over the studied time periods. They added that estimated effectiveness in combatting symptomatic Covid-19 was shown to be 57% at days 14 to 20 after the first dose, rising to 94% seven or more days after the second dose.
In reducing hospitalisation, estimated effectiveness was seen to be 74%, rising to 87% seven or more days after the second dose. In reducing the incidence of severe disease, estimated effectiveness was 62%, rising to 92% seven or more days after the second dose.
The researchers said the estimated effectiveness in preventing death from Covid-19 was 72% on days 14 to 20 after the first vaccine dose.
Of those study participants who died from Covid-19, nine were fully vaccinated and 32 were unvaccinated.
“Estimated effectiveness in specific subpopulations assessed for documented infection and symptomatic Covid-19 was consistent across age groups, with potentially slightly lower effectiveness in persons with multiple coexisting conditions,” Dagan et al. said.
Each group in the study included 596,618 people. Matched participants in the unvaccinated cohort were younger than the eligible population overall and had a lower prevalence of chronic conditions because there was a smaller pool of potential unvaccinated matches for older vaccine recipients, owing to high vaccination rates in the older population.
Reports of adverse reactions
The Israeli People`s Committee, which is an independent citizens’ group that includes doctors, attorneys, and researchers from various disciplines, said in its report updated with data up to August 5 that it had received 484 reports of deaths occurring in proximity to Covid vaccination. A total 227 of these reports were of “sudden death”, 170 were from “cardiac arrest/heart attack”, 22 were deaths from a stroke, 19 were deaths from Covid-19 after vaccination, and six were deaths from multi-system failure.
The committee says it has already received reports about deaths occurring very soon after administration of booster (third) vaccine doses.
The people’s committee had said in its report published on April 25 that it had received 309 reports of deaths occurring in proximity to Covid vaccination.
In its previous report, also published in April, in which it cited 288 deaths, the committee said that 90% of those deaths occurred up to 10 days after vaccination and 64% of those who died were men.
“According to the Ministry of Health’s figures: only 45 deaths occurred in proximity to the vaccination,” the committee said.
“According to data from the Central Bureau of Statistics (CBS), during January–February 2021, in the midst of the vaccination operation, there was a 22% increase in overall mortality in Israel compared to the bi-monthly average mortality in the previous year.
“The period of January–February 2021 is the deadliest one in the last decade, with the highest overall mortality rates, when compared to the corresponding months over the last 10 years.”
Among the 20–29 age group, the increase in the mortality rate was even more dramatic, the committee said. “In this group, during the same vaccination period, January–February 2021, there has been a 32% increase in overall mortality compared to the bi-monthly average mortality in 2020,” the committee said.
“A statistical analysis of data from the CBS combined with information from the Ministry of Health leads to the conclusion that the mortality rate amongst the vaccinated is estimated at 1:5,000 (1:13,000 for ages 20–49, 1:6,000 for ages 50–69, 1:1600 for ages 70+).”
The people’s committee has concluded that the risk of death after the second vaccine dose is higher than the risk after the first dose.
In its report updated to include data up to August 5, the committee said it had received 3,754 reports of adverse events after Covid vaccination (3,454 analysed and 300 others received, but not yet analysed).
In its report updated on April 25, the committee had said it had received 2,256 reports of adverse events after Covid vaccination (1,956 analysed and 300 others received, but not yet analysed).
“These reports indicate damage to almost every system in the human body,” the committee stated.
“These figures also highlight the inconceivable gap between official Israeli media reports and what is actually happening, enabling a ‘two worlds’ situation …”
The committee said it had registered a “relatively high” rate of cardiac-related injuries after Covid vaccination.
“Twenty-six percent of all cardiac events occurred in young people below the age of 40, the most common diagnosis in these cases being myocarditis or pericarditis,” the committee said.
The committee also reported a high prevalence of what it describes as “massive vaginal bleeding” and reports of neurological, skeletal, and skin damage.
“It should be noted that a significant number of adverse events reported are related, directly or indirectly, to coagulopathy (myocardial infarction, stroke, miscarriages, disruption of blood flow to the limbs, and pulmonary embolism),” the committee added.
“The reporting of adverse events from hospitals and HMO [health maintenance organisation] clinics has been very low, and there is a tendency for a diagnostic bias that excludes the possibility of a link between the adverse events and the vaccination.”
The committee also listed 178 reports of pain, including 44 reports of extreme headache, and a total 246 reports of lymphadenopathy (swollen or enlarged lymph nodes), syncope (fainting), extreme fatigue, a reduced ability to perform daily activities, or mental disorders.
Vaccination incentives
It was reported in the Israeli media in February that demand for Covid vaccination had plummeted. The Times of Israel reported on February 9 that the health ministry had been aiming to carry out 200,000 vaccinations per day, but demand was running at barely half that total so the ministry and some companies were looking at ways to incentivise Israelis to get vaccinated.
Promising treatment results
The promising results in Israel of small trials of two drugs that combat the immune-cell hyperactivation and inflammatory response (cytokine storm) that can occur in patients with Covid-19 have revived the argument that developing successful treatments is preferable to mass vaccination.
A cytokine storm is an immune response in which the body starts to attack its own cells and tissues rather than just fighting off the virus.
There is also increasing evidence that ivermectin is successful as a treatment, but the results of a Phase 1 trial of the drug EXO-CD24, which has been used to treat moderate-to-serious cases of Covid-19, are a breakthrough that has hit the mainstream headlines. Thirty patients given the treatment all recovered, 29 of them within three to five days..
EXO-CD24 uses exosomes to deliver the CD24 protein called to the lungs. “The preparation is inhaled once a day for a few minutes, for five days,” Nadir Arber from Tel Aviv’s Ichilov Medical Centre told The Times of Israel. “EXO-CD24 is administered locally, works broadly and without side effects.”
There have also been promising results from a small Phase 2 trial of the drug Allocetra, which is also used to combat the cytokine storm in Covid-19 patients. Israel’s Channel 13 reported that 90% of twenty seriously ill patients treated with the drug recovered.
The drug is now entering Phase 3 trials and will be given to more than 100 people.
One patient, 49-year-old Yair Tayeb, who has now been discharged from hospital, told Channel 13: “They gave me the drug. Suddenly after two hours I started feeling something strange in my body. I stopped coughing, my breathing started to come back, I was feeling better. I stopped sweating. I couldn’t believe it. I was afraid to tell people I was okay, I was so excited.”
‘We need the raw data’
In an article published on January 4, 2021, Peter Doshi said he had new concerns about the trustworthiness and meaningfulness of the efficacy results published by Pfizer and Moderna: “We need more details and the raw data,” Doshi wrote.
Doshi noted that two journal publications and about 400 pages of summary data were available in the form of multiple reports presented by and to the FDA. “While some of the additional details are reassuring, some are not,” Doshi said.
Pfizer reported 170 PCR-confirmed Covid-19 cases, split eight to 162 between the vaccine and placebo groups, he notes, but these numbers were dwarfed by cases of “suspected covid-19” – people with symptomatic Covid-19 that was not PCR confirmed.
According to the FDA’s report about the Pfizer vaccine, there were 3,410 total cases of suspected, but unconfirmed Covid-19 in the overall study population. A total 1,594 occurred in the vaccine group and 1,816 in the placebo group.
With twenty times more suspected than confirmed cases, this category of disease cannot be ignored simply because there was no positive PCR test result,” Doshi wrote. “Indeed this makes it all the more urgent to understand.”
“A rough estimate of vaccine efficacy against developing covid-19 symptoms, with or without a positive PCR test result, would be a relative risk reduction of 19% – far below the 50% effectiveness threshold for authorisation set by regulators.
“Even after removing cases occurring within seven days of vaccination (409 on Pfizer’s vaccine vs. 287 on placebo), which should include the majority of symptoms due to short-term vaccine reactogenicity, vaccine efficacy remains low: 29%.”
Doshi said that an analysis of severe disease irrespective of etiologic agent – namely, rates of hospitalisations, ICU cases, and deaths amongst trial participants – seemed warranted, and was “the only way to assess the vaccines’ real ability to take the edge off the pandemic”.
Pfizer didn’t mention the 3,410 suspected Covid-19 cases in its 92-page report or its article in the New England Journal of Medicine, Doshi noted. “The only source that appears to have reported it is FDA’s review of Pfizer’s vaccine.”
Referring to the trial results reported by Pfizer and Moderna, Doshi wrote in his opinion piece published on November 26 that the results referred to the trials’ primary endpoint of Covid-19 of essentially any severity, “and importantly not the vaccine’s ability to save lives, nor the ability to prevent infection, nor the efficacy in important subgroups (e.g. frail elderly)”. Those, Doshi wrote, remained unknown.
He said the results reflected a time point relatively soon after vaccination, adding “we know nothing about vaccine performance at three, six, or 12 months, so cannot compare these efficacy numbers against other vaccines like influenza vaccines (which are judged over a season)”.
Children, adolescents, and immunocompromised individuals were largely excluded from the trials, so data was still lacking about these important populations, Doshi wrote.
Doshi argued that the trials studied the wrong endpoint, and said there was an urgent need to correct course and study more important endpoints like the prevention of severe disease and transmission in high- risk people.
“Yet, despite the existence of regulatory mechanisms for ensuring vaccine access while keeping the authorisation bar high (which would allow placebo-controlled trials to continue long enough to answer the important question), it’s hard to avoid the impression that sponsors are claiming victory and wrapping up their trials,” Doshi wrote.
Doshi also questions the way decisions were taken about which trial participants should be tested for SARS-CoV-2 infection. The trial protocols for Moderna and Pfizer’s studies contain explicit language instructing investigators to use their clinical judgment to decide whether to refer people for testing, he says.
“In a proper trial, all cases of Covid-19 should have been recorded, no matter which arm of the trial the case occurred in. (In epidemiology terms, there should be no ascertainment bias, or differential measurement error.),” Doshi wrote.
”… if referrals for testing were not provided to all individuals with symptoms of Covid-19 – for example because an assumption was made that the symptoms were due to side-effects of the vaccine – cases could go uncounted.”
Also, Doshi says, if people in the vaccine arm of the trials took pain and fever reducing medicines prophylactically more often or for a longer duration of time than those in the placebo arm, this could have led to greater suppression of Covid-19 symptoms following SARS-CoV-2 infection in the vaccine arm, translating into a reduced likelihood of being suspected of having Covid-19, a reduced likelihood of testing, and a reduced likelihood of meeting the primary endpoint.
In an article published on December 11, Maryanne Demasi from The Institute for Scientific Freedom in Denmark said there were also some outstanding unknowns about the Pfizer vaccine.
“How long will immunity last? Is the vaccine safe and efficacious for children under 16 years of age, or for the elderly (the group with the highest fatality risk)? And will the vaccine prevent community transmission of the virus?,” Demasi wrote.
“Those with antibodies to SARS-CoV-2 were excluded from participating in the trial. It is not understood, therefore, how the vaccine might affect people who have already been exposed to Covid-19, which could be substantial.”
In a BMJ article published on October 21, 2020, Doshi wrote: “None of the trials currently under way are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths. Nor are the vaccines being studied to determine whether they can interrupt transmission of the virus.”
Demasi wrote: “The data for the Pfizer vaccine suggests that the benefits outweighs its harms, but this is still short-term data (only two months). On the first day of rolling out the Pfizer vaccine in the UK, two NHS workers experienced an ‘anaphylactoid reaction’ shortly after receiving the jab, causing the UK regulator to issue a warning that people with a history of allergic reactions should not be vaccinated.
“It’s not surprising; people with a history of severe allergic reactions such as anaphylaxis were excluded from the original studies, a common problem when trials do not recruit participants that reflect ‘real world’ populations.”
Writing for the Mises Wire, Gilbert Berdine, who is an associate professor of medicine at the Texas Tech University Health Sciences Centre in the US, talked about “what the Covid vaccine hype fails to mention”.
Commenting about the Pfizer-BioNTech and Moderna trials, he wrote: “There was no information about the cycle number for the PCR tests. There was no information about whether the ‘cases’ had symptoms or not. There was no information about hospitalisations or deaths.”
Berdine added: “The Moderna announcement claimed that eleven cases in the control group were ‘severe’ disease, but ‘severe’ was not defined. If there were any hospitalisations or deaths in either group, the public has not been told.
“When the risks of an event are small, odds ratios can be misleading about absolute risk. A more meaningful measure of efficacy would be the number to vaccinate to prevent one hospitalisation or one death. Those numbers are not available.”
Berdine said he had asked a number of his colleagues, who include resident physicians and faculty physicians who work with Covid patients on a daily basis. whether they would be first in line for the new vaccine and he had yet to hear any of them respond affirmatively.
“The reasons for hesitancy are that the uncertainties about safety exceed what they perceive to be a small benefit,” Berdine wrote. “In other words, my colleagues would prefer to take their chances with Covid rather than beta test the vaccine.
“Many of my colleagues want to see the safety data after a year of use before getting vaccinated; these colleagues are concerned about possible autoimmune side effects that may not appear for months after vaccination.”
Trials halted twice because of illness
On September 6, 2020, AstraZeneca, halted all trials of its AZD1222 vaccine, which was previously designated as ChAdox1 nCoV-19, because one of the participants in the Phase 3 trial in the UK had what was initially described as “an unexplained illness”.
It was later reported that the participant who became ill experienced neurological symptoms consistent with the spinal inflammatory disorder transverse myelitis.
After an investigation, regulators approved the resumption of trials of the AstraZeneca vaccine in the US, the UK, Brazil, South Africa, India, and Japan.
AstraZeneca said that suspension of the trials of its vaccine was a “routine action” that had to happen whenever there was a potentially unexplained illness in one of the trials.
“On 6 September, the standard review process triggered a voluntary pause to vaccination across all global trials to allow review of safety data by independent committees, and international regulators,” the company said.
The American TV station CNN said it obtained an initial internal safety report by AstraZeneca that stated that the study volunteer, a previously healthy 37-year-old woman, “experienced confirmed transverse myelitis” after receiving her second dose of the AZD1222 vaccine, and was hospitalised on September 5.
According to CNN, the document describes how the study participant had trouble walking and suffered weakness and pain in her arms and other symptoms.
The internal safety report is dated September 10, and, on September 11, it was sent out to doctors running the study’s clinical trial sites, CNN reported on September 17.
The news of the suspension of the trials of the AstraZeneca vaccine was first reported on the STAT news website.
STAT journalist Adam Feuerstein reported that the participant who became ill experienced neurological symptoms consistent with transverse myelitis.
Feuerstein said this was revealed by Pascal Soriot during a private conference call with investors.
The journalist said Soriot told investors that the board tasked with overseeing the data and safety components of the AstraZeneca clinical trials confirmed that the participant who became ill was injected with the vaccine, not a placebo.
Soriot also confirmed that the clinical trial was halted once previously, in July, after a participant experienced neurological symptoms, Feuerstein reported. Soriot said that, upon further examination, that participant was diagnosed with multiple sclerosis, deemed to be unrelated to the Covid-19 vaccination, Feuerstein added.
The trial participant information sheet dated July 12, 2020, states that the person who became ill “developed symptoms of transverse myelitis …, which has not required medical treatment and is being investigated, though the cause is uncertain”.
An August update of the information sheet removed the reference to transverse myelitis and said the participant developed neurological symptoms that caused the study to be paused, and that the volunteer was later diagnosed with what was described as “an unrelated neurological illness”.
AstraZeneca said on October 23 that clinical trials of its Covid vaccine had resumed across the world. The company gave no explanation about the illness that triggered the halt in the trials.
The company had earlier announced that the trials had restarted in the UK after the MHRA stated that it was safe to resume the testing.
The UK committee had concluded its investigations and had recommended to the MHRA that it was safe to resume the UK trials, the company said, adding that it could not disclose further medical information relating to the trial participant’s illness.
In its statement about the suspension of the trials, Oxford University said: “We cannot disclose medical information about the illness for reasons of participant confidentiality.”
The university added: “Globally some 18,000 individuals have received study vaccines as part of the trial. In large trials such as this, it is expected that some participants will become unwell and every case must be carefully evaluated to ensure careful assessment of safety.
“The independent review process has concluded and following the recommendations of both the independent safety review committee and the UK regulator, the MHRA, the trials will recommence in the UK.”
Anvisa said on October 21 that a volunteer in the trial of the AstraZeneca vaccine in Brazil had died. Comments reported by the Reuters news agency suggest that the volunteer received the meningitis control vaccine, not AZD1222.
CNN Brasil reported that the volunteer was a 28-year-old man who lived in Rio de Janeiro and died from Covid-19 complications.
An AstraZeneca spokesperson said that all significant medical events were carefully assessed by trial investigators, an independent safety monitoring committee, and regulatory authorities. These assessments had not led to any concerns about continuation of the study in Brazil, the company spokesperson said.
Cases of transverse myelitis, in which an immune-mediated process causes neural injury to the spinal cord, have been triggered by vaccination, but the disorder can also be caused by viral infections.
Johnson & Johnson also paused trials
Johnson & Johnson said it paused trials of its Covid vaccine because of “an unexplained illness in a study participant”.
The company said on October 12: “We have temporarily paused further dosing in all our Covid-19 vaccine candidate clinical trials, including the Phase 3 ENSEMBLE trial, due to an unexplained illness in a study participant.
“Following our guidelines, the participant’s illness is being reviewed and evaluated by the ENSEMBLE independent Data Safety Monitoring Board as well as our internal clinical and safety physicians.”
Johnson & Johnson said on October 23 that, after review, it was preparing to resume recruitment to the Phase 3 ENSEMBLE trial in the US.
“The independent Data Safety and Monitoring Board overseeing the ENSEMBLE study has recommended resuming trial recruitment,” the company said.
Johnson & Johnson said that, “after a thorough evaluation of a serious medical event experienced by one study participant”, no clear cause had been identified.
“There are many possible factors that could have caused the event. Based on the information gathered to date and the input of independent experts, the company has found no evidence that the vaccine candidate caused the event,” Johnson & Johnson added.
The company states that adverse events (“illnesses, accidents, etc.”) – and even those that are serious – “are an expected part of any clinical study, especially large studies”.
It distinguishes between a study pause, which is what is occurring in the case of the the JNJ-78436735 vaccine, and a “regulatory hold”.
In the case of a study pause, recruitment or dosing is paused by the study sponsor, and is a standard component of a clinical trial protocol, Johnson & Johnson says.
“While the company informs all study investigators, we typically do not communicate study pauses publicly.”
The director of the Drug Safety Research Unit (DSRU) in Britain, Saad Shakir, said after the Johnson & Johnson trials were halted that serious adverse events were expected in a clinical trial that included 60,000 vaccinees.
Shakir said that the Data Safety Monitoring Board (DSMB) couldn’t say whether the event occurred in a person who received the active vaccine or the comparator because divulging this would compromise the blinding of the study and it could not announce the clinical details of the adverse event for confidentiality reasons.
“The description of the event as an ‘unexplained illness’ is interesting and somewhat unusual. They are likely to be investigating its nature in detail, in collaboration with the doctors who are treating the patient,” Shakir said. “Given the description ‘unexplained illness’, an educated guess is that it could be an event that affected the nervous system, though this is by no means certain.
“While the monitoring board looks for causality when assessing serious adverse events, it is acknowledged that regulators or members of the DSMB may be forced to act even in the absence of a definite causal relationship.”
Russia
On April 19, the Gamaleya National Research Centre for Epidemiology and Microbiology and the RDIF announced that the Sputnik V vaccine demonstrated efficacy of 97.6%.
They said the conclusion was based on the analysis of data about the SARS-CoV-2 infection rate among Russians vaccinated with two doses of Sputnik V.
According to the data from 3.8 million Russians vaccinated with two doses of Sputnik V between December 5, 2020, and March 31, 2021, the infection rate starting from the 35th day from the date of the first injection was 0.027%.
Over the same period, and starting from the 35th day after the launch of mass vaccination in Russia, the infection rate among the unvaccinated adult population was reported to be 1.1%.
The following formula was used to calculate the vaccine’s efficacy:
The Gamaleya research centre and the RDIF said the data and calculations relating to their latest efficacy statement would be published in a peer-reviewed medical journal in May.
Alexander Gintsburg, said: “The actual efficacy of the Sputnik V vaccine may be even higher than the results of our analysis demonstrate since the data on the case registration system allows a time lag between the collection of the sample (the actual date of the disease) and the diagnosis.”
In a report published in The Lancet on February 2, 2021, Denis Y Logunov et al. had said that, in an interim analysis of a Phase 3 clinical trial, Sputnik V had 91.6% efficacy against Covid-19.
That percentage is slightly higher than the 91.4% announced by the Gamaleya research centre and the RDIF on December 14.
Both calculations were based on an analysis of 78 confirmed cases of Covid-19 (62 cases in the placebo group and 16 in the vaccinated group).
The data reported upon on February 2 relates to 19,866 volunteers who received two doses of the Sputnik V vaccine or a placebo.
“Efficacy in the elderly group of 2,144 volunteers over 60 years old was 91.8% and did not differ statistically from the 18-60 group,” the researchers reported.
From 21 days after the first dose of vaccine (the day of dose 2), 16 of 14,964 participants in the vaccine group and 62 of 4,902 in the placebo group were confirmed to have Covid-19, Logunov et al. report, so vaccine efficacy was shown to be 91·6%.
Ninety-four percent of the reported adverse events were mild and included flu-like syndromes, injection site reactions, headache and asthenia, Logunov et al. reported.
Forty-five of 16,427 participants in the vaccine group and 23 of 5,435 participants in the placebo group had serious adverse events, but none were considered associated with vaccination, and this was confirmed by the independent data monitoring committee, they said. There were no reported cases of anaphylactic shock.
The twenty confirmed severe cases of Covid-19 were all recorded in the placebo group.
Four deaths were reported during the study (three of 16 427 participants in the vaccinated group and one of 5,435 participants in the placebo group). None of the deaths were considered to be related to the vaccine, Logunov et al. said.
The researchers said that more than 98% of the trial participants developed humoral immune response and 100% – cellular immune response.
“The level of virus neutralising antibodies of volunteers vaccinated with Sputnik V is 1.3–1.5 times higher than the level of antibodies of patients who recovered from Covid-19, they added.
In a linked comment published in The Lancet, Ian Jones and Polly Roy said that the vaccine efficacy, based on the numbers of confirmed Covid-19 cases from 21 days after the first dose, and the suggested lessening of disease severity after one dose was “particularly encouraging for current dose-sparing strategies.”
More than 200,000 people have already been vaccinated against Covid-19 as part of Russia’s mass vaccination programme, which began in September alongside the Moscow-based trial.
Phase 3 clinical trials are ongoing in Belarus, the UAE, Venezuela and other countries, and Phase 2/3 trials are continuing in India.
The two vectors being used in Sputnik V, which is also known as Gam-COVID-Vac, are a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for the SARS-CoV-2 spike glycoprotein.
Logunov, says that, if there is booster vaccination that uses the same adenovirus vector, the immune system may recognise and attack the vector. The Russians used two vectors to try and avoid this.
The RDIF says that the cost of the Sputnik V vaccine for international markets will be less than $10 per dose.
Russia has also granted approval for a second SARS-CoV-2 vaccine, EpiVacCorona, which is a peptide vaccine that consists of artificially synthesised short fragments of viral proteins. It was developed by the Vector State Research Centre of Virology and Biotechnology in Siberia. One trial involving 100 volunteers has been carried out and 40,000 people are to be enrolled for the next stage of testing.
A whole-virion inactivated vaccine is meanwhile being developed at the Chumakov Federal Scientific Centre for the Research and Development of Immune and Biological Products. Phase 2 trials have begun in Kirov and Saint Petersburg.
The US, British, and Canadian governments have accused Russia of using hackers to steal vaccine research from Western labs. Russia has denied the allegation.
In August last year, Russia became the first country to register a Covid vaccine. Sputnik V was registered by the Russian Ministry of Health on August 11 despite having only undergone Phase 1 and Phase 2 clinical trials involving just 76 participants in total.
On September 8, the health ministry said the first batch of the vaccine had passed the necessary quality tests in the Roszdravnadzor laboratories and had been released into civil circulation.
Phase 1 and 2 non-randomised clinical trials of the two formulations (frozen and freeze-dried) of the two-part vaccine were completed on August 1. Results from the two 42-day trials were published on September 4 in The Lancet.
The frozen formulation of Sputnik V is envisaged for large-scale use using the existing global supply chains for vaccines while the freeze-dried formulation has been developed for hard-to-reach regions as it is more stable and can be stored at 2–8 degrees Celsius.
In January, the Russian Ministry of Health authorised the storage and transportation of a new liquid formulation of the vaccine at 2–8 degrees Celsius.
In February, Alexander Gintsburg said storage of the liquid vaccine at 2–8 degrees Celsius was allowed for just two months, but developers hoped to extend this to six months.
Naor Bar-Zeev and the director of the Center for Health Security at the Johns Hopkins Bloomberg School of Public Health, Tom Inglesby, wrote a linked comment about the September 4 report. Neither commentator was involved in the study.
They said that the studies carried out by Logunov and his colleagues were encouraging, but small.
“The immunogenicity bodes well, although nothing can be inferred on immunogenicity in older age groups, and clinical efficacy for any Covid-19 vaccine has not yet been shown.”
They added: “Unlike clinical trials of therapeutics, in which safety is balanced against benefit in patients, vaccine trials have to balance safety against infection risk, not against disease outcome. Since vaccines are given to healthy people and, during the Covid-19 pandemic, potentially to everyone after approval following Phase 3 trials, safety is paramount.”
Bar-Zeev and Inglesby said that licensure in most settings should depend on proven short-term and long-term efficacy against disease, not just immunogenicity, and more complete safety data.
Surveillance would be vital for showing transmission reduction, the two scientists said, adding that, with Covid-19, the general public could expect striking reductions in disease transmission after widespread vaccine introduction.
“Such effects would be very welcome if they occur, but they are far from certain,” the scientists said. “A vaccine that reduces disease but does not prevent infection might paradoxically make things worse. It could falsely reassure recipients of personal invulnerability, thus reducing transmission mitigating behaviours.
“In turn, this could lead to increased exposure among older adults in whom efficacy is likely to be lower, or among other higher-risk groups who might have lower vaccine acceptance and uptake.”
On October 17, the Russian Direct Investment Fund and the Indian multinational pharmaceutical company Dr Reddy’s Laboratories announced that they had received approval from the Drugs Controller General of India (DCGI) to conduct an adaptive Phase 2/3 clinical trial for the Sputnik V vaccine in India.
Under the partnership agreement signed by Dr Reddy’s and the RDIF in September, the RDIF will supply 100 million doses of the vaccine to Dr Reddy’s upon regulatory approval in India.
The RDIF and one of the leading pharmaceutical groups in Egypt, Pharco (acting through its key operational subsidiary, Biogeneric Pharma), have agreed that 25 million doses of the Sputnik V vaccine will be supplied to Egypt.
On April 5, the RDIF and Panacea Biotec in India announced that they would cooperate to produce 100 million doses per year of Sputnik V.
The RDIF has also agreed to supply up to 35 million doses of the Sputnik V vaccine to Uzbekistan. Upon approval by Uzbekistan’s regulators up to ten million doses will be delivered in 2020 and up to 25 million doses in 2021.
Also subject to approval by the country’s regulators, the RDIF has agreed to supply 32 million doses of Sputnik V to Mexico.
To date Sputnik V has been approved for use in 70 countries.
India
Six Covid vaccines have been approved by the Drugs Controller General of India for restricted emergency use. The approvals were given after the Central Drugs Standard Control Organisation’s Subject Expert Committee (SEC) recommended authorisation.
The first vaccines to be authorised (in January) were the whole-virion inactivated virus vaccine Covaxin, which is being developed by Bharat Biotech in collaboration with the Indian Council of Medical Research’s National Institute of Virology in Pune, and Covishield, which is being manufactured by the Serum Institute of India.
On April 13, the DCGI also approved the Sputnik V vaccine for emergency use in India (India was the 60th country to authorise the vaccine’s use).
The RDIF said authorisation was given based on the results of clinical trials in Russia and positive data from additional Phase 3 trials in India, conducted in partnership with Dr Reddy’s Laboratories.
The fund said it had reached agreements with five pharmaceutical companies in India – Gland Pharma, Hetero Biopharma, Panacea Biotec, Stelis Biopharma, and Virchow Biotech – with the aim of producing more than 850 million doses per year. The approval for Covaxin was given while Phase 3 trials were still underway.
On June 29, the Moderna vaccine was also approved for emergency use in India for people aged 18 years and above and, on August 7, Johnson & Johnson was given emergency use authorisation for the Janssen Biotech vaccine, also for people aged 18 years and above.
On August 20, the DCGI gave Zydus Cadila, which is headquartered in Ahmedabad, emergency use authorisation for ZyCoV-D, which is a three-dose plasmid DNA vaccine that is administered using a needle-free system in which an injector delivers the vaccine using a narrow stream of fluid to penetrate the skin. The authorisation was issued for use for children and adults aged 12 years and above.
The company conducted clinical trials of ZyCoV-D in more than 50 centres. This included testing the vaccine in about 1,000 trial participants aged 12–18 years. Zydus Cadila said on July 1 that “the tolerability profile was similar to that seen in the adult population”.
Zydus Cadila said that, in an interim analysis of results of a Phase 3 trial involving more than 28,000 participants, ZyCoV-D had been shown to have 66.6% efficacy against symptomatic Covid-19.
The company said no moderate cases of Covid-19 were observed in the vaccine arm of the trial after the third dose, suggesting 100% efficacy against moderate Covid-19.
“No severe cases or deaths due to Covid-19 occurred in the vaccine arm after administration of the second dose of the vaccine,” the company said.
Zydus Cadila has also evaluated a two-dose regimen for ZyCoV-D, using three-milligram doses, and says the immunogenicity results were equivalent to those of the three-dose regimen.
The DCGI has also authorised Bharat Biotech to test Covaxin on children and teenagers aged two to 18 years.
Bharat Biotech is also reported to have been authorised to give some trial participants a third dose of its Covid vaccine as a booster six months after the second dose.
The SEC recommended that the booster should only be given to participants in the Phase 2 trial who received six-microgramme doses of the antigen, local media reported.
Pfizer withdrew an application for emergency use authorisation of its Covid vaccine in India, Reuters reported on February 5.
Based on the deliberations at a meeting with India’s drugs regulator, and Pfizer’s understanding that the regulator may need additional information, the company had decided to withdraw its application for now, Pfizer told Reuters.
Pfizer added that it would continue to engage with the regulator and resubmit its approval request with additional information as it becomes available in the near future.
The Central Drugs Standard Control Organisation (CDSCO) had declined to accept Pfizer’s request for approval without a small local bridging trial to test the vaccine’s safety and immunogenicity for Indians, Reuters reported.
India has sent Covishield to several other countries, including Bhutan, the Maldives, Bangladesh, Sri Lanka, Brazil, and Nepal.
Other Indian companies that have developed Covid vaccines are Biological E, based in Hyderabad; and Gennova Biopharmaceuticals, based in Pune.
Biological E has signed an agreement to license the recombinant protein SARS-CoV-2 vaccine developed at the Baylor College of Medicine in Houston, Texas, in the US.
Gennova Biopharmaceuticals has developed the HGC019 mRNA vaccine in collaboration with its US partner HDT Bio.
HDT Bio is receiving $8.2 million from NIAID in support of pre-clinical and clinical studies of the vaccine, which is designated as HDT-301 in the US.
In announcing emergency use authorisation for Covaxin (BBV152), India’s health ministry said the SEC had reviewed the data on safety and immunogenicity and recommended that permission should be given for restricted emergency use “in public interest as an abundant precaution, in clinical trial mode, to have more options for vaccinations, especially in case of infection by mutant strains”.
The ministry said that Bharat Biotech had generated safety and immunogenicity data in various animal studies and had conducted challenge studies on non-human primates (rhesus macaques) and hamsters.
Phase I and 2 trials had involved about 800 participants and the results had demonstrated that the vaccine was safe and provided a robust immune response, the ministry said.
Bharat Biotech has released the results of its phase 3 trial of Covaxin and says the vaccine has 93.4% general efficacy against severe infection and provides 65.2% protection against the Delta variant. The results were published as a preprint on medRxiv on July 2.
The study was funded by Bharat Biotech and the ICMR. One of the co-authors is the chairman and managing director of Bharat Biotech, Krishna Ella, and another is his son, Raches Ella, who is the company’s head of business development and advocacy.
Between November 16, 2020, and January 7, 2021, 12,221 trial participants received two doses of Covaxin (BBV152) and 12,198 received a placebo. The trial was conducted over 25 sites in India and involved participants aged between 18 and 98 years.
A total 130 cases of symptomatic Covid-19 were reported in 16,973 participants (0.77%) with follow-up at least two weeks after the second vaccination. Twenty-four cases occurred in the vaccine group and 106 in placebo recipients. This gives an overall vaccine efficacy of 77.8% (95% CI: 65.2, 86.4), Raches Ella et al. report.
Sixteen cases of severe symptomatic Covid-19 were reported (one in the vaccine group and 15 among the placebo recipients). This gave a vaccine efficacy of 93.4% (57.1, 99.8), Ella et al. said.
Efficacy against asymptomatic Covid-19 was 63.6% (29.0, 82.4), the researchers added.
“BBV152 conferred 65.2% (95% CI: 33.1, 83.0) protection against the SARS-CoV-2 Variant of Concern, B.1.617.2 (Delta),” they wrote.
There were 15 deaths during the trial, none of which were considered by the investigators to be related to the vaccine or the placebo. Six deaths were reported to be related to Covid-19.
“In BBV152 recipients there were five deaths all due to causes unrelated to vaccination: cerebellar haemorrhage, haemorrhagic stroke, ovarian cancer with metasases, sudden cardiac death, and Covid-19,” Ella et al. report.
“Ten placebo recipients died, also from unrelated conditions: alcohol overdose, myocardial infarction, cardiac arrest with underlying hypertension, five from Covid-19 and two which remain to be determined. No anaphylactic events were reported.”
Ella et al. say a total of 79 variants were reported from 16,973 samples (18 in the vaccine group and 61 in the placebo group).
“Among 50 Delta (B.1.617.2) positive-confirmed cases, 13 and 37 participants were in the vaccine and placebo arms, resulting in vaccine efficacy of 65.2% (95% CI: 33.1–83.0),” the researchers wrote.
“In breakthrough symptomatic Delta variant infections, based on Ct values, the viral load in the vaccine arm was significantly lower than the placebo arm.”
Efficacy against the Kappa (B.1.617.1) variant was 90.1% (95% CI: 30.4–99.8), the researchers say.
No cases of severe variant-related cases of Covid-19 were reported in the vaccinees but four severe cases were reported in the placebo recipients, who were infected with Alpha, Kappa, Delta, or unclassified variants.
“As previously reported, BBV152-induced antibodies show no significant decrease in neutralisation activity against the Alpha (B.1.1.7) variant, but demonstrate marginal reductions in neutralisation activity, by 2-, 2-, 3-, and 2.7-fold, respectively, of the B.1.1.28, B.1.617.1, B.1.351 (Gamma), and B.1.617.2 (Delta) variants,” Ella et al. reported.
Ella et al. say that vaccination with BBV152 was well tolerated “with an overall incidence of adverse events observed over a median of 146 days that was lower than that observed with other Covid-19 vaccines”.
Serious adverse events occurred in 99 participants, the researchers wrote. Thirty-nine of these participants were in the vaccine group and sixty received the placebo.
“Two related serious adverse events were reported among BBV152 recipients,” the researchers added. “Long-term safety monitoring will continue for one year after administration of the first dose of BBV152.”
Overall, incidence rates were lower after the second dose than the first, and tended to be slightly higher in the BBV152 group than in the placebo group. However, all incidence rates were low, with only 12·4% reporting any solicited adverse events after receiving the vaccine or the placebo, Ella et al. wrote.
The most frequent solicited systemic adverse event overall was headache, followed by pyrexia, fatigue, and myalgia, but at incidences below 1% in both groups, the researchers said.
Rates of local and systemic adverse events reported in the BBV152 group as mild (11.2%), moderate (0.8%), or severe (0.3%) were comparable to those in the placebo group: mild (10.8%), moderate (1.1%), and severe (0.4%), they added.
The researchers said their study had several limitations. Due to the low number of Covid-19 cases reported between doses one and two, they could not calculate vaccine efficacy after a single dose, they said.
“This report contains a median safety follow-up of 146 days for all participants, so long-term safety follow-up of BBV152 is required and is currently underway,” they added.
“The data presented on efficacy against variants other than Delta must be considered preliminary as the numbers reported are small. Additional efforts to assess the clinical efficacy of BBV152 against VoC are being planned.”
In the Phase 2 trial of Covaxin, two formulations of BBV152 were used. Ella et al. reported in a preprint published on medRxiv on December 22 that the Phase 1/2 data showed that levels of neutralising antibodies in those who received one of the two formulations were similar to those in people who had recovered from Covid-19.
Half of the 380 volunteers (healthy children and adults aged 12 to 65 who had tested negative for SARS-CoV-2) received three microgrammes of the antigen and half received six microgrammes. Two five-millilitre doses were administered four weeks apart. Covaxin incorporates the adjuvant Algel-IMDG, which is an imidazoquinoline molecule chemisorbed on alum (Algel) that is designed to traffic vaccine antigen directly to draining lymph nodes without diffusing into the systemic circulation.
The imidazoquinoline molecule, which is a toll-like receptor (TLR) 7/8 agonist, is used to stimulate cell-mediated responses. Alum does not itself have the ability to induce cell-mediated responses.
Ella et al. reported that, among the trial participants who received the three-microgramme formulation, 92.9% developed neutralising antibodies on day 56 and, among those given the six-microgramme formulation, the percentage was 98.3%.
The responses of those who received the six-microgramme formulation with Algel-IMDG were comparable to those observed in convalescent serum collected from patients who had recovered from Covid-19, Ella et al. said.
The six microgramme with Algel-IMDG vaccine formulation was selected for the Phase 3 efficacy trial.
Ella et al. reported that, after two vaccine doses, 9.7% of those in the group who received the three-microgramme vaccine formulation experienced “solicited local and systemic adverse reactions”. Among those who received the six-microgramme formulation the percentage was 10.3%. Most adverse reactions resolved within 24 hours of onset, the researchers said, and no serious adverse events were reported.
Adverse events included pain and swelling at the injection site, fever, fatigue, malaise, muscle pain, body aches, headache, nausea, vomiting, anorexia, chills, a generalised rash, and diarrhoea.
On January 21, Ella et al. published a paper in The Lancet about the Phase 1 trial of BBV152. The paper is a peer-reviewed, and more detailed, version of a pre-print that was published on medRxiv on December 15.
The Indian Council of Medical Research and others were accused of putting a spin on the Phase 1 trial results.
In an article in The Wire, public health physician, independent researcher, and epidemiologist Jammi Nagaraj Rao, who is based in the UK, said that much of the report’s contents were known already, but added “as disinformation campaigns go, this one takes the biscuit”.
On January 23, The Times of India published a story under the headline ‘Amid efficacy row, Covaxin gets thumbs-up from Lancet’, Rao noted.
The ICMR took to Twitter to exclaim that the Phase 1 trial results were “remarkable”.
The ICMR’s director-general, Balram Bhargava, is one of the report’s authors.
The Phase 1 trial involved 375 volunteers in 11 centres around India. Groups of 100 participants received one of three vaccine formulations and 75 were randomly assigned to the control group, who received only the Algel adjuvant.
In the Phase 1 trial, more than 80% of patients in each vaccine group seroconverted, with at least a four-fold increase in binding antibody titres, Ella et al. reported.
In a linked commentary, Christina Rostad and Evan Anderson from the Emory University School of Medicine in Atlanta in the US said that, despite favourable Phase 1 results, concerns lingered about the potential for an inactivated whole-virus vaccine to elicit antibody-dependent enhancement of infection or vaccine-associated enhanced respiratory disease if the vaccinee was later infected with SARS-CoV-2.
“Both of these effects are thought to be attributable to the development of binding, poorly neutralising antibodies that can promote either enhanced infection of Fc bearing immune cells or immune complex deposition with T-helper-2 cell-biased allergic inflammation,” Rostad and Anderson said.
Questions remained, they wrote. “Will BBV152 be efficacious? Is IMDG sufficient to subvert a Th2 response? Will enhanced disease occur?
“These questions might only be answered in a more diverse multinational Phase 3 trial, which must comprehensively assess efficacy and long-term safety.”
In vitro studies and some animal studies with other coronaviruses had raised concern about antibody-dependent enhancement of infection and vaccine-associated enhanced respiratory disease, but, to date, neither had been observed in SARS-CoV-2 vaccine clinical trials, Rostad and Anderson wrote
“The inactivated platform raises concern because inactivation might alter antigenic structures and thereby elicit binding, non-neutralising antibodies. Thus, achieving high titres of neutralising antibodies and T-helper-1 (Th1)-biased cellular responses are considered important safety metrics in the assessment of candidate vaccines,” they added.
“Although not yet published in peer-reviewed journals, preclinical studies of BBV152 in hamsters and rhesus macaques showed that the vaccine elicited high titres of neutralising antibodies and protected against SARS-CoV-2 challenge without evidence of enhanced respiratory disease.”
Ella et al. followed up their preprint published on medRxiv on December 22 with another paper about the Phase 2 trial that was published in The Lancet on March 8. The paper in The Lancet also included a report on the three-month follow-up of the Phase 1 trial.
The researchers said: “With several reports questioning the efficacy of SARS-CoV-2 vaccines against antigenically divergent strains, we previously reported neutralising antibody responses in homologous and heterologous strain assessments.
“Day 56 serum samples from 38 participants in the 6 µg with Algel-IMDG group of the Phase 2 trial effectively neutralised a SARS-CoV-2 variant of concern (lineage B.1.1.7 or 20B/501Y. V1).”
When vaccines are made from an inactivated virus, they don’t lead to as strong an immune response as those made using a live virus. Several doses, including boosters at regular intervals, are usually necessary, and the virus has to be grown in large quantities.
The Research Institute for Biological Safety Problems in Kazakhstan; the Wuhan Institute of Biological Products, which is a manufacturing entity of the state-run China National Pharmaceutical Group Corporation (Sinopharm) and is working in collaboration with the Wuhan Institute of Virology; the Institute of Medical Biology under the Chinese Academy of Medical Sciences; Sinovac Biotech; and the Beijing Institute of Biological Products are also developing vaccines made from an inactivated virus.
In a discussion in the New York Times in June, the director of the Center for Virology and Vaccine Research at the Beth Israel Deaconess Medical Center in Boston, Dan Barouch, said there were safety concerns about inactivated virus vaccines.
“If the virus is not fully inactivated, the danger is that it might actually cause the disease,” said Barouch, who is also a professor of medicine at Harvard Medical School.
In the same discussion, associate professor of medicine at Columbia University and cancer physician and researcher Siddhartha Mukherjee said that great care needed to be taken with RNA and DNA vaccines.
“The data discussed by Moderna in May would suggest that their vaccine can elicit antibodies in humans. It did so in eight patients. But whether that is protective against SARS-CoV-2, and how long the protection lasts, is an open question,” Mukherjee said.
Mukherjee emphasised that elderly people needed particular protection, so it needed to be understood how much the Moderna vaccine, or others like it, were eliciting long-term immunity in the elderly, whose immune systems might be already somewhat attenuated in their response.
Bharat Biotech and the American biopharmaceutical company Ocugen announced on December 22 that they had signed a binding letter of intent to co-develop Covaxin for the US market.
Adverse reactions
The Indian government has confirmed that a 68-year-old man died as a result of anaphylaxis after receiving a Covishield vaccination on March 8.
The cause of death was confirmed by the national committee responsible for studying reports of serious Adverse Events Following Immunisation (AEFI), which described the death as a “vaccine product related reaction”.
The Press Trust of India (PTI) quoted the chairperson of the AEFI committee, Dr N. K. Arora, as saying: “It is the first death linked to Covid-19 vaccination due to anaphylaxis. It re-emphasises the need to wait for thirty minutes at the inoculation centre after receiving the jab. Most of the anaphylactic reactions occur during this period and prompt treatment prevents deaths.”
The committee assessed 31 reported AEFIs, 28 of which were deaths. As per data collated in the first week of April, the reporting rate was 2.7 deaths per million vaccine doses administered and 4.8 hospitalisations per million vaccine doses administered, the committee said.
“Mere reporting of deaths and hospitalisations as serious adverse events does not automatically imply that the events were caused due to vaccines,” the immunisation division of the Ministry of Health and Family Welfare said in a report published on June 4. “Only properly conducted investigations and causality assessments can help in understanding if any causal relationship exists between the event and the vaccine.”
Eighteen of the reported deaths were classified as having an “inconsistent causal association to vaccination (coincidental – not linked to vaccination)”, seven were classified as indeterminate, and two were found to be unclassifiable. Of the three patients who were hospitalised and recovered, two of the adverse reactions, which were cases of anaphylaxis (one after administration of Covishield and one after administration of Covaxin), were found to be vaccine-product related and one, which was a case of fainting after the administration of Covaxin, was described as anxiety related.
In the case of anaphylaxis after administration of Covishield the patient was female and aged 21, and in the case of anaphylaxis after administration of Covaxin, the patient was male and aged 22.
In the case of many of the fatalities, there were cardiac or thrombotic disorders, including one case in which the patient had thrombocytopenia.
During a presentation to the AEFI committee on March 31, an analysis was presented of 492 of the adverse reaction reports received. (There were reported to be at least 617 serious adverse events as of March 29, including 180 deaths.)
it was stated that, of the 492 reports for which a detailed analysis was provided, more than 90% of hospitalisations of people suffering adverse reactions (276 of 305 people), more than 87% of cases of severe adverse reactions (55 of 63 cases), and 93 out of 124 deaths of people who had suffered adverse reactions happened within three days of Covid vaccination.
Interval between vaccination and deaths.
Time between vaccination and hospitalisation.
The Ministry of Health and Family Welfare reported on May 17 that, since the Covid vaccination drive started, more than 23,000 adverse events were reported through the CoWIN platform, from 684 of the 753 districts in the country.
Of these, 700 cases (about 9.3 cases per million doses administered) were reported to be serious and severe, the ministry said.
The national AEFI committee noted that, as of April 3, 75,435,381 vaccine doses had been administered (68,650,819 doses of Covishield and 6,784,562 doses of Covaxin). Of these, 65,944,106 were first doses and 9,491,275 were second doses.
The ministry said that the AEFI committee had completed an in-depth case review of 498 serious and severe events, of which 26 cases had been reported to be potential thromboembolic events following administration of the Covishield vaccine. This was a reporting rate of 0.61 cases per million doses, the ministry said.
There were no potential thromboembolic events reported following administration of the Covaxin vaccine, the ministry added.
“The reporting rate of these events in India is around 0.61/million doses, which is much lower than the 4 cases/million reported by UK’s regulator … Germany has reported 10 events per million doses.”
In a report on July 12, the ministry reported on the results of a causality assessment for 88 cases that was completed on June 28.
The ministry said that 61 of the 88 cases were found to have “consistent causal association to vaccination”.
“Of these 61 cases, 37 were vaccine product related reactions, 22 cases were immunisation anxiety related reactions, and two cases were immunisation error related reactions,” the ministry said.
“Eighteen cases have inconsistent causal association to vaccination (coincidental – not linked to vaccination).”
This included three deaths, the ministry said, adding that nine cases, including two deaths, were in an “indeterminate category”.
According to Indian government data accessed by CNN-News18, there had been 26,200 reports of adverse reactions after Covid vaccination, including 488 deaths, as of June 7. A total 2,318 of those reporting adverse reactions were hospitalised.
Of the 488 people who died, 457 received the Covishield vaccine and twenty received Covaxin, CNN-News18 reported. Details for 11 people were missing from the government data.
CNN-News18 reported that at least 27 of those who died were aged under 39 years and at least ten of them were aged under 29 years. The youngest person reported to have died was a 21-year-old man from Jammu and Kashmir and the oldest was reported to be a 97-year-old man from Karnataka.
A total 235 million Covid vaccine doses had been administered as of June 7 (26,200 is 0.01 percent of that total).
A total 24,703 cases (94.2% of the adverse reaction cases) were linked to Covishield and 1,497 were linked to Covaxin. As of June 7, 210 million doses of Covishield and 25 million doses of Covaxin had been administered.
A total 1.57% of the adverse reactions (412 cases) were described as severe and about 3.39% (887) cases were categorised as serious.
About 16.15% of those who reported adverse reactions (4,230) had underlying health conditions, according to the government data.
The most common adverse reaction was fever, which was reported in more than 45 percent (11,859) of the cases.
A total of 23,022 (87.87%) adverse reactions were reported after the first vaccine dose and 3,718 (14.19%) after the second dose, CNN-News18 reported. Just over 25% (6,560) of the adverse reactions were reported to have occurred within 30 minutes after vaccination.
In just over 28% of the cases, those affected were aged 51 years and above; in just over 26% of cases they were aged between 18 and 30 years, in just over 24% of cases they were aged between 31 and 40 years, and in nearly 21% of cases, they were aged between 41 and 50 years.
There were 5,622 more adverse reactions reported by women than by men, although 16.1 million more men were vaccinated during the time period, CNN-News18 reported.
A man in Chennai, India, who was a volunteer in the trial of Covishield launched a legal action against the SII for 50 million rupees (about US$680,000) in compensation. He says he suffered serious adverse effects after vaccination, including a severe neurological illness and impairment of his cognitive functions.
According to local media, the SII said the allegations made by the trial participant were “malicious and misconceived” and the SII would seek more than 1 billion rupees in damages.
The SII stated: “The incident with the Chennai volunteer, though highly unfortunate, was in no way induced by the vaccine.”
The legal notice issued by the volunteer’s lawyer states that the man received the Covishield vaccine on October 1, 2020, and, on October 11, he started suffering severe headaches and vomiting, and was not able to respond to questions.
His wife was quoted as saying there was a total “behavioural change” in her husband and he seemed unaware of his surroundings. “He showed irritation towards light and sound, and was resisting any effort to make him get up from bed,” she is quoted as saying.
The trial participant alleges that he became unable to speak or recognise anyone, and was completely disoriented. He was admitted to an intensive care unit.
The volunteer says he suffered acute encephalopathy. He says that he was discharged from the hospital on October 26, but his health is still not stable, he has severe mood swings and problems with comprehension, and still finds it difficult to do simple, routine things.
He says he was led to believe that Covishield had already been shown to be safe and that there was no risk of any side effects, let alone severe adverse effects.
He has called for the testing, manufacture, and distribution of Covishield to be stopped immediately in India.
The SII said Covishield was “safe and immunogenic”. It said it was sympathetic with the volunteer’s medical condition, but that all the requisite regulatory and ethical processes and guidelines were followed diligently and strictly.
The institute says the volunteer is falsely laying the blame for his medical problems on the vaccine trial. . “There is absolutely no correlation with the vaccine trial and the medical condition of the volunteer,” the SII said.
The SII said the concerned authorities were informed and the principal investigator, the Data and Safety Monitoring Board (DSMB), and the ethics committee, independently concluded that the volunteer’s health problems were not related to the vaccine trial.
“We would want to assure everyone that the vaccine won’t be released for mass use unless it is proven immunogenic, and safe,” the SII said. “Taking into consideration the complexities and existing misnomers about vaccination and immunisation; the legal notice was sent therefore to safeguard the reputation of the company which is being unfairly maligned.”
According to The Economic Times, a participant in the Phase 1 clinical trial of Covaxin, which was developed by Bharat Biotech in collaboration with the ICMR, fell ill and had to be hospitalised after being vaccinated in July 2020, but the trial was not halted and no public disclosure was made about the incident.
The Times of India reported that the adverse event occurred in a 35-year old participant with no co-morbidities during the trial at a site in western India. The participant was hospitalised with viral pneumonitis a couple of days after being vaccinated and was discharged after a week’s stay in hospital, the Times of India reported.
Bharat Biotech said the adverse event was investigated thoroughly and was determined not to be vaccine related.
In an article published in The Lancet on January 23, 2021, Anoo Bhuyan says participants in a Covaxin trial in Bhopal recounted that they could not read consent forms and were unable to report adverse events.
Many Bhopal residents told how a vehicle with a loudspeaker had come around their neighbourhood in December, 2020, Bhuyan, who covers health policy for The Wire, reported.
Bhuyan says the residents alleged that they were told that, if they went to the People’s University private hospital, they could get a Covid-19 vaccine and 750 rupees (about US$10).
Bhuyan tells the story of 57-year-old Ramesh, who said he got his first Covaxin vaccination on December 7, 2020.
Bhuyan also writes about carpenter Jai Ram, who said he had difficulty reporting adverse events. She quotes Ram as saying: “I felt quite weak after taking the injection for many days. I did not know what to do but someone advised me to drink juice made from ginger and so I did that.”
Ram said he didn’t have a phone so had not spoken to anyone from the hospital. “Thus his complaint of feeling weakness would not be recorded as an adverse event,” Bhuyan wrote.
Bhuyan quotes the dean of People’s University, A.K. Dixit, as saying there was a videographer in the room who took audio-video recordings of the informed consent. “However, both Ramesh and Ram said that they did not see anyone recording their consent,” she wrote.
“The Covaxin trial was not paused despite the alleged death of a participant. In an official statement, Bharat Biotech has said that the participant had died nine days after taking part in the trial.
“The post-mortem report says that the person had died from a ‘suspected poisoning’. The company’s statement says that their own investigation has concluded that the death was ‘not related to vaccine or placebo’.
Bharat Biotech and the ICMR did not respond to Bhuyan’s requests for comment.
Both Bharat Biotech and the ICMR have brushed aside allegations that there were protocol violations in the Covaxin phase 3 trials at a hospital in Bhopal.
There is a constantly updated account under the #VAERS_India hashtag on Twitter of adverse reactions, deaths, and Covid-19 cases occurring after Covid vaccination.
A Mumbai-based company, Gem Tours and Travels, caused controversy when it said it would offer ‘vaccine tourism’ packages for customers, and would facilitate vaccination in the US.
The company said in a WhatsApp message that it would facilitate tours to the US for ‘VVIP’ clients as soon as Pfizer’s vaccine gets final approval.
Pfizer said it was not working with any other partner at this time and had not authorised any agency to conduct or facilitate vaccination against SARS-CoV-2.
The company said it would supply its vaccine only to governments across the world on the basis of agreements with respective government authorities and following regulatory authorisation or approval.
Business Today in India reported that Gem Tours and Travels had issued a clarification in which the company stated: “We are not taking any money as of now. This opportunity is for people who are co-morbid and in need of the vaccination. This advertisement was misunderstood.”
China
Photo credit: CanSino Biologics
The Chinese authorities authorised three vaccines – CoronaVac, Ad5-nCoV, and BBIBP-CorV – for limited or emergency use without Phase 3 trials having being conducted. Only BBIBP-CorV has been given conditional approval for general public use. The authorisation was given by China’s top drug regulator, the National Medical Products Administration (NMPA). It was the first NMPA approval for a Covid-19 vaccine.
The Ad5-nCoV viral vector vaccine was approved for use for one year by the military in advance of Phase 3 trials. The same vaccine is being tested in Canada.
The manufacturer, CanSino Biologics, said that clinical trials had shown the vaccine to be safe and indicated some efficacy. The company is reported to be in talks with several countries to get emergency approval for its use.
Reuters reports that eight SARS-CoV-2 vaccines have been approved in China for human trials at home and abroad and five are at the stage of Phase 3 trials.
On December 9, the United Arab Emirates’ Ministry of Health and Prevention (MOHAP) announced the official registration of BBIBP-CorV.
The MOHAP said that, in collaboration with the Abu Dhabi Department of Health, it had reviewed Sinopharm’s interim analysis of the Phase 3 vaccine trials. The trials showed the vaccine to have 86 percent efficacy, the ministry said.
On 30 December, 2020, Sinopharm had announced 79.34% efficacy.
Results of the Phase 1/2 trial of BBIBP-CorV, which was jointly developed by the Beijing Institute of Biological Products and the China Centres for Disease Control and Prevention, were published in The Lancet online on October 15 last year.
Researchers found that humoral responses against SARS-CoV-2 were induced in all vaccine recipients on day 42.
“Two-dose immunisation with 4 μg vaccine on days 0 and 21 or days 0 and 28 achieved higher neutralising antibody titres than the single 8 μg dose or 4 μg dose on days 0 and 14, Xiaoming Yang et al. said.
Humoral immune responses are mediated by antibodies produced by B cells whereas cell-mediated immune responses do not involve antibodies.
Xiaoming Yang et al. said their research indicated that BBIBP-CorV was “safe and well tolerated” at all tested doses in two age groups and induced neutralising antibodies.
The vaccine was tested in 640 healthy volunteers. In Phase 1, 192 volunteers aged between 18 and 80 years were enrolled and were separated into two age groups, those aged 18–59 and those aged 60 or older. The trial participants were randomly assigned to receive the vaccine or a placebo in a two-dose schedule.
In Phase 2, the 448 participants were aged 18–59 years. They were randomly assigned to receive the vaccine or a placebo in a single-dose or two-dose schedule.
In Phase 1, at least one adverse reaction was reported within the first seven days of vaccination in 42 of 144 vaccine recipients.
“The most common systematic adverse reaction was fever (18–59 years, one [4%] in the 2 μg group, one [4%] in the 4 μg group, and two [8%] in the 8 μg group; ≥60 years, one [4%] in the 8 μg group),” Yang et al. reported. “All adverse reactions were mild or moderate in severity. No serious adverse event was reported within 28 days post vaccination.”
In phase 2, at least one adverse reaction within the first seven days was reported in 76 of 336 vaccine recipients. Again, the most common systematic adverse reaction was fever.
In a comment published in The Lancet, Irina Isakova-Sivak and Larisa Rudenko from the Institute of Experimental Medicine in Saint Petersburg, Russia, noted that the older age group in the Phase 1/2 trials had lower rates of “solicited adverse events” than the younger adults.
“The overall rates of adverse events within 28 days after vaccination were 34 (47%) of 72 participants in the group aged 18–59 years, compared with 14 (19%) of 72 participants in the group aged 60 years and older,” Isakova-Sivak and Rudenko wrote. “At the same time, in both age groups the vaccine was similarly immunogenic.”
Isakova-Sivak and Rudenko noted that the trials included an assessment of the effect on the vaccine’s immunogenicity of shortening the interval between two doses from 28 days to 21 or 14 days.
“The 4 μg dose of the vaccine was the most immunogenic when given at the 21-day interval (neutralising antibody titre 283), but its immunogenicity significantly decreased when the interval was reduced to 14 days (neutralising antibody titre 170), suggesting that the interval cannot be shorter than 3 weeks,” Isakova-Sivak and Rudenko wrote.
The two researchers say that encouraging results have been obtained when testing BBIBP-CorV in various animal models, where no disease enhancement on SARS-CoV-2 challenge was found.
“However, we need to acknowledge that for this new infection, all possible animal models have not yet been worked out for simulating antibody-dependent disease enhancement in humans,” they wrote.
“Therefore, long-term careful monitoring of quantitative and qualitative characteristics of the induced SARS-CoV-2 antibodies after vaccination with inactivated SARS-CoV-2 vaccines is critically important.”
Isakova-Sivak and Rudenko also said that more studies were needed to establish whether the inactivated SARS-CoV-2 vaccines were capable of inducing and maintaining virus-specific T-cell responses, “because CD4-positive T-cell help is important for optimal antibody responses, as well as for cytotoxic CD8-positive T-cell activation, which, in turn, are crucial for viral clearance if neutralising antibody-mediated protection is incomplete”.
On December 13, the National Health Regulatory Authority (NHRA) in Bahrain announced that it had approved the registration of BBIBP-CorV.
The MOHAP in the UAE said in its announcement on December 9 that no serious safety concerns were reported in the trials of BBIBP-CorV. The ministry granted the vaccine emergency use authorisation in September.
The UAE is conducting post-authorisation safety and efficacy studies. The MOHAP says the safety and efficacy results are similar to those reported in Sinopharm’s interim analysis.
Phase 3 vaccine trials were carried out in several countries, including in the UAE, where 31,000 volunteers participated.
The NHRA in Bahrain said its decision to approve and use BBIBP-CorV was based on clinical trial data conducted in several countries.
Results from Phase 3 clinical trials showed an 86% efficacy rate, a 99% seroconversion rate of neutralising antibodies, and 100% effectiveness in preventing moderate and severe cases of Covid-19, following testing on 42,299 volunteers, the regulator said.
In a report in Nature on January 15 this year, Smriti Mallapaty said that results of trials in Brazil of CoronaVac “were tinged with disappointment and confusion”.
Researchers in Brazil reported that the vaccine was 50.4% effective at preventing severe and mild Covid-19 in late-stage trials.
The efficacy statistics were much lower than those from early trials of CoronaVac in Turkey and Indonesia and those first reported by the researchers from the Butantan Institute in São Paulo, who had announced on January 7 that the vaccine’s efficacy was 78%, Mallapaty reported.
The researchers now point out that the earlier statistic was based on the criteria of people needing medical attention.
In the trial in Brazil, 252 cases of Covid-19 were recorded (85 in the vaccinated group and 167 among those who received the placebo). None of the participants who received the vaccine had to be hospitalised with severe Covid-19.
In late December, researchers said that, in the trial in Turkey, CoronaVac had been shown to be 91.25% effective at preventing symptomatic disease. The result was based on just 29 Covid-19 cases among 1,322 trial participants.
Indonesia has authorised CoronaVac for emergency use and started its national vaccination programme on January 13.
In a trial involving about 1,600 people, researchers found the vaccine to be 65.3% effective at preventing symptomatic disease, Mallapaty reported. This calculation was made based on the confirmation of just 25 Covid-19 cases, he wrote, quoting a vaccinologist at Gadjah Mada University in Yogyakarta, Jarir At Thobari.
Researchers involved with the Brazil trial say the lower efficacy compared with other vaccines could be because the two shots were administered only two weeks apart, which did not leave sufficient time for participants to reach peak immunity, Mallapaty wrote.
“They also say that the trial, which recruited only health professionals, who are more likely to be exposed to the virus, report symptoms and get tested, probably identified more mild infections than did trials in Indonesia and Turkey, which included the public,” he added.
The results of the Phase 1 and 2 trials of CoronaVac, which took place in Jiangsu province, China. were published in The Lancet on November 17, 2020.
Just 144 participants were involved in Phase 1 and 600 in Phase 2. Volunteers were aged 18 to 59 years.
Anvisa authorised the emergency use of CoronaVac and the AstraZeneca-Oxford vaccines on January 17.
Anvisa said on November 9 last year that it had ordered the interruption of the clinical trial of CoronaVac after a serious adverse incident.
On November 11, the Reuters news agency reported that Anvisa said it suspended the trial because of the suicide of a participant. Reuters quoted the head of Anvisa, Antonio Barra Torres, as saying: “We had no choice but to suspend the trials given the event.”
Reuters had earlier quoted Dimas Covas, who is the head of Butantan, the medical research institute conducting the Brazilian trial, as saying the death was not related to the vaccine.
Sinovac stated on November 10: “After communicating with the Brazilian partner Butantan Institute, we learned the head of Butantan Institute believed that this serious adverse event is not related to the vaccine.
“Sinovac will continue to communicate with Brazil on this matter. The clinical study in Brazil is strictly carried out in accordance with GCP requirements and we are confident in the safety of the vaccine.”
Sinovac has been conducting Phase 3 trials abroad because the number of active cases of SARS-CoV-2 infections in China is too low to provide trial cohorts.
The company said that Phase 2 trials involving 600 people in China indicated that CoronaVac appeared to be safe and induced detectable antibody-based immune responses in the participants.
China’s foreign ministry spokesman Wang Wenbin announced on February 3 that China had, at the request of the WHO, decided to provide ten million Covid-19 vaccine doses to COVAX.
Authorisations in the EU
On January 29, the EC granted a conditional marketing authorisation for the AstraZeneca-Oxford vaccine. This followed a recommendation from the EMA.
The EMA said: “Combined results from four clinical trials in the United Kingdom, Brazil and South Africa showed that Covid-19 Vaccine AstraZeneca was safe and effective at preventing Covid-19 in people from 18 years of age.”
The agency said it based its calculation of how well the vaccine worked on the results from studies conducted in the UK and Brazil.
“The other two studies had fewer than six Covid-19 cases in each, which was not enough to measure the preventive effect of the vaccine,” the EMA said.
“In addition, as the vaccine is to be given as two standard doses, and the second dose should be given between four and 12 weeks after the first, the agency concentrated on results involving people who received this standard regimen.”
The EMA said the results showed a 59.5% reduction in the number of symptomatic Covid-19 cases in people given the vaccine (64 of 5,258 people got Covid-19 with symptoms) compared with those given control injections (154 of 5,210 got Covid-19 with symptoms).
“This means that the vaccine demonstrated around a 60% efficacy in the clinical trials,” the EMA said.
AstraZeneca points out that its vaccine can be stored, transported and handled at normal refrigerated conditions (two-eight degrees Celsius/36-46 degrees Fahrenheit) for at least six months.
The vaccine has been granted a conditional marketing authorisation or emergency use in nearly fifty countries on four continents.
On December 21, the EC granted a CMA for use of the Pfizer-BioNTech Covid vaccine for individuals aged 16 years and above.
The FDA’s EUA for BNT162b2a was issued on December 11 and allows the vaccine to be distributed in the US and to be given to individuals aged 16 years and older.
The EC’s decision followed a recommendation by the EMA earlier in the day that the CMA should be granted.
The CMA was the first marketing authorisation of a Covid-19 vaccine in the European Union (EU) by the EC. The EC’s decision applies to all 27 EU member states. The vaccine will be marketed in the EU under the brand name Cominarty.
On January 6, the commission granted a CMA for use of the Moderna Covid vaccine for people aged 18 years and above.
On March 11, the EC granted a CMA for use, for people aged 18 years and above, of the Covid-19 vaccine developed by Janssen Biotech.
The EMA had recommended the authorisation, saying that its Committee for Medicinal Products for Human Use concluded by consensus that the data about the vaccine were robust and met the criteria for efficacy, safety, and quality.
On March 4, the CHMP announced that it had started a rolling review of the Sputnik V vaccine. The EU applicant for the review is R-Pharm Germany GmbH.
The CHMP said its decision to start the review was based on results from laboratory studies and clinical studies in adults.
“The EMA will evaluate data as they become available to decide if the benefits outweigh the risks,” the committee said. The rolling review would continue until enough evidence was available for a formal marketing authorisation application, it added.
“The EMA will assess Sputnik V’s compliance with the usual EU standards for effectiveness, safety and quality. While the EMA cannot predict the overall timelines, it should take less time than normal to evaluate an eventual application because of the work done during the rolling review.”
In November 2020, Pfizer and BioNTech reached an agreement with the EC to supply 200 million doses of their Covid vaccine in 2020 and 2021, with an option for the EC to request an additional 100 million doses.
The EC said that distribution of the full 200 million doses was scheduled to be completed by September 2021 and the commission and the member states were working to activate the additional 100 million doses.
The EMA said that Pfizer would continue to provide results from the main vaccine trial, which would continue for two years. “This trial and additional studies will provide information on how long protection lasts, how well the vaccine prevents severe Covid-19, how well it protects immunocompromised people, children and pregnant women, and whether it prevents asymptomatic cases.”
Pfizer would also carry out studies “to provide additional assurance on the pharmaceutical quality of the vaccine as the manufacturing continues to be scaled up”, the EMA said.
Pfizer and BioNTech previously said that their vaccine needed to be stored in an ultra-cold freezer at temperatures between -80ºC and -60ºC (-112ºF to ‑76ºF) and could remain stored at these temperatures for up to six months. This temperature condition is cited in the emergency use authorisation granted in the US.
The FDA announced on February 25, however, that it would allow undiluted frozen vials of the vaccine to be transported and stored at conventional temperatures found in pharmaceutical freezers for a period of up to two weeks.
“This reflects an alternative to the preferred storage of the undiluted vials in an ultra-low temperature freezer … ,” the FDA said.
“This alternative temperature for transportation and storage of the undiluted vials is significant and allows the vials to be transported and stored under more flexible conditions.”
The FDA’s announcement was in response to the companies’ submission of new data that they say demonstrate the stability of the vaccine when it is stored at -25°C to -15°C (-13°F to 5°F), temperatures more commonly found in pharmaceutical freezers and refrigerators.
The data were submitted to the FDA to support a proposed update to the EUA prescribing Information, which would allow for vaccine vials to be stored at these lower temperatures for a total of two weeks as an alternative or complement to storage in an ultra-cold freezer.
The alternative temperature for storage of frozen vials is not applicable to the storage of thawed vials before dilution, which can be held in a refrigerator for up to five days, or the storage of thawed vials after dilution, which can be held at refrigerator or room temperature for use within six hours.
The storage data are also being submitted to other regulatory agencies, Pfizer and BioNTech said.
According to current labelling, the Pfizer-BioNTech vaccine needs to be shipped in a specially designed thermal container that can be used as temporary storage for a total of up to thirty days by refilling with dry ice every five days.
The labelling says that, before it is mixed with a saline diluent, the vaccine can also be refrigerated for up to five days at a standard refrigerator temperature, between 2⁰C and 8⁰C (36⁰F and 46⁰F).
Pfizer and BioNTech now say that, as additional stability data are obtained, they anticipate that the shelf life and/or expiration date of the vaccine could be extended.
Development of CSL vaccine stops because of false HIV positives
The Australian government announced on September 7, 2020, that it had struck Covid vaccine supply and production agreements with AstraZeneca and the Australian biotechnology company CSL. Under the agreements, and on the condition that clinical trials were successful, CSL would manufacture the AstraZeneca vaccine. Australia has also ordered vaccine doses from Novavax and Pfizer-BioNTech.
CSL was developing a vaccine against SARS-CoV-2 in collaboration with the University of Queensland (UQ), but the Australian government terminated its agreement with the CSL subsidiary Seqirus to supply 51 million doses of its vaccine after trial participants returned false positive test results for HIV. The participants subsequently tested negative for HIV.
CSL said in a statement on December 11 that, following consultation with the Australian government, the company would not conduct Phase 2/3 clinical trials of its vaccine.
The company said the Phase 1 data showed the generation of antibodies directed towards fragments of the Gp41 protein, which were being used to stabilise the vaccine.
“Trial participants were fully informed of the possibility of a partial immune response to this component, but it was unexpected that the levels induced would interfere with certain HIV tests,” CSL said.
CSL said there was no possibility that the vaccine caused infection, and routine follow-up tests confirmed that there was no HIV virus present.
“With advice from experts, CSL and UQ have worked through the implications that this issue presents to rolling out the vaccine into broad populations,” the company added.
“It is generally agreed that significant changes would need to be made to well-established HIV testing procedures in the healthcare setting to accommodate rollout of this vaccine. Therefore, CSL and the Australian government have agreed vaccine development will not proceed to Phase 2/3 trials.”
The Phase 1 trial would continue, CSL said. “Further analysis of the data will show how long the antibodies persist, with studies so far showing that levels are already falling. The University of Queensland plans to submit the full data for peer review publication,” the company added.
The chief scientific Officer for CSL, Andrew Nash, said the manufacture of approximately 30 million doses of the AstraZeneca-Oxford vaccine was underway, with the first doses planned for release to Australia early next year.
“In addition, CSL has agreed, at the request of the Australian government, to manufacture an additional 20 million doses,” Nash said.
Virologist Nikolai Petrovsky from Flinders University in Adelaide, who is developing a SARS-CoV-2 vaccine candidate that is in phase 1 trials, told The Australian that he had warned the federal government months before it struck a deal with CSL that there would be a big problem with the Gp41 protein UQ scientists were using in a molecular clamp to stabilise the vaccine. Given that the clamp was from HIV, antibodies against HIV would obviously be generated, Petrovsky said.
Facebook clampdown
Facebook has stepped up its clampdown on what it considers to be misinformation about Covid-19 and vaccines.
On February 10, the tech giant removed the Instagram account of the lawyer and environmentalist Robert F. Kennedy, Jr because of his statements about Covid vaccination.
Kennedy, who is the founder, chairman, and chief legal counsel of the organisation Children’s Health Defense, has endlessly repeated that he is not “anti-vax”, but is pro vaccine safety.
In his statement in response to being deplatformed from Instagram, he said: “Every statement I put on Instagram was sourced from a government database, from peer-reviewed publications and from carefully confirmed news stories. None of my posts were false.
“Facebook, the pharmaceutical industry and its captive regulators use the term ‘vaccine misinformation’ as a euphemism for any factual assertion that departs from official pronouncements about vaccine health and safety, whether true or not.
Kennedy, whose Facebook account remains active, says the pharmaceutical industry has hastily created “risky new products” that are exempt from liability and long-term safety testing and have not received FDA approval.
Emergency use authorisation is a “mass population scientific experiment ”, Kennedy says.
Kennedy is one of 12 people whom the Center for Countering Digital Hate (CCDH) in the US has dubbed the ‘Disinformation Dozen’. The organisation says the 12 are responsible for about 70% of what they describe as “anti-vaccine content” that is shared on Facebook.
Facebook’s vice-president for content policy, Monika Bickert, wrote on August 18, that there had been a debate about whether the global problem of Covid-19 vaccine misinformation could be solved simply by removing 12 people from social media platforms.
“People who have advanced this narrative contend that these 12 people are responsible for 73% of online vaccine misinformation on Facebook,” she said. “There isn’t any evidence to support this claim.
“Moreover, focusing on such a small group of people distracts from the complex challenges we all face in addressing misinformation about COVID-19 vaccines.”
Bickert said Facebook had removed more than three dozen pages, groups and Facebook or Instagram accounts linked to the 12 people.
“We have also imposed penalties on nearly two dozen additional pages, groups or accounts linked to these 12 people, like moving their posts lower in News Feed so fewer people see them or not recommending them to others,” she added.
Bickert said that the 12 people dubbed the ‘Disinformation Dozen’ were only responsible for about 0.05% of all views of vaccine-related content on Facebook. “This includes all vaccine-related posts they’ve shared, whether true or false, as well as URLs associated with these people,” she added.
“The report upon which the faulty narrative is based analysed only a narrow set of 483 pieces of content over six weeks from only 30 groups, some of which are as small as 2,500 users.”
Bickert said there was no explanation for how the CCDH identified the content they describe as “anti-vax” or how they chose the thirty groups they included in their analysis.
“There is no justification for their claim that their data constitute a ‘representative sample’ of the content shared across our apps,” she added.
Bickert said that, since the beginning of the pandemic, across the entire Facebook platform, the company had removed more than 3,000 accounts, pages and groups “for repeatedly violating our rules against spreading Covid-19 and vaccine misinformation” and had removed more than 20 million pieces of content for breaking these rules.
At the top of the CCDH’s list is the well-known American osteopathic physician and author Joseph Mercola, who is now removing all his online articles (more than 15,000 in number, written over 25 years). He says he will continue to publish new articles, but each one will be available for only 48 hours and will then be removed from his website.
“There was a recent NY Times article attacking me and it was one of the most widely distributed stories in the world,” Mercola said. “The article was loaded with false statements made about me and my organisation.”
Mercola say he and his staff have been harassed and threatened. He says CNN crews followed him from his home with two vehicles while he bicycled to the beach.
The White House press secretary, Jen Psaki, said the US administration had recommended to social media platforms that they form an enforcement strategy against those promoting false statements about the Covid-19 pandemic.
The president of Children’s Health Defense, Mary Holland, said: “Covid-19 vaccines use novel technology never before used in a human population. With that comes great unknown risks. The people of the world deserve to have this crucial information to protect their health and that of their children.”
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