This article has been updated. Latest update 8/5/2021.
- The Pfizer-BioNTech, AstraZeneca-Oxford, and Moderna vaccines are being administered under emergency use authorisations in the UK.
- The FDA in the US issued emergency use authorisations for the Pfizer-BioNTech and Moderna vaccines and the vaccine developed by the Johnson & Johnson subsidiary Janssen Biotech. It later recommended a pause in use of the Janssen Biotech vaccine “out of an abundance of caution”, then said use should resume.
- 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.
- Covid vaccination is underway in India. Two vaccines have been approved for restricted emergency use.
- Vaccine manufacturers are seeking strategies to combat virus variants.
- 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 started trials involving children aged 6 months to 11 years.
- There are concerns that there may be disease enhancement with some vaccines.
- Covid vaccination “passports” have been introduced in some countries. They are expected to become increasingly widespread and to be required to fly and cross borders and, in many countries, to use public transportation, access certain facilities, and attend particular events.
Massive Covid vaccination drives are underway around the world, mostly under emergency use authorisations.
According to the Our World in Data website, more than 1.24 billion vaccine doses had been administered worldwide by May 6.
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 effects, and the lack of evidence that vaccination will prevent SARS-CoV-2 infection or virus spread.
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 new mix-and-match experiments that could lead to people being given one dose of one vaccine and a booster of a different one.
The British-Swedish pharmaceutical giant AstraZeneca announced on December 11 that it plans to start a clinical trial combining its AZD1222 vaccine, now known as Covid-19 Vaccine AstraZeneca, with Russia’s Sputnik V to assess the safety and immunogenicity of the combination. Volunteers aged 18 and older will be enrolled.
The trial is expected to start soon in Azerbaijan, the United Arab Emirates, and other countries in the Middle East.
“Both AZD1222 and Sputnik V are adenoviral vector vaccines that contain genetic material of the SARS-CoV-2 virus spike protein,” AstraZeneca said. “The adenovirus itself is unable to replicate so it can only act as a carrier of genetic material.”
Sputnik V is happy to share one of its two human adenoviral vectors with @AstraZeneca to increase the efficacy of AstraZeneca vaccine. Using two different vectors for two vaccine shots will result in higher efficacy than using the same vector for two shots. #SputnikV
— Sputnik V (@sputnikvaccine) November 23, 2020
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.
After vaccination, the surface spike protein is produced, priming the immune system to attack the SARS-CoV-2 virus if it later infects the body.
This means that when the adenovirus enters vaccinated people’s cells it also delivers the spike protein genetic code.
Reuters reported that Russia’s sovereign wealth fund, the Russian Direct Investment Fund (RDIF), was also set to announce a joint trial with one of the vaccine developers in China.
Researchers at the University of Oxford are meanwhile enrolling volunteers in an 820-person trial in the UK in which volunteers will be given one dose of the Pfizer-BioNTech vaccine and one dose of the AstraZeneca vaccine.
The 13-month 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 researchers will also gather data about the effects of different intervals between the first and second doses in a mixed-vaccine regimen compared with control groups in whic the same vaccine is used for both doses.
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.”
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.
“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.”
Misunderstandings about efficacy
There is widespread misunderstanding among the general public about what vaccine effectiveness means and many people misguidedly believe that, once vaccinated, they can cast aside their masks and hug their family members without risk. The reality is that vaccination may only prevent severe Covid-19 disease.
The main efficacy percentages 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 relate to disease prevention, not the prevention of infection.
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 251 million doses have been given so far.
In the UK, where Covid vaccination began on December 8, more than 51 million doses have been administered.
The Seychelles, Israel, and the United Arab Emirates are the three countries that have vaccinated their populations the fastest.
Israel has seen a sharp drop in daily mortality and infection rates since the pandemic peaked in late January and the number of Covid-19 patients in serious condition dropped below 100 on May 3. In the Seychelles, however, there has been a surge in Covid cases and restrictions, including school closures, have been reimposed.
In China, more than 297 million Covid vaccine doses are reported to have been administered. More than 21 million doses are reported to have been administered in Russia.
India started administering Covid vaccinations on January 16 and more than 162 million doses have been administered so far.
In north Africa, Morocco has started its vaccination drive after the delivery of shipments of the BBIBP-CorV vaccine developed by the Chinese company Sinopharm and the AstraZeneca-Oxford vaccine, which is branded as Covishield in India.
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.
Egypt began the vaccination of medical staff on January 25, administering the BBIBP-CorV vaccine at a hospital in the northeastern province of Ismailia.
On February 4, The Palestinian Authority received 10,000 doses of the Sputnik V vaccine.
The authority had already begun vaccinating health workers on February 2 in the occupied West Bank 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 from COVAX programme, 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.
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 COVAX, 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 has said it will provide advance procurement commitment guarantees of up to US$2 billion to the manufacturers on behalf of countries.
Brazil started administering the CoronaVac vaccine, developed by the Chinese company Sinovac Biotech, on January 17 and, since then, more than 46 million doses have been administered.
The Centers for Disease Control and Prevention (CDC) says in updates about quarantine recommendations that fully vaccinated people “who meet criteria” will 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 adds.
According to CNN, the “criteria” are 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 quotes the CDC as saying it’s not known how long protection lasts, so people who had their last vaccine dose three months or more earlier should still quarantine if they are exposed to a case of Covid-19.
“They also should quarantine if they show symptoms,” CNN quotes the CDC as saying.
The new recommendation has been criticised as being ill thought out and premature.
@Reuters @CDCDirector @CDCgov THIS IS INADVISABLE AND PREMATURE POLICY:
• New strains will quickly become predominant and lead to increased disease severity
• There is an absence of evidence that vaccines protect from transmission
• We are nowhere near herd immunity pic.twitter.com/o9938sTVIq
— Andre Watson 🧬💊💉🎹 (@nanogenomic) February 11, 2021
On March 8, the CDC updated its guidelines about what people can and cannot do after vaccination.
The new guidelines state that, if you’ve been fully vaccinated, you can do the following:
- You can gather indoors with fully vaccinated people without wearing a mask.
- You can 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.
- If you’ve been around someone who has Covid-19, you do not need to stay away from others or get tested unless you have 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.
While there is literal jubilation in many quarters about the new guidelines, there are also many people who are shocked at the separation of people according to their vaccination status.
One person tweeted: “Vaccinated people can gather, no restrictions. But if you are around unvaccinated, all have to mask & SD. This causes a wedge, leads to division, fear, anger, resentment, and lastly compliance/acceptance.”
The CDC issued its new guidelines despite admitting that they are still learning how effective the Covid vaccines are against SARS-CoV-2 variants, how well they prevent people from spreading the virus, and how long any protection they offer may last.
Do Covid vaccines prevent transmission of SARS-CoV-2 from person to person?
Andre Watson, who is the founder and CEO of the regenerative medicine and pandemic defence biotechnology company Ligandal, based in San Francisco, said: “The vaccines have not been shown to prevent asymptomatic infection, only clinical illness. It is assumed for now that individuals who have been vaccinated can still acquire the SARS-CoV-2 virus and may transmit to others.”
In a briefing document released on December 8, ahead of the VRBPAC meeting on December 10, the FDA says 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 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.
“Additional evaluations including data from clinical trials and from vaccine use post-authorisation will be needed to assess the effect of the vaccine in preventing virus shedding and transmission, in particular in individuals with asymptomatic infection.”
When asked by NBC’s Lestor Holt, during an interview aired in early December, whether someone could still transmit the virus after vaccination the Pfizer CEO Albert Bourla said that the company was not certain about this and it was something that needed to be examined.
Several reports have since been published that are being taken as evidence 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.
“Under real-world conditions, mRNA vaccine effectiveness of full immunisation (≥14 days after second dose) was 90% against SARS-CoV-2 infections regardless of symptom status,” the CDC said. “Vaccine effectiveness of partial immunisation (≥14 days after first dose but before second dose) was 80%.”
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 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.
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 use of leaky vaccines can facilitate the evolution of pathogen strains that put unvaccinated hosts at greater risk of severe disease,” Read et al. wrote.
“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.
“Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist,” the researchers wrote.
“Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts.”
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 altogether.
On May 3, the Danish Health Authority said it was excluding the Janssen Biotech vaccine from its vaccination programme.
The authority said it had concluded that the benefits of using the vaccine did not outweigh the risk of causing the possible adverse effect, VITT, in those who received it.
The Danish Health Authority has reviewed the use of the COVID-19 vaccine from Johnson & Johnson in the Danish COVID-19 vaccination programme based on international data and statements released in the last month. In addition, a team of Danish experts has 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.
“However, taking the present situation in Denmark into account, what we are currently losing in our effort to prevent severe illness from Covid-19 cannot outweigh the risk of causing possible side effects in the form of severe blood clots in those we vaccinate. One should also bear in mind that, going forward, we will first and foremost be vaccinating younger and healthy people.”
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.
Indonesia said it would delay the rollout of the AstraZeneca-Oxford vaccine and Venezuela announced that it would not authorise its use.
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 European Medicines Agency (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 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.
“These are women between 25 and 65 years old,” Lareb said. Three patients had extensive pulmonary embolisms. One died and one also had a brain haemorrhage. Another patient had extensive abdominal vein thrombosis. One patient developed a thrombosis of the arteries in the legs.”
Lareb said it had previously reported on three reports involving a combination of thrombosis with a reduced number of platelets.
“At that time it was not sufficiently clear whether the picture was the same as that seen in other countries. Two reports have now been added and more information is available about the previous reports. There is also more clarity about the nature of the reports from other countries,” 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.”
As of March 30, Germany’s federal institute for vaccines and biomedicines, the Paul-Ehrlich-Institut, reported 31 cases of cerebral venous sinus thrombosis (CVST) among people who received the AstraZeneca-Oxford vaccine.
Reuters reports that in nine of the cases the patient died and in 19 of the cases there was a deficiency of blood platelets.
With the exception of two cases, all the reports concerned women between the ages of twenty and 63, Reuters reports. The two men were 36 and 57 years old.
The EMA said on April 9 that the agency’s Pharmacovigilance Risk Assessment Committee (PRAC) was investigating thromboembolic events after vaccination with the single-dose Covid vaccine developed by the Johnson & Johnson subsidiary Janssen Biotech.
“PRAC has started a review of a safety signal to assess reports of thromboembolic events (formation of blood clots, resulting in the obstruction of a vessel) in people who received Covid-19 Vaccine Janssen,” the EMA said.
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.
“All cases occurred in people under 60 years of age within three weeks after vaccination, the majority in women. Based on the currently available evidence, specific risk factors have not been confirmed.”
The PRAC chairwoman, Sabine Straus, said: “After a careful review of the cases of blood clots combined with low platelets reported after vaccination with Janssen’s Covid-19 vaccine, the PRAC has concluded that there is a possible link between the occurrence of these blood blood clots combined with the low levels of blood platelets, thrombocytopenia, and the vaccination with the Covid-19 vaccine Janssen.
“The product information will be updated to reflect this information and will include a warning and an update of the side effects.”
Straus said there was a “strong association” between the cases of thrombosis with thrombocytopenia and administration of the Janssen vaccine.
She added that the eight patients in the US were aged between 18 and 49.
The EMA said that, as of April 13, 2021, more than seven million people had received Janssen Biotech’s vaccine in the US.
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 cases reviewed were very similar to the cases that occurred after vaccination with the AstraZeneca-Oxford vaccine, the PRAC said.
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, at present, no clear causal relationship had been established between these “rare events” and the Janssen Biotech vaccine.
On April 23, the EMA announced that its Committee for Medicinal Products for Human Use (CHMP) recommended that people should receive a second dose of the AstraZeneca-Oxford vaccine (now known as Vaxzevria) 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.
“However, there has not been enough exposure and follow-up time to determine whether the risk of blood clots with low blood platelets after a second dose will differ from the risk after the first dose. At present there are no or limited data to change current recommendations.”
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”.
The director of the FDA’s Center for Biologics Evaluation and Research, 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.
“In these cases, a type of blood clot called cerebral venous sinus thrombosis (CVST) was seen in combination with low levels of blood platelets (thrombocytopenia),” Marks and Schuchat said.
“All six cases occurred among women between the ages of 18 and 48, and symptoms occurred six to 13 days after vaccination.”
“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.”
Marks and Schuchat said that, until investigations into the cases were completed, they were recommending a pause in the use of the Janssen Biotech vaccine “out of an abundance of caution”.
On April 23 the FDA and CDC lifted the pause. They said that “following a thorough safety review”, including two meetings of the CDC’s Advisory Committee on Immunisation Practices, they had determined that the recommended pause should be lifted and use of the vaccine should resume.
The FDA and the CDC said they had confidence that the Janssen Biotech vaccine was safe and effective in preventing Covid-19. They said the FDA had determined that “the available data show that the vaccine’s known and potential benefits outweigh its known and potential risks in individuals 18 years of age and older”.
The agencies said that, at this time, 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.
They added: “Today, the agencies can confirm that a total of 15 cases of TTS have been reported to VAERS, including the original six reported cases. All of these cases occurred in women between the ages of 18 and 59, with a median age of 37 years. Reports indicated symptom onset between 6 and 15 days after vaccination.”
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.
Marks said during a press conference when the pause was announced: “The issue here with these types of blood clots is that, if one administers the standard treatments that we as doctors have learned to give for blood clots, one can actually cause tremendous harm or the outcome can be fatal.”
He added: “One needs to make sure that providers are aware that if they see people who have low blood platelets, or if they see people who have blood clots, they need to inquire about a history of recent vaccination and then act accordingly in the diagnosis and management of those individuals.”
Marks said: “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.”
He said he was unable to make a broad statement yet, but added: “they are from the same general class of viral vectors”.
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.
A CDC spokeswoman said in an email that in one of the cases the patient was male and in the other case the patient was female, and both patients were under 60 years old, Bloomberg reported.
“The new reports bring the total number of cases to 17 out of about 8.1 million doses administered in the US,” Bloomberg added. The CDC noted that the patients in the 15 earlier cases were all women.
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 has concluded that clotting disorders are “very rare” side effects of the #AstraZeneca-Oxford vaccine and the risk of dying from Covid-19 is 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 for these “very rare side effects”.
Straus said the committee members had learned “from the very detailed review of the cases” that there was “a strong association with the AstraZeneca vaccine and the adverse events”.
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.
Most of the cases reported have occurred in women under 60 years of age within two weeks of them receiving their first vaccine dose.
The PRAC says one plausible explanation for the combination of blood clots and low blood platelets is 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 meanwhile that “the benefits of the vaccine far outweigh the risks for the vast majority of adults”.
The spokesperson added, however, that it was preferable for people under the age of 30 with no underlying health conditions to be offered an alternative vaccine where possible.
“Everybody who has already had a first dose of the AstraZeneca vaccine should receive a second dose of the same brand, irrespective of age, except for the very small number of people who experienced blood clots with low platelet counts from their first vaccination,” the spokesperson said.
“The government will follow today’s updated advice, which sets out that, as a precaution, it is preferable for people under the age of 30 with no underlying health conditions to be offered an alternative vaccine where possible once they are eligible.”
The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) said that, by the end of March, 79 people (51 women and 28 men), who were aged between 18 and 79 years (three of them under 30), had suffered rare blood clots after vaccination with the AstraZeneca-Oxford vaccine and 19 of them died. The agency notes that more women than men have been vaccinated with the AstraZeneca-Oxford vaccine.
Forty-four of the 79 patients had CVST with thrombocytopenia and 35 had thrombosis in other major veins with thrombocytopenia. Of the 19 people who died 13 were women.
By March 31, 20.2 million doses of the AstraZeneca-Oxford vaccine had been given in the UK meaning that the overall risk of the blood clots was approximately four people in a million who receive the vaccine, the MHRA said.
The chairman of the UK’s Commission on Human Medicines (CHM), Sir Munir Pirmohamed, said the CHM had advised that the link between the vaccine and blood clots in cerebral and other veins, occurring together with lowered platelets, was getting firmer, “but absolute proof of the link between the vaccine and adverse events will need extensive scientific work”.
Pirmohamed said that, based on available evidence, the benefit-risk remained favourable for the vast majority of people, but was more finely balanced for younger people. “We are advising that this evolving evidence should be taken into account when considering the use of the vaccine,” he added.
He said pregnant woman should continue to discuss with their healthcare professional whether the benefits of having the vaccine outweigh the risks for them.
“People with a history of blood disorders that increase the risk of clotting should only have the Covid-19 vaccine AstraZeneca when the benefits outweigh any potential risks,” Pirmohamed said
“Anyone who experienced cerebral or other major blood clots occurring together with low levels of platelets, after the first vaccine of Covid-19 AstraZeneca should not have the second dose.”
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 UK’s Joint Committee on Vaccination and Immunisation (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.
“Adults who are aged 18 to 29 years old who do not have an underlying health condition that puts them at higher risk from serious Covid-19 disease should be offered an alternative Covid-19 vaccine in preference to the AstraZeneca vaccine where such an alternative vaccine is available,” Lim said.
He added: “We are not advising a stop to any vaccination for any individual in any age group. We are advising a preference for one vaccine over another vaccine for a particular age group, really out of the utmost caution rather than because we have any serious safety concerns.”
AstraZeneca noted in a statement that the regulators had requested updates to the UK and EU labels for its vaccine.
“Neither agency identified any risk factors, such as age or gender, or a definite cause for these extremely rare events,” the company said. “However, they came to the view that these events have a possible link to the vaccine and requested they be listed as an extremely rare potential side effect.”
The company added: “AstraZeneca has been actively collaborating with the regulators to implement these changes to the product information and is already working to understand the individual cases, epidemiology, and possible mechanisms that could explain these extremely rare events.”
AstraZeneca noted the WHO’s statement that, based on current information, a causal relationship was considered plausible, but was not confirmed. The WHO added that further specialised studies were needed to fully understand the potential relationship between vaccination and possible risk factors.
When reporting on the PRAC meeting held from April 6–9 the EMA said the committee had started assessing “safety signal” reports of capillary leak syndrome in people who were vaccinated with the AstraZeneca-Oxford vaccine.
“Five cases of this very rare disorder, characterised by leakage of fluid from blood vessels causing tissue swelling and a drop in blood pressure, were reported in the EudraVigilance database,” the EMA said.
“At this stage, it is not yet clear whether there is a causal association between vaccination and the reports of capillary leak syndrome.”
Marco Cavaleri, who is in charge of vaccine strategy at the EMA, told Italy’s Il Messaggero newspaper in an interview published on April 6 that there was a connection between rare blood clotting and the AstraZeneca-Oxford vaccine.
“In my opinion, we can say it now, it is clear there is an association with the vaccine. But we still do not know what causes this reaction,” Cavaleri said.
“It is now increasingly difficult to say that there is no cause-and-effect relationship between vaccination with AstraZeneca and very rare cases of unusual blood clots associated with low platelet counts.”
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”.
On March 11, the Danish Health and Medicines Authority said it had halted vaccination with the AstraZeneca-Oxford vaccine. The authority said its decision was based on a “precautionary principle” and the suspension of use of the vaccine would last for 14 days.
The director of Denmark’s National Board of Health, Søren Brostrøm, said: “We are in the middle of the largest and most important vaccination rollout in Danish history. And right now we need all the vaccines we can get. Therefore, putting one of the vaccines on pause is not an easy decision. But precisely because we vaccinate so many, we also need to respond with timely care when there is knowledge of possible serious side effects. We need to clarify this before we can continue to use the vaccine from AstraZeneca.”
Brostrøm added: “It is important to emphasise that we have not opted out of the AstraZeneca vaccine, but that we are putting it on hold.”
The Danish Medicines Agency sent out an updated letter to people who had received the AstraZeneca-Oxford vaccine within the previous 14 days.
“If you have been vaccinated with the AstraZeneca vaccine within the last 14 days and you experience signs of skin or mucosal bleeding, you should see a doctor. This could for example be easy bruising – except for at the injection site, which is normal – or small red spots on the skin or bleeding that does not stop as normal,” the agency wrote.
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.
Use of the Janssen Biotech vaccine has meanwhile been put on hold in Norway until more information becomes available from ongoing investigations,
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 13, the Norwegian health authorities received three more reports of severe cases of blood clots or brain haemorrhages in younger people who had received the AstraZeneca-Oxford vaccine.
“Common to these patients is that they have had a reduced number of blood platelets,” the NIPH added. “Blood clots and subsequent brain haemorrhages are a rare condition.”
The director of the division of infection control and environmental health at the NIPH, Geir Bukholm, said it was now the Norwegian Medicines Agency’s role “to follow up on these suspected side effects and take the necessary measures in this serious situation”.
The NIPH and the Norwegian Medicines Agency said they had initiated analyses to investigate the association between the AstraZeneca-Oxford vaccine and various forms of blood clots, such as stroke and blood clots in the lungs.
The Norwegian Medicines Agency said it would now look extra closely at reports of blood clots and bleeding for all coronavirus vaccines.
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.
VG quoted Holme as saying: “There is nothing in these patients’ history that can give such a powerful immune response. I am confident that the antibodies that we have found are the cause, and I see no other explanation than it being the vaccine that triggered it.”
On March 15, the Paul-Ehrlich-Institut, said: “Following intensive consultations on the serious thrombotic events that have occurred in Germany and Europe, the Paul-Ehrlich-Institut recommends the temporary suspension of vaccinations with the Covid-19 vaccine AstraZeneca.
“Compared to the status on 11 March 2021, additional cases (as of Monday, 15 March 2021) have now been reported in Germany.
“Analysing the new data status, the experts of the Paul-Ehrlich-Institut now see a striking accumulation of a special form of very rare cerebral vein thrombosis (sinus vein thrombosis) in connection with a deficiency of blood platelets (thrombocytopenia) and bleeding in temporal proximity to vaccinations with the Covid-19 vaccine AstraZeneca.”
The institute said that vaccinations with the AstraZeneca-Oxford vaccine would be suspended in Germany until the EMA’s evaluation was complete. The decision affected both initial and follow-up vaccinations, the institute said.
The institute said that, as of March 15, a specific form of severe cerebral venous thrombosis associated with thrombocytopenia and bleeding had been identified in seven cases in temporal association with vaccination with the AstraZeneca-Oxford vaccine. Three of the patients died.
The affected individuals had ages ranging from about twenty to fifty years, the institute said.
“Six of the affected persons had a particular form of cerebral venous thrombosis, called sinus vein thrombosis. All six individuals were younger to middle-aged women,” the institute said. Another case of cerebral haemorrhage with platelet deficiency and thrombosis was medically very comparable, it added.
“All cases occurred between four and 16 days after vaccination with Covid-19 Vaccine AstraZeneca. This presented as a comparable pattern.
“The number of these cases after vaccination with Covid-19 AstraZeneca is statistically significantly higher than the number of cerebral venous thromboses that normally occur in the unvaccinated population.”
The institute said that an observed-versus-expected analysis was performed, comparing the number of cases expected without vaccination in a 14-day time window with the number of cases reported after approximately 1.6 million AstraZeneca vaccinations in Germany.
“About one case would have been expected, and seven cases had been reported,” the institute said. “The younger to middle-aged population affected by the severe cerebral venous thrombosis with platelet deficiency is not the population at high risk for a severe or even fatal Covid-19 course.”
In addition to the experts from the Paul-Ehrlich-Institut, other experts in thrombosis and haematology, and an adenovirus specialist, were consulted with the details of the reported cases, the institute added.
“All experts agreed unanimously that a pattern could be discerned here and that a connection between the reported above-mentioned diseases and the vaccination with Covid-19 Vaccine AstraZeneca was not implausible.”
The institute said it had recommended that vaccination with the AstraZeneca-Oxford vaccine be suspended in Germany as a precautionary measure in order to further analyse the cases and the German Federal Ministry of Health had followed this recommendation.
The institute has advised people who have received the AstraZeneca-Oxford vaccine and feel increasingly unwell more than four days after vaccination – for example, with severe and persistent headache or pinpoint bleeding of the skin – to seek medical treatment immediately.
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 following the deaths this month of Stefano Paterno, a 43-year-old navy officer, and Davide Villa, a 50-year-old policeman, who had both received vaccines from the ABV2856 batch.
Paterno died of a suspected heart attack on Tuesday, the day after his vaccination, Reuters reported, and Villa died at the weekend, about 12 days after his vaccination.
Local media said Villa fell ill within 24 hours of his vaccination and reported that doctors had diagnosed a deep vein thrombosis, which later resulted in a brain haemorrhage.
Reuters reported that magistrates in Sicily had opened investigations into the deaths of Paterno and Villa.
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.
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.
“Whether these antibodies are autoantibodies against PF4 induced by the strong inflammatory stimulus of vaccination or antibodies induced by the vaccine that cross-react with PF4 and platelets requires further study,” Greinacher et al. wrote.
The researchers suggested naming “this novel entity” vaccine-induced immune thrombotic thrombocytopenia (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”.
They say their research has shown that AstraZeneca-Oxford vaccine constituents form antigenic complexes with PF4, that the constituent ethylenediaminetetraacetic acid EDTA, which is a calcium-binding agent and stabiliser, increases microvascular permeability, and that components of the vaccine cause acute inflammatory reactions.
“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.
“We have provided evidence that VITT is not a consequence of antibodies directed against the SARS-CoV-2 spike protein (produced by all vaccines) cross-reacting with PF4,” Greinacher et al. wrote.
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.
“The degree of acute inflammatory response induced by the vaccine components appears as an important – potentially remediable – co-factor that could be diminished by reducing impurities and omitting EDTA,” they wrote.
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.
“Antibodies in normal sera cross-reacted with human proteins in the vaccine and likely contribute to commonly observed acute ChAdOx1 nCov-19 post-vaccination inflammatory reactions,” the scientists wrote.
“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.
“Following intramuscular injection, vaccine components and platelets come into contact, resulting in platelet activation,” they wrote.
“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.
“EDTA in the vaccine increases capillary leakage at the inoculation site, likely by endothelial (VE)-cadherin disassembly.”
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.
“This all happens on day one or two after vaccination. The B cells then start to produce antibodies against PF4, which reach high titer in the blood circulation in the second week after vaccination.
“At that time, the vaccine is gone and the platelets are no longer activated by the vaccine. The primary inflammatory response is also gone.
“However, the resulting anti-PF4 antibodies become auto-antibodies that bind to PF4 on the platelets and activate them.”
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.
“Increased vascular permeability facilitates dissemination of these proteins into the blood,” they wrote
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.
“Antibodies against SARS-CoV-2 spike protein do not cross-react with PF4 or PF4/heparin complexes through molecular mimicry. These findings make it very unlikely that the intended vaccine-induced immune response against SARS-CoV-2 spike protein would itself induce VITT.”
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.
“Another factor was tPA [tissue plasminogen activator], but assuming the mechanism of VITT is identical for the Janssen Biotech and AstraZeneca-Oxford vaccines, then we can rule out tPA because it is used in the AstraZeneca-Oxford vaccines, but not in the Janssen Biotech one. So that leaves the adenovirus vector or the DNA as the likely suspects.”
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.”
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’s chief medical officer, Ann Taylor, said: “The nature of the pandemic has led to increased attention in individual cases and we are going beyond the standard practices for safety monitoring of licensed medicines in reporting vaccine events, to ensure public safety.”
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.
“The DSMB expressed concern that AstraZeneca may have included outdated information from that trial, which may have provided an incomplete view of the efficacy data,” the NIAID said. “We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible.”
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.”
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.
When reporting the highlights of its March 8–11 meeting the PRAC added that, following the assessment of a “safety signal” about cases of anaphylaxis (severe allergic reactions) after administration of the AstraZeneca-Oxford vaccine, it had recommended an update to the product information to include anaphylaxis and hypersensitivity (allergic reactions) as side effects, “with an unknown frequency”, and to update the existing warning to reflect that cases of anaphylaxis have been reported.
“The update is based on a review of 41 reports of possible anaphylaxis seen among around five million vaccinations in the United Kingdom,” the PRAC state. “After careful review of the data, PRAC considered that a link to the vaccine was likely in at least some of these cases.”
Any person developing an anaphylactic reaction after the first vaccine dose should not be given a second dose, the PRAC added. “This advice, which is aligned across all the Covid-19 vaccines authorised in the EU, remains unchanged and the update to the product information does not require any change in clinical practice.”
On May 7, 2021, the WHO’s pharmacovigilance database, VigiBase, listed 660,733 reports of adverse events following Covid vaccination, including 4,314 deaths.
The database of the Centers for Disease Control and Prevention’s Vaccine Adverse Event Reporting System (VAERS) in the US lists 157,277 total adverse event reports after Covid vaccination. The figure relates to reports up to April 30. A total 710,531 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 3,837 as of April 30 (3,700 from US territories or a location reported as unknown and 137 from foreign locations). A total 1,839 deaths followed administration of the Moderna vaccine, 1,719 followed administration of the Pfizer-BioNTech vaccine, and 261 followed administration of the Janssen vaccine. In 19 cases, the name of the vaccine manufacturer was not specified in the report. (There’s a discrepancy between the 3,837 figure and the 3,838 total.)
A total 67,759 reports relate to adverse events after administration of the Moderna vaccine (301,616 individual-symptom events), 59,792 refer to the Pfizer-BioNTech vaccine (266,072 individual-symptom events), 29,288 refer to the Janssen Biotech vaccine (140,762 individual-symptom events), and 515 relate to an unknown vaccine manufacturer (2,258 individual-symptom events). There’s a discrepancy between the 157,277 total and this one (157,354).
The total number of adverse reactions resulting in permanent disability is put at 2,277. VAERS lists 1,125 cases after administration of the Pfizer-BioNTech vaccine, 911 after administration of the Moderna vaccine, and 237 after administration of the Janssen vaccine. In five cases, the vaccine manufacturer was not specified. There’s again a discrepancy in the totals.
MedAlerts, which uses the VAERS database, also puts the number of deaths following Covid vaccination at 3,837 (as of April 30) and lists the number of total adverse events as 157,277.
The independent OpenVAERS website reports the same statistics.
EudraVigilance lists 208,873 individual cases up to May 8 for the AstraZeneca-Oxford vaccine, with the most listed in the Netherlands (25,771), followed by France (13,712), and Italy (12,646).
A total 170,528 cases are listed for the Pfizer-BioNTech vaccine (tozinameran). The most reports are from Italy (42,468), followed by France with 17,593, and 17,140 in the Netherlands.
A total 22,985 cases are listed for the Moderna vaccine. Most are from the Netherlands (4,218), followed by Spain (1,904), and Italy with 1,891.
A total 2,873 cases are listed for the Janssen Biotech vaccine. Most are from the Netherlands (1,334), followed by Poland (62), and Italy with 32.
In its weekly summary of Yellow Card reporting, updated on May 6, the MHRA said that, up to and including April 28, 2021, it had received and analysed 160,543 total reports of suspected adverse reactions to the AstraZeneca-Oxford vaccine. The total number of listed adverse reactions is 598,985 (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 April 28, 2021, in the UK, 54,139 reports of adverse reactions had been submitted relating to vaccination with the Pfizer-BioNTech vaccine, which was first administered on December 9, 2020. These include a total of 154,776 suspected reactions.
For the Pfizer-BioNTech and AstraZeneca-Oxford vaccines the overall reporting rate was about three to six Yellow Cards per 1,000 vaccine doses administered.
A total 683 Yellow Card reports related to the Moderna vaccine. These include a total of 1,996 suspected reactions. The first report was received on April 7.
There were 574 reports of adverse reactions in which the brand of the vaccine was not specified (1,807 total suspected reactions).
The MHRA has received 722 UK reports of suspected adverse reactions to the AstraZeneca-Oxford vaccine in which the patient died shortly after vaccination. There were 364 reports of deaths after vaccination with the Pfizer-BioNTech vaccine and two after administration of the Moderna vaccine. Fourteen deaths were reported in which the vaccine brand was unspecified.
The majority of these reports related to elderly people or people with underlying illness, the MHRA says. Usage of the AstraZeneca-Oxford vaccine had increased rapidly, 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. Review of individual reports and patterns of reporting does not suggest the vaccine played a role in the death,” the MHRA said.
The reports about the AstraZeneca-Oxford vaccine include 129,651 nervous system disorders (127 fatal), 7,600 vascular disorders (40 fatal), 4,969 blood disorders (six fatal), 6,070 cardiac disorders (90 fatal), 8,841 eye disorders, including 143 cases of blindness, 60,645 gastrointestinal disorders (ten fatal), 1,933 immune system disorders (one fatal), 73,591 muscle and tissue disorders (one fatal), 18,759 respiratory disorders (92 fatal), 36,006 skin disorders (two fatal), 11,325 psychiatric disorders (two fatal), 12,332 cases of infection (65 fatal), 2,835 reports of reproductive and breast disorders (including 284 cases of vaginal haemorrhage, 321 cases of delayed menstruation, and 242 cases of breast pain), 607 reports of a cerebrovascular accident (30 fatal), 107 reports of cerebral haemorrhage (29 fatal), and 74 reports of an ischaemic stroke (three fatal). The cardiac disorders include 109 reports of cardiac arrest (26 fatal). There were 486 reports of anaphylactic reaction (one fatal).
There are 483 reports of thrombocytopenia (four fatal), 139 reports of “immune thrombocytopenia” (one fatal), and 818 reports of non-site specific thrombosis (17 fatal).
The reports about the Pfizer-BioNTech vaccine include 28,920 nervous system disorders (36 fatal), 2,185 vascular disorders (nine fatal), 5,278 blood disorders (one fatal), 1,984 cardiac disorders (51 fatal), 2,438 eye disorders, including 33 cases of blindness, 16,086 gastrointestinal disorders (16 fatal), 838 immune system disorders (one fatal), 20,360 muscle and tissue disorders, 6,520 respiratory disorders (34 fatal), 11,481 skin disorders (one fatal), 2,538 psychiatric disorders, 3,826 cases of infection (63 fatal), 1,130 reports of reproductive and breast disorders (including 98 cases of vaginal haemorrhage, 129 cases of delayed menstruation, and 164 cases of breast pain), 192 reports of a cerebrovascular accident (13 fatal), 21 reports of cerebral haemorrhage (six fatal), and 25 reports of an ischaemic stroke (one fatal). There were 246 reports of anaphylactic reaction (one fatal).
There are 67 reports of thrombocytopenia (one fatal), 37 reports of “immune thrombocytopenia”, and 106 reports of non-site specific thrombosis (six fatal).
The MHRA says that, in the week since the previous summary to April 21, 2021, it received a further 7,445 Yellow Cards for the AstraZeneca-Oxford vaccine, 2,009 for the Pfizer-BioNTech vaccine, 455 for the Moderna vaccine, and 33 where the brand was not specified.
The agency said that data from the UK public health agencies showed that at least 34,094,048 people had received their first vaccination in the UK by the week ending April 28, 2021, and 14,043,961 second doses had been administered.
The MHRA said the current priority groups for Covid vaccination included people over the age of 45 years, the clinically vulnerable, care home residents and workers, and frontline health and social care workers.
As of April 28, an estimated 22.6 million first doses of the AstraZeneca-Oxford vaccine and 11.4 million first doses of the Pfizer-BioNTech vaccine had been administered, plus about 8.1 million and 5.9 million second doses of the Pfizer-BioNTech vaccine and AstraZeneca-Oxford vaccines respectively.
About 0.1 million first doses of the Moderna vaccine have also been administered.
The MHRA said that, up to and including April 28, it had received Yellow Card reports of 242 cases of major thromboembolic events with concurrent thrombocytopenia in the UK following vaccination with the AstraZeneca-Oxford vaccine.
The events occurred in 141 women and 100 men aged between 18 and 93 years and 49 of the patients died. Six of the cases were reported after a second vaccine dose.
Cerebral venous sinus thrombosis was reported in 93 cases (average age 47 years) and 149 patients (average age 55 years) had other major thromboembolic events with concurrent thrombocytopenia.
Given the estimated number of first doses of the AstraZeneca-Oxford vaccine administered in the UK by April 28, the overall case incidence was 10.5 per million doses, the agency 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 compared to the older groups,” the MHRA said.
“The MHRA advises that this evolving evidence should be taken into account when considering the use of the vaccine. There is now 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 agency also said it had received six 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.
The MHRA says the current evidence does not suggest that capillary leak syndrome is caused by the AstraZeneca-Oxford vaccine. “The MHRA will continue to monitor this issue closely,” the agency said.
In its report for the period from December 27, 2020, to April 30, 2021, the Paul-Ehrlich-Institut said there were 49,961 suspected cases of adverse reactions or vaccine complications reported from Germany in temporal association with Covid vaccination.
There were 26,206 reports of adverse effects after vaccination with the AstraZeneca-Oxford vaccine, 20,160 after vaccination with the Pfizer-BioNTech vaccine, 3,073 after vaccination with the Moderna vaccine, and three after vaccination with the Janssen Biotech vaccine. In 519 cases the vaccine manufacturer was unspecified.
The institute said the reporting rate for all the vaccines together was 1.7 per 1,000 vaccine doses, and for reports of serious reactions 0.2 per 1,000 vaccine doses.
It said that, according to the Robert Koch Institute, 28,774,580 vaccinations had been carried out by April 29, 2021, of which 21,329,667 were with the Pfizer-BioNTech vaccine, 1,667,261 were with the Moderna vaccine, 5,775,546 were with the AstraZeneca-Oxford vaccine, and 2,106 were with the Janssen Biotech vaccine.
The flaws in the VAERS and other reporting systems are highlighted at length by reporters working for pro-vaccine media who 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 and fostering vaccine hesitancy.
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.”
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.
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.”
The FDA said in its briefing document for the Vaccines and Related Biological Products Advisory Committee (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 reports 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 do not represent a frequency above that expected in the general population. The FDA refers 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.”
Up to January 31, the MHRA in the UK received 99 reports of facial paralysis or paresis (weakness of voluntary movement, partial loss of voluntary movement, or impaired movement) after vaccination with the Pfizer-BioNTech vaccine. There were 15 reports of facial paralysis after administration of the AstraZeneca-Oxford vaccine.
According to the MHRA, the number of reports of facial paralysis received so far is similar to the expected natural rate.
There was 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.
The Standing Vaccine Commission at Germany’s main public health agency, the Robert Koch Institute, said there were “insufficient data currently available to ascertain how effective the vaccination is above 65 years” and the vaccine should only be offered to people aged 18–64 years.
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.
In Belgium, the Superior Health Council had also recommended that the AstraZeneca-Oxford vaccine should only be given to people younger than 55, but also later made an about-turn and said it would be administered to older people.
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%.
Differences in viewpoints about Covid vaccination, and particularly about the prospect of mandatory vaccination and obligatory “vaccine passports”, are causing relationship breakdowns, including traumatic splits in families, with pro-vaccination zealots shaming and pressuring those who are against vaccination or are simply vaccine hesitant.
Testing Covid vaccines on children
Pfizer 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 companies are evaluating the efficacy and safety of the vaccine for children aged six months to 11 years. The first doses were given to the cohort aged five to 11 years.
Pfizer said that Phase 1 of the new 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 is starting 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 says the Phase 2/3 part of the trial will 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 will be enrolled in the US and Europe.
At the six-month follow-up visit, all participants will be unblinded and those who originally received a placebo will be given the opportunity to receive BNT162b2.
The primary endpoints of the study are to evaluate the safety and immunogenicity of the vaccine, Pfizer says. “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.
On April 9, Pfizer and BioNTech requested amendments to the EUA that covers use of their vaccine to authorise its use for adolescents aged 12 to 15 years.
The companies said they planned to request similar authorisation from other regulatory authorities worldwide in the subsequent days.
“These requests are based on data from the pivotal Phase 3 trial in adolescents 12 to 15 years of age with or without prior evidence of SARS-CoV-2 infection, which demonstrated 100% efficacy and robust antibody response after vaccination with the Covid-19 vaccine,” the companies stated.
Pfizer and BioNTech SE said on March 31 that the Phase 3 trial of its vaccination demonstrated 100% efficacy in participating adolescents aged 12 to 15 years.
A total 2,260 adolescents were enrolled for the trial in the United States. Eighteen cases of Covid-19 were observed in the placebo group (1,129 participants) versus none in the vaccinated group (1,131 participants).
Pfizer said that vaccination with BNT162b2 elicited SARS-CoV-2–neutralising antibody geometric mean titers (GMTs) of 1,239.5, “demonstrating strong immunogenicity in a subset of adolescents one month after the second dose”.
The company said this compared well (“was non-inferior”) to GMTs elicited by participants aged 16 to 25 years in an earlier analysis ((705.1 GMTs).
“Further, BNT162b2 administration was well tolerated, with side effects generally consistent with those observed in participants 16 to 25 years of age,” Pfizer said.
The companies said they planned to submit the data to the FDA and the EMA as soon as possible “to request expansion of the emergency use authorization and EU conditional marketing authorization for BNT162b2”.
The Pfizer CEO, Albert Bourla, said he hoped that vaccination of the 12 to 15 age would commence before the start of the next school year.”
Pfizer says that children younger than six months of age may subsequently be evaluated “once an acceptable safety profile has been established”.
If safety and immunogenicity is confirmed, and pending agreement with and endorsement from regulators, Pfizer and BioNTech say they hope to receive authorisation for vaccination of younger children by early 2022.
The EMA said on May 3 that it had started evaluating an application for the Pfizer-BioNTech vaccine to be authorised for use for 12- to 15-year-olds.
In the EU, the vaccine is currently authorised for administration to people aged 16 and older.
The EMA said its CHMP would carry out an accelerated assessment of data about the vaccine, including results from the ongoing clinical study involving adolescents aged above 12 years.
The CHMP’s opinion will then be forwarded to the European Commission, which will issue a final legally binding decision that would be applicable in all EU member states.
The EMA said it expected that, unless supplementary information was needed, its evaluation would be completed by June.
Pfizer and BioNTech are also planning studies to further evaluate their vaccine in people with compromised immune systems.
A trial in Britain in which the AstraZeneca-Oxford vaccine was being tested on children has been halted because of the reports of blood clotting in adults who received the vaccine.
A spokesperson from the University of Oxford said: “Whilst there are no safety concerns in the paediatric clinical trial, we await additional information from the MHRA on its review of rare cases of thrombosis/thrombocytopaenia that have been reported in adults before giving any further vaccinations in the trial.
“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 have 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 add 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 expects 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.”
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 news 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.”
It is probable that, in the future, a certificate of Covid vaccination will be required to fly and to cross borders, to attend certain educational institutions, and even to go to certain events or use public transportation.
IBM has been developing a Digital Health Pass, using blockchain technology, that will store 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.
“Once a vaccine is administered, an individual would be issued a verifiable health credential via the IBM Digital Health Pass that would be included only in that individual’s encrypted digital wallet on their smartphone.”
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, has announced that the government is 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.
Schengenvisainfo.com also reports that Greece’s Prime Minister, Kyriakos Mitsotakis, has called on the European Commission (EC) to introduce a Covid vaccination certificate. Mitsotakis addressed his request in a letter sent to the EC President Ursula von der Leyen, SchengenVisaInfo.com reported.
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, at this stage, 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.
Etihad Airways and Emirates are about to introduce a digital travel pass, developed by the International Air Transport Association (IATA) that will show whether passengers have been vaccinated and/or have tested negative for SARS-CoV-2.
Singapore Airlines, the Anglo-Spanish multinational airline IAG (the International Airlines Group), and Qatar Airways are also reported to be involved in the pilot phase of development of the IATA travel pass framework.
Writing in the Weekend Australian published on February 7, Christine Kellett quotes the Minister for Government Services, Stuart Robert, as saying it is “highly likely” that vaccination certificates will be required for international travel.
“There is still a range of decisions for governments to make, it’s highly likely that a certificate will be required for international visitors to Australia and we will continue to work with our international counterparts on our framework for vaccination certificates,” Kellett quoted Robert as saying.
The CEO of the Australian airline Qantas, Alan Joyce, has said that proof of Covid vaccination will 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 33,000 people.
The UK-based independent tour operator Tradewinds Travel says it will 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 says that it will not accept any guest who has not received a Covid vaccination.
“We have taken the decision to introduce the requirement that all guests must be fully vaccinated,” Saga states 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 will be required to bring evidence of vaccination with them at the time of boarding. No one who is exempt from vaccination will be accepted on a Saga cruise.
Israel has already introduced a “green pass”, a certificate verifying that people have either been vaccinated against or recovered from Covid-19. Having one is now a requirement for entering certain businesses and events.
Haaretz recently reported that non-Israeli citizens who have received the Covid-19 vaccine – including diplomats, migrant workers, and foreign students – are currently unable to obtain the “green passport”.
The health ministry told Haaretz that “special populations”, including foreign students, migrant workers, non-nationals, and those who are not registered with an Israeli health care provider, cannot currently be issued a “green passport”.
The passport, which has a unique QR code for those who download it to their smartphone, is now needed to officially gain access to most public spaces, Haaretz reports. “For example, green passport holders are allowed to eat indoors at Israeli restaurants, while those without it can only dine outside.”
The following businesses are listed as requiring a green pass:
- gyms and studios,
- swimming pools,
- restaurants and cafes,
- stadiums, pitches, and sporting events and venues,
- theatres, cinemas, and cultural venues,
- cultural events,
- exhibitions (outside of museums),
- event gardens,
- attractions, and
- mikvehs for men.
In the case of those who are vaccinated, the pass is valid for six months from the week after they receive their second vaccine dose. In the case of those who have “recovered” from Covid-19, the pass is valid until June 30, 2021.
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.
“This kind of censorship is counterproductive if our objective is a safe and effective vaccine supply.”
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.
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.”
Authorisations in the US, Britain, and Australia
The mRNA BNT162b2 vaccine developed by the American multinational Pfizer and the German biotech firm BioNTech and the mRNA-1273 vaccine manufactured by the American company Moderna have both been granted emergency use authorisations by the Food and Drug Administration (FDA) in the US.
The BNT162b2 vaccine has also 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.
The European Commission has granted conditional marketing authorisations (CMAs) for the Pfizer-BioNTech, AstraZeneca-Oxford, Moderna, and Janssen Biotech 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. 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 (EUA) 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.
SARS-CoV-2 variants present new challenges
Three new SARS-CoV-2 variants – initially discovered in the UK, South Africa, and in travellers from Brazil – are spreading 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 receptor binding domain (RBD) and multiple mutations outside the RBD.
A combination of the N501Y, K417N, and E484K mutations has been found in B.1.351 and 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.
“The N501Y mutation is the only mutation in the B.1.1.7 variant that is located on the portion of the spike protein that binds to the human ACE2 receptor, which is the enzyme on the surface of our cells that serves as the entry gate for SARS-CoV-2,” he said.
British government researchers recently discovered that the B1.1.7 variant has acquired the E484K mutation seen in the South Africa variant and in the P1 variant, which was first identified in Brazil. The E484K mutation 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.
I think this is one part of the answer.
I still think, to some extent, it has a stabilizing effect on the 501Y – structurally it appears to me together the 2 mutations “grip” onto Ace2 better since they are at the end of a loop pic.twitter.com/0GZTLi9You
— Björn Meyer (@_b_meyer) February 1, 2021
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. report 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 most important site is E484, where neutralisation by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil.”
The National Institute for Communicable Diseases (NICD) states on its website that the N501Y and K417N mutations in the spike protein of SARS-CoV-2 “have 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.
“501Y.V2 shows substantial or complete escape from neutralising antibodies in Covid-19 convalescent plasma,” Wibmer et al. said.
“These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines.”
In a preprint published on bioRxiv on January 13, Gard Nelson et al. report: “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 report 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.
“In this trial, we found that two doses of the ChAdOx1 nCoV-19 vaccine had no efficacy against the B.1.351 variant in preventing mild-to-moderate Covid-19,” the researchers wrote.
“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.”
This, Fratev says, may explain the increased spread of SARS-CoV-2 observed in the UK and South Africa and “also raises an important question about the possible human immune response and the success of already available vaccines”.
Andre Watson says that, in the case of the newly discovered mutated variants, antibody binding is not likely to be tremendously different, so vaccines are still likely to confer similar protection as they would against other strains identified previously.
He tweeted, 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 adds that clinical evidence suggests that the antibody response is six times weaker against the new South Africa strain.
Watson adds: “It’s still early to say for certain with respect to the N501Y mutant’s effect on neutralising antibody responses, reinfection, and vaccine efficacy. This mutant causes enhanced ACE2 receptor binding, though is unlikely to significantly affect antibody binding by itself.
“This is not to say that the enhanced ACE2 binding couldn’t contribute to antibody escape and inefficacy of neutralising antibodies against this virus in the presence of ACE2, which already competes with neutralising antibodies with similar binding strength.”
In an article published in Science Direct on March 12, Wilfredo F. Garcia-Beltran et al. say their study findings highlight the potential for virus variants to escape from neutralising humoral immunity.
“While the clinical impact of neutralisation resistance remains uncertain, these results highlight the potential for variants to escape from neutralising humoral immunity and emphasise the need to develop broadly protective interventions against the evolving pandemic,” Garcia-Beltran et al. said.
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.
“We find that although neutralisation is largely preserved against many variants, those containing the K417N/T, E484K, and N501Y RBD mutations, namely, P.1 and B.1.351 variants, have significantly decreased neutralisation even in fully vaccinated individuals,” Garcia-Beltran et al. said.
“Individuals that received only a single recent dose of vaccine had weaker neutralisation titers overall and did not exhibit detectable neutralisation of B.1.351 variants in our assays.”
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.
“Ultimately, development of new vaccines capable of eliciting broadly neutralising antibodies may be necessary to resolve the ongoing pandemic.”
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.
“It is possible that current vaccines will still provide clinical benefit against variants that exhibit poor cross-neutralisation, such as P.1 and B.1.351, by reducing Covid-19 disease severity, but this has yet to be determined.
“Ultimately, it will be important to develop interventions capable of preventing transmission of diverse SARS-CoV-2 variants, including vaccine boosters that target these variants or technologies capable of eliciting or delivering broadly neutralising antibodies.”
In a paper published on the medRxiv preprint server on April 9 Timothy A. Bates et al. say there is 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. note that the B.1.1.7 and B.1.351 variants have been associated with increases in infections and hospitalisations in their countries of origin and all have 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 note. RBD mutations, they say, 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.
“Although the effect is more pronounced in the vaccine cohort, both B.1.1.7 and B.1.351 show significantly reduced levels of neutralisation by vaccinated and convalescent sera,” Bates et al. wrote.
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 say 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 note, however, that the variant’s prevalence in Israel is low, so the sample size was small, and the research has 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.
“Those infected between two weeks after the first dose and one week after the second dose, were disproportionally infected by B.1.1.7 (odds ratio of 26:10), suggesting reduced vaccine effectiveness against both VOCs under different dosage/timing conditions,” the researchers said.
“Nevertheless, the B.1.351 incidence in Israel to-date remains low and vaccine effectiveness remains high against B.1.1.7, among those fully 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.
“Our analysis revealed that even though the N501Y mutant can bind and enter our cells more readily, it can still be neutralised by antibodies that block the entry of the unmutated version of the virus into cells,” Subramaniam said.
“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 recently reported with cases centred in Cebu Island, Philippines.
“Whole genome sequencing revealed that the 33 samples with the Ph-B.1.1.28 emergent variant merit further investigation as they all contain the E484K, N501Y, and P681H spike mutations previously found in other variants of concern such as the South African B.1.351, the Brazil P.1 and the UK B.1.1.7 variants.
“This is the first known report of these mutations co-occurring in the same virus”
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.)
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.
Variants in India
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.
“The analysis of samples from Maharashtra has revealed that, compared to December 2020, there has been an increase in the fraction of samples with the E484Q and L452R mutations,” the ministry said.
“Such mutations confer immune escape and increased infectivity. These mutations have been found in about 15–20% of samples and do not match any previously catalogued VOCs.”
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 the global repository 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.
The presence of the double-mutant variant has been reported in the US, the UK, Germany, Ireland, New Zealand, Australia, Singapore, and South Africa.
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.
“This change also arms the virus for better entry into human cells, because now the ‘key’ or the spike protein has a better fit into the locks of human cells.
“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.
The WHO said on April 28 that, up to April 27, B.1.617 had been detected in more than 1,200 sequences uploaded to GISAID from at least 17 countries. The most sequences were uploaded from India, the UK, the US, and Singapore.
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.
Moderna is examining two strategies to deal with the new virus variants. It plans to test an additional dose of mRNA-127 to see if it will increase neutralising titers against emerging strains and is 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.
“Neutralisation against the virus with the three key mutations present in the South African variant (E484K+N501Y+D614G) was slightly lower when compared to neutralisation of virus containing the other mutations that were evaluated.
“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.
“Clinical data are needed for firm conclusions about vaccine effectiveness against variant viruses.”
The researchers said the ongoing evolution of SARS-CoV-2 necessitated continuous monitoring of the significance of changes for vaccine efficacy.
“This surveillance should be accompanied by preparations for the possibility that future mutations may necessitate changes to vaccine strains,” they added.
Bloomberg reports that Pfizer and BioNTech are developing booster shots against new variants.
“Every time a new variant comes up we should be able to test whether or not [our vaccine] is effective,” Albert Bourla was quoted as saying. “Once we discover something that it is not as effective, we will very, very quickly be able to produce a booster dose that will be a small variation to the current vaccine.”
People might require a one-shot annual Covid vaccine that is developed each year to combat whatever strain is anticipated to circulate, Bourla told Bloomberg, and Pfizer was working on next-generation versions of its vaccine that have easier storage requirements.
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.
“The vaccine was 100% effective against severe disease as defined by the US Centers for Disease Control and Prevention, and 95.3% effective against severe Covid-19 as defined by the US Food and Drug Administration,” the companies said.
“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 and BioNTech said: “These data support previous results from immunogenicity studies demonstrating that BNT162b2 induced a robust neutralising antibody response to the B.1.351 variant, and, although lower than to the wild-type strain, it does not appear to affect the high observed efficacy against this variant.”
Pfizer’s CEO, Albert Bourla, said the results positioned the company to submit a biologics licence application to the FDA.
“The high vaccine efficacy observed through up to six months following a second dose and against the variant prevalent in South Africa provides further confidence in our vaccine’s overall effectiveness,” he said.
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.
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 has applied to the Indian authorities to conduct a small domestic trial of Novavax’s Covid vaccine. The SII’s CEO Adar Poonawalla said he was hopeful that Novavax’s vaccine would be launched in India by June this year, under the local brand name Covovax.
Moderna and 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.
“Despite this reduction, neutralising titer levels with B.1.351 remain above levels that are expected to be protective,” Moderna said.
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.”
The German chancellor Angela Merkel has said that if vaccines do not work on variants of SARS-CoV-2, then “we start all over again”. Covid vaccines may be needed for many years to come, she says. “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 (SII), 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.
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 Medicines and Healthcare Products Regulatory Agency (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 states: “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 MHRA said on May 6 that it had received 283 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.”
The MHRA has received 590 reports of “spontaneous adverse reactions associated with anaphylaxis or anaphylactoid reactions” after administration of the AstraZeneca-Oxford vaccine.
The agency said that these reactions were also rare, but added that an update to the product information had been made “to reflect the fact that cases of anaphylaxis have been reported for the AstraZeneca vaccine”.
Two 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.
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.
“I think it’s pretty unlikely. There are cases of people being allergic to polyethylene glycol, but it’s quite rare. I think it’s far more likely that there’s an allergic reaction to one or more of the components of the spike protein cross reacting with some T cells that build up an immune response or even antibodies that build up an immune response to parts of the spike that they wouldn’t bind to otherwise.
“It’s much easier to blame the delivery system and say it’s PEG, than it is to admit that perhaps spike protein vaccines are causing this problem.”
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.
“If you start generating T-cell responses against some of those side portions and if any of those overlap with reactivity to one or more proteins that are in your body that can contribute to autoimmunity, and/or cross talking with T helper 2 cells.
“There can then be an imbalance and a response from the Th2 cells that relate to allergy as opposed to the Th1 cells that relate to immunity.”
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 being 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.
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).
“With spike protein vaccines, there may be even more drift over time towards antibody-dependent enhancement and off-target antibody generation that can enhance disease.
“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”.
“The specific and significant Covid‐19 risk of ADE should have been and should be prominently and independently disclosed to research subjects currently in vaccine trials, as well as those being recruited for the trials and future patients after vaccine approval, in order to meet the medical ethics standard of patient comprehension for informed consent.”
Cardozo and Veazey wrote: “Covid‐19 vaccines designed to elicit neutralising antibodies may sensitise vaccine recipients to more severe disease than if they were not vaccinated.
“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.
The risk of ADE was sufficiently obscured in clinical trial protocols and consent forms for ongoing Covid‐19 vaccine trials “that adequate patient comprehension of this risk is unlikely to occur, obviating truly informed consent by subjects in these trials”, Cardozo and Veazey said.
“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.”
The researchers added: “The informed consent process for ongoing Covid‐19 vaccine trials does not appear to meet this standard. While the Covid‐19 global health emergency justifies accelerated vaccine trials of candidates with known liabilities, such an acceleration is not inconsistent with additional attention paid to heightened informed consent procedures specific to Covid‐19 vaccine risks.”
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.
“Ligandal’s drug is intended to be both a prophylactic and a therapeutic,” Watson said. “We are at the preclinical stage of developing an antidote-vaccine and are studying the immune effects of its use before and after infection.”
Watson and his colleagues published a pre-print paper on bioRxiv on August 6 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.
“They’re all going to lead to strong immune responses, but may not create quite the right immune response.”
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.
“When you get exposed to the actual virus, your body will recognise just the parts it needs to.”
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.
“This is why the Russians are using two different viral vectors, to avoid the body generating an immune response to the first vector and attacking it.”
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 are reports that Russia is set to launch a single-dose 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 will remain the main version used within Russia. The fund is responsible for marketing Sputnik V abroad,
“‘Sputnik-Light’ can serve as an effective temporary solution for many countries, which are experiencing a peak of coronavirus infection,” Dmitriev was quoted as saying.
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.
A Phase 1/2 trial for “Sputnik Light” has been registered.
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 team added: “The Gamaleya centre, which carries out strict quality control of all Sputnik V production sites, confirmed that no replication-competent adenovirus was found in any of the Sputnik V vaccine batches that were produced.”
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.
“Only non-replicating adenoviral vectors of type E1 and E3, which are harmless to the human body, are used in the production of the Sputnik V vaccine.”
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
Physician-scientist Hooman Noorchashm from Pennsylvania in the US has written a ‘letter of warning’ to the FDA And Pfizer about “the immunological danger of Covid-19 vaccination in the recently convalescent and asymptomatic carriers”.
Noorchashm, who makes clear that he is not taking an anti-vaccination stance, 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)”.
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.
“If a majority of younger more robust patients might tolerate such vascular injury from a vaccine immune response, many elderly and frail patients with cardiovascular disease will not.”
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.
“I do think there is a reasonable scientific rationale for screening older and frail patients or those with co-morbidities (i.e. obesity, diabetes, hypertension, high cholesterol or history of cardiovascular disease), like Mr Aaron, for Covid-19 prior to vaccinating them.
“If folks in these categories do turn out to be asymptomatic carriers, I would advocate for delaying their vaccination by 3–4 weeks with good social isolation instructions – followed by vaccination.
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.
“Based on emerging data, I would even go as far as to say that asymptomatic carriers may be better candidates for the Regeneron or Eli Lilly antibodies, instead of the Covid-19 vaccine.”
Deaths after Covid vaccination
A doctor and translational researcher (molecular bio, neurooncology) in the US, 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.
— AMM, MD (@AMcA32449832) February 4, 2021
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 (ITP), a rare autoimmune disorder in which a person’s blood doesn’t clot properly because the immune system destroys the blood-clotting platelets..
“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 … .
“A team of expert doctors tried for two weeks to raise his platelet count to no avail. Experts from all over the country were involved in his care. No matter what they did, the platelets count refused to go up. He was conscious and energetic through the whole process but two days before a last resort surgery, he got a haemorrhagic stroke caused by the lack of platelets that took his life in a matter of minutes.”
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.
“I believe that people should be aware that side effects can happen, that it is not good for everyone and, in this case, destroyed a beautiful life, a perfect family, and has affected so many people in the community.”
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.”
Earlier this month, 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.
“In previous studies, the risk of developing ITP increased after administration of measles-mumps-rubella (MMR) … hepatitis A, varicella, and diphtheria-tetanus-pertussis vaccines in children and adolescents,” they wrote.
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.
In the section listing deaths on the same day as vaccination (65 deaths recorded) it includes that of a 58-year-old woman who died on January 4.
There are 306 records of deaths occurring within seven days of vaccination.
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.
Inflammatory and other reactions
Of the 660,733 reports of adverse events after Covid vaccination listed on VigiBase as of May 7, 27,067 were reports of blood and lymphatic system disorders and 25,235 were reports of cardiac disorders.
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, which is an inflammation of the heart muscle, five days after receiving his second vaccine dose of the coronavirus 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.
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.
“Data from the military smallpox vaccination programme are consistent with a causal association between vaccination and myopericarditis, although this association is not proven,” the CDC stated.
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.
Rare life-threatening multi-system inflammatory syndrome (MIS) following BNT162b2 mRNA covid-19 vaccination in a 23 y old social worker was identified at our Department of Medicine B at Hadassah Medical Center, Jerusalem, Israel and reported to MOH and WHO. >>
— Dror Mevorach (@DrorMevorach) January 9, 2021
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 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.
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.
On May 1, there were 81,481 total reports about adverse effects after Covid vaccination listed on https://vaxpain.us/ .
The UK drugs regulator has 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 says in its tender request that it is 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.
Hospitals in France suspend vaccination
Local media 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.
The French National Drug Safety Agency (ANSM) says in its situation report published on April 30 that, since Covid vaccination began in the country on December 26, 2020, there have been 29,752 reports of adverse reactions.
A total 2,540 new adverse reaction reports were registered between April 16 and April 22, the ANSM said.
The agency said 16,030 adverse reactions had been reported after vaccination with the Pfizer-BioNTech vaccine as of April 22, including 1,042 cases reported between April 16 and April 22.
Most of the reactions were not serious, the ANSM said, adding that more than 13,660,000 doses of the vaccine had been administered as of April 22.
The ANSM reports five cases of myocarditis or myopericarditis (inflammation of both the pericardium and the heart muscle) after administration of the Pfizer-BioNTech vaccine. In two of the cases, given the timeline and a negative PCR test, implication of the vaccine could not be excluded, the agency said.
The agency said 1,283 adverse reactions had been reported after vaccination with the Moderna vaccine as of April 22, including 265 reported between April 16 and April 22. More than 1,483,000 doses of the vaccine had been administered to that date.
A total 12,439 adverse reaction reports were received relating to vaccination with the AstraZeneca-Oxford vaccine, including 1,233 reported between April 16 and April 22. This was after administration of more than 3,605,000 doses.
The ANSM reported that that there had been one new case of what it describes as “atypically located thrombosis”, bringing the number of cases since the start of vaccination to 28 (average age 64), including eight deaths. Fourteen of the patients were male and 14 were female.
In 24 of the cases the patient had cerebral venous sinus thrombosis and/or splanchnic vein thrombosis. In two cases there was disseminated intravascular coagulation (DIC) alone and in two cases there was DIC with a pulmonary embolism.
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.
Frequency of grade 3 adverse events ‘higher than for most vaccines’
Associate editor of The BMJ 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
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”.
They added, however: “We need to consider their long-term consequences carefully, especially when they are administered to otherwise healthy individuals as well as young adults and children.”
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.
“Thus, these in vivo studies demonstrated that the spike protein of SARS-CoV-1 (without the rest of the virus) reduces the ACE2 expression, increases the level of angiotensin II, and exacerbates the lung injury.”
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.
“These experiments using transient transfection may reflect the intracellular effects of the spike protein that could be triggered by the RNA- and viral vector-based vaccines.”
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.
“However, recent observations suggest that the SARS-CoV-2 spike protein can by itself trigger cell signalling that can lead to various biological processes.”
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.
“In addition to cardiovascular cells, other cells that express ACE2 have the potential to be affected by the SARS-CoV-2 spike protein, which may cause adverse pathological events,” the researchers wrote.
“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.”
The researchers added: “While human data on the possible long-term consequences of spike protein-based Covid-19 vaccines will not be available soon, it is imperative that appropriate experimental animal models are employed as soon as possible to ensure that the SARS-CoV-2 spike protein does not elicit any signs of the pathogenesis of PAH or any other chronic pathological conditions.”
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
“This previously unknown mechanism could cause symptoms before substantial viral replication occurs,” Solopov said.
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.
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 country’s Joint Committee on Vaccination and Immunisation (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.
According to Our World in Data, more than 10 million vaccine doses had been administered in Israel as of May 4.
In a report published in The Lancet on May 5, Eric J. Haas et al. say nationwide data in Israel shows 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.”
Hilla De-Leon et al. had reported in a preprint published on medRxiv on 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.
“Our results show that infections occurring 12 days or longer following vaccination have significantly reduced viral loads, potentially affecting viral shedding and contagiousness as well as severity of the disease,” Idan Yelin et al. wrote.
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.
Reports of adverse reactions
The Israeli People`s Committee, which is an independent citizens’ group that includes doctors, attorneys, and researchers from various disciplines, says in a report published on April 25 that it has received 309 reports of deaths occurring in proximity to Covid vaccination.
In its previous report, in which it cites 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 on April 25, it says it has received 2,256 reports of adverse events after Covid vaccination (1,956 analysed and 300 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 says it has 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 reports 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 lists 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.
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.
‘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 notes that two journal publications and about 400 pages of summary data are now 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 7 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 says that an analysis of severe disease irrespective of etiologic agent – namely, rates of hospitalisations, ICU cases, and deaths amongst trial participants – seems warranted, “and is 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 notes. “The only source that appears to have reported it is FDA’s review of Pfizer’s vaccine.”
Doshi wrote in an opinion piece published in The BMJ on November 26 that Pfizer and Moderna are reporting relative risk reduction rather than absolute risk reduction, which, Doshi says, appears to be less than 1%.
“Second, these results refer 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 still remain unknown,” Doshi writes.
“Third, these results reflect a time point relatively soon after vaccination, and 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).”
Fourthly, Doshi says, children, adolescents, and immunocompromised individuals were largely excluded from the trials, so data was still lacking about these important populations.
Doshi argues that the trials have been studying the wrong endpoint, and says there is 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 writes.
”… 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 says there are 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 writes.
“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.”
Demasi points to “the questions everyone wants answered”: Will the vaccines prevent people from getting seriously ill and hospitalised from Covid-19 and will the vaccines prevent deaths?
She cites a BMJ article, published on October 21, in which Peter Doshi said the vaccine trials were not designed to answer those questions.
In the BMJ article 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, talks about “what the Covid vaccine hype fails to mention”.
Commenting about the Pfizer-BioNTech and Moderna trials, he writes: “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 country’s Medicines Health Regulatory Authority (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.”
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 sixty countries.
In India, two Covid vaccines have been approved by the Central Drugs Standard Control Organisation (CDSCO) for restricted emergency use.
They are the 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 (SII).
The approvals came after a CDSCO expert committee recommended emergency use authorisation for both vaccines.
On April 13, the Drugs Controller General of India authorised the Sputnik V vaccine for emergency use in the country. The Central Drugs Standard Control Organisation’s Subject Expert Committee had recommended authorisation. India is the 60th country to authorise use of the vaccine.
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. There are reports that Bharat Biotech will soon begin testing the vaccine on children and teenagers aged two to 18 years if it gets government approval.
The SEC is reported to have given Bharat Biotech permission to give some trial participants a third dose of its Covid vaccine as a booster six months after the second dose.
The committee recommends 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 has withdrawn an application for emergency use authorisation of its Covid vaccine in India, the company told Reuters 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.
India’s Central Drugs Standard Control Organisation 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.
In addition to Zydus Cadila and Bharat Biotech, other Indian companies involved in developing 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 being developed at the Baylor College of Medicine in Houston, Texas, in the US.
Gennova Biopharmaceuticals is developing 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 CDSCO’s subject expert committee had reviewed the data on safety and immunogenicity of the vaccine 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 clinical trial that was ongoing in India would continue.
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.
The ongoing Phase 3 trial, which is being condutced over 25 sites in India, involveS 25,800 volunteers who are between 18 and 98 years of age. They include 2,433 participants over the age of 60 and 4,500 people with comorbidities.
On March 3, Bharat Biotech issued a press release in which it stated that Covaxin “demonstrated 81% interim efficacy in preventing Covid-19 in those without prior infection after the second dose”.
This interim analysis is based on 43 cases of Covid-19 that occurred during the Phase 3 trial with onset at least 14 days after the second vaccine dose. Thirty-six of the cases were in the placebo group and seven were in the vaccinated group. This, the company said, resulted in “a point estimate of vaccine efficacy of 80.6%.”
“The interim analysis included a preliminary review of the safety database, which showed that severe, serious, and medically attended adverse events occurred at low levels and were balanced between vaccine and placebo groups,” the company said
Bharat Biotech also says that an analysis from the National Institute of Virology, which has been published on the bioRxiv preprint server, “indicates that vaccine-induced antibodies can neutralise the UK variant strains and other heterologous strains”.
The company says an additional interim analysis is planned for when 87 Covid-19 cases occur during the trial, and the final analysis will be done when 130 cases are observed.
India’s health ministry said that AstraZeneca had submitted safety, immunogenicity, and efficacy data from overseas clinical studies of Covishield that involved about 23,745 participants aged 18 years or older and the overall vaccine efficacy was found to be 70.42%.
The SII was granted permission to conduct Phase 2/3 clinical trials of Covishield in India involving 1,600 participants and the interim safety and immunogenicity data generated from those trials was comparable with that from the overseas clinical studies, the ministry added. The ongoing Phase 2/3 trials in India would continue.
The CDSCO also granted permission to Zydus Cadila to conduct a Phase 3 clinical of its Covid vaccine that will involve 26,000 participants.
The health ministry said Phase 1/2 trials of Zydus Cadila’s vaccine were ongoing in India and involved more than 1,000 participants.
“The interim data suggests that the vaccine is safe and immunogenic with three doses when administered intradermally,” the ministry said.
Bharat Biotech’s ongoing trial is the largest Phase 3 efficacy trial ever conducted for any vaccine in India.
The company says that, in the Phase 1 and 2 trials, BBV152 , which is a whole-virion inactivated vaccine, elicited strong Immunoglobulin G (IgG) antibody responses against the SARS-CoV-2 spike protein’s receptor binding domain and its nucleocapsid protein.
“In a follow-up of the Phase 1 trial, BBV152 produced high levels of neutralising antibodies that remained elevated in all participants three months (at day 104) after the second vaccination,” Bharat Biotech said.
“Based on these results, we hypothesise that BBV152 can generate antibodies that may persist for 6-12 months.”
Twice as many neutralising titres were observed in the Phase 2 study than in Phase 1.
In the Phase 2 trial, two formulations of BBV152 were used. Researchers Raches 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. report 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.
“Based on follow-up data from the phase 1 trial, at day 104 (three months after the second dose), despite a marginal expected decline in neutralising antibody titres, BBV152 has exhibited the potential to provide durable humoral immunity and cell-mediated immunity,” they reported.
“Immune responses were significantly higher than those in the Phase 1 trial … It is hypothesised that the humoral and cell-mediated responses reported in this study may persist until at least 6-12 months after the second vaccination dose.”
Ella et al. said the results they reported did not permit efficacy assessments. “The evaluation of safety outcomes requires extensive Phase 3 clinical trials. We were unable to assess other immune responses (binding antibody and cell-mediated responses) of convalescent serum due to the limited quantity.
“No additional data on the severity of disease from symptomatic individuals were obtained … this study population lacked ethnic diversity, further underscoring the importance of evaluating BBV152 in other populations.”
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 say, 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 (ICMR) and others have been 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”.
.@TheLancetInfDis publishes findings from trial of inactivated SARS-CoV-2 vaccine, BBV152 developed by @BharatBiotech & ICMR. @TheLancet @MoHFW_INDIA @DeptHealthRes Read more: https://t.co/KKZJOf6Ew1 pic.twitter.com/ZCfu2pfOwb
— ICMR (@ICMRDELHI) January 22, 2021
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 a paper 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.
Ella et al said that, in the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses, compared with the findings in the Phase 1 trial.
In the phase 1 trial, the vaccine had induced high neutralising antibody responses that remained elevated in all participants at three months after the second vaccination.
The researchers reiterated that, based on follow-up data from the Phase 1 trial, despite a marginal expected decline in neutralising antibody titres at day 104, BBV152 had shown the potential to provide durable humoral and cell-mediated immune responses.
They added: “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.
A man in Chennai, India, who was a volunteer in the trial of Covishield is suing 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 and, on October 11, he started suffering severe headaches and vomiting, and was not able to respond to questions.
His wife is 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 is being developed by Bharat Biotech in collaboration with the Indian Council of Medical Research (ICMR), fell ill and had to be hospitalised after being vaccinated in July, 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).
“This hospital was one of the sites conducting the Covxin trial,” Bhuyan wrote. “Many locals have been unemployed over the past year and children have been out of school because of the pandemic, so the small sum of money was attractive enough for them to take part in the trial.”
Bhuyan tells the story of 57-year-old Ramesh, who said he got his first Covaxin vaccination on December 7, 2020.
“I was told it is the Covid-19 vaccine,” Bhuyan quotes Ramesh as saying. ‘’I did not know it was a trial. The people at the hospital did not give me any time to see what I was told to sign. I did not know that I could refuse the injections.”
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 Indian Council of Medical Research did not respond to Bhuyan’s requests for comment.
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.”
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.
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