This article has been updated. Latest update 5/3/2021.
- The Pfizer-BioNTech and AstraZeneca-Oxford vaccines are being administered under emergency use authorisations in the UK.
- The FDA in the US has issued emergency use authorisations for the Pfizer-BioNTech and Moderna vaccines and the vaccine developed by the Johnson & Johnson subsidiary Janssen Biotech.
- The European Commission has granted conditional marketing authorisations for the Pfizer-BioNTech, AstraZeneca-Oxford, and Moderna 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 many tens of thousands of reported adverse reactions after Covid vaccination, including hundreds of deaths.
- AstraZeneca is doing mix-and-match experiments with vaccine doses from other companies.
- Pfizer and BioNTech are testing their vaccine on pregnant women, and plan trials involving children younger than five.
- There are concerns that there may be disease enhancement with some vaccines.
- Vaccination certificates could be required to fly, cross borders, and use public transportation.
Massive Covid vaccination drives are underway around the world, many under emergency use authorisations.
According to the Our World in Data website, more than 275 million vaccine doses had been administered in 66 countries by March 3.
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, RNA, and viral vector 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 reports that the Russian Direct Investment Fund (RDIF) is 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.”
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 disease.
The efficacy percentages vaunted by the front-running manufacturers only relate to a small 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 percentages relate to disease prevention, not the prevention of infection.
The number of Covid-19 cases analysed ranges from just 39 during the Sputnik V trial in Russia to 170 during the trial of the Pfizer-BioNTech vaccine.
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 80 million doses have been given so far.
In the UK, where Covid vaccination began on December 8 and priority has been given to the elderly, more than 21 million doses have been administered.
Israel and the United Arab Emirates are the two countries that have vaccinated their populations the fastest. About one-quarter of their populations have already received at least one Covid vaccine dose.
In China, about 52 million Covid vaccine doses are reported to have been administered. More than five million doses are reported to have been administered in Russia.
India started administering Covid vaccinations on January 16 and more than 16 million doses have been administered so far.
No Covid vaccines have as yet been administered in sub-Saharan Africa. 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 Covisield 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.
The WHO says COVAX aims to start shipping nearly 90 million Covid-19 vaccine doses to Africa this month.
The rollout of the AstraZeneca-Oxford vaccine in Africa is subject to it being listed for emergency use by the WHO.
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 six 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
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.
[UPDATE] Three reports have since been published that are being taken as evidence that Covid vaccination can prevent SARS-CoV-2 infection in those vaccinated and reduce virus transmission.
The first 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.”
The second 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 the third 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. [ENDS UPDATE]
Headlines vaunt progress, but there are doubts about safety and efficacy
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.
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.
On March 5, 2021, the World Health Organisation’s pharmacovigilance database, VigiBase, listed more than 177,000 reports of adverse events following Covid vaccination, including 1,585 deaths.
On February 21, the database of the Centers for Disease Control and Prevention’s Vaccine Adverse Event Reporting System (VAERS) in the US listed 19,907 total adverse event reports after Covid vaccination. The figure relates to reports up to February 19. A total 94,296 individual-symptom events are listed (many reports include more than one symptom).
A total 12,729 reports relate to adverse events after administration of the Pfizer-BioNTech vaccine (58,123 individual-symptom events), 7,152 refer to the Moderna vaccine (36,000 individual-symptom events), and 28 relate to an unknown vaccine manufacturer. There’s a discrepancy between the 19,907 total and this one (19,909).
VAERS puts the number of reports, in all locations, of death following Covid vaccination at 1,095 as of February 19. (966 from US territories or a location reported as unknown and 129 from foreign locations).
On the CDC’s website it’s stated: “Over 41 million doses of Covid-19 vaccines were administered in the United States from December 14, 2020, through February 7, 2021. During this time, VAERS received 1,170 reports of death (0.003%) among people who received a Covid-19 vaccine.”
MedAlerts, which uses the VAERS database, also puts the number of deaths at 1,095 as of February 18 and lists the number of total adverse events as 19,907 (25,871 individual-symptom events).
On the independent OpenVAERS website, the number of reported deaths to February 19 is also put at 1,095, and the total number of adverse events at 19,907.
The European database of suspected adverse drug reaction reports, EudraVigilance, lists 78,305 individual cases up to February 27 for the Pfizer-BioNTech vaccine (tozinameran). The most cases were in Italy (27,917) followed by 5,775 in Spain and 5,662 in France. Each individual case generally refers to a single patient.
A total 3,266 cases are listed for the Moderna vaccine (the most cases were from Spain and numbered 473, followed by 363 cases in Italy) and 336 in the Netherlands.
A total 13,983 cases are listed for the AstraZeneca-Oxford vaccine, with the most listed in France (1,193) followed by Italy (720) and Austria (544).
The Medicines and Healthcare products Regulatory Agency (MHRA) in the UK said that, up to and including February 21, 2021, it had received and analysed 42,917 total reports of suspected adverse reactions to the AstraZeneca-Oxford vaccine. The number of listed adverse rections is 157,637 (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.
The number of reported adverse reactions to the AstraZeneca-Oxford vaccine is now more than the number related to the Pfizer-BioNTech vaccine, which was first administered on December 9, 2020.
The MHRA has recorded 85,179 adverse reactions in 29,715 total reports (received between December 9, 2020, and February 21, 2021) about the Pfizer-BioNTech vaccine.
The MHRA says it has received 244 UK reports of suspected adverse reactions to the AstraZeneca-Oxford vaccine in which the patient died shortly after vaccination. There were 212 reports of deaths after vaccination with the Pfizer-BioNTech vaccine and four deaths were reported in which the vaccine brand was unspecified.
The majority of these reports were in elderly people or people with underlying illness, the MHRA says. Usage of the AstraZeneca 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 1,274 vascular disorders (one fatal), 799 blood disorders, 1,516 cardiac disorders (thirty fatal), 1,613 eye disorders, 17,597 gastrointestinal disorders (five fatal), 410 immune system disorders, 19,241 muscle and tissue disorders, 34,656 nervous system disorders (14 fatal), 4,059 respiratory disorders (ten fatal), 7,872 skin disorders, 2,773 psychiatric disorders, and 3,016 cases of infection (32 fatal).
The reports about the Pfizer-BioNTech vaccine include 992 vascular disorders (one fatal), 2,033 blood disorders (one fatal), 1,032 cardiac disorders (25 fatal), 1,242 eye disorders, 9,360 gastrointestinal disorders (11 fatal), 466 immune system disorders, 11,565 muscle and tissue disorders, 16,107 nervous system disorders (14 fatal), 3,575 respiratory disorders (12 fatal), 6,042 skin disorders (one fatal), 1,235 psychiatric disorders, and 1,863 cases of infection (33 fatal).
The MHRA says that, in the week since the previous summary for February 14, 2021, it received a further 2,892 Yellow Cards for the Pfizer/BioNTech vaccine, 11,490 for the AstraZeneca-Oxford vaccine, and 111 where the brand was not specified. A higher number of doses of the AstraZeneca-Oxford vaccine were administered in the last week than the Pfizer-BioNTech vaccine, the MHRA said.
For both vaccines the overall reporting rate is around three to five Yellow Cards per 1,000 doses administered.
Additionally, up to and including February 21, 2021, the MHRA received 177 Yellow Card reports in which the brand of vaccine was not specified by the person reporting the reaction.
The MHRA said that, as of February 21, an estimated 9.4 million first doses of the Pfizer-BioNTech vaccine and 8.4 million doses of the AstraZeneca-Oxford vaccine had been administered. About 0.6 million second doses, mostly of the Pfizer-BioNTech vaccine, had been administered.
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.
There was a similar about-turn in France, where those aged between 65 and 74 can now receive the AstraZeneca-Oxford vaccine. Those aged over 75 will be offered either the Pfizer-BioNTech or Moderna vaccine.
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 and BioNTech say they expect to start vaccine trials involving children between the ages of five and 11 over the next couple of months, and involving children younger than five later in 2021.
The companies say that vaccine safety and efficacy in children aged 12 to 15 years are already being evaluated in a global Phase 3 study and they will submit the relevant data to regulatory authorities in the second quarter of 2021.
Pfizer and BioNTech are also planning studies to further evaluate their vaccine in people with compromised immune systems.
A new trial is meanwhile set to begin in Britain in which the AstraZeneca-Oxford vaccine will be tested on children.
The University of Oxford has launched the study, which will take place at sites in Oxford, Southampton, London, and Bristol.
Children and teenagers aged 6–17 years will be enrolled in the trial, which is due to involve up to 150 participants aged 6–11 years and up to 150 aged 12–17 years. Those placed in the control group will be given a meningococcal vaccine, not a saline placebo.
The Oxford researchers argue that, because a saline placebo has no adverse effects, participants who have 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 argue.
The same vaccine dose will be given as in the trials involving adults. Recruitment into the study will happen in stages, with the vaccine being given first to those aged 12–17 years. Data will be reviewed before the vaccine is given to younger children.
The researchers say that, because this is the first time the AstraZeneca-Oxford vaccine has been tested on children, only healthy children will be 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.
In the trial, in the case of children under the age of 16, their parents must give full informed consent and the participant must also assent to taking part. Written assent will be taken from children aged 11–16 and verbal assent will be required for those under the age of 11.
Teenagers aged 16–17 years will be able to consent themselves, but must be accompanied by a parent or guardian on their first visit.
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.
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 to introduce a Covid vaccination certificate. Mitsotakis addressed his request in a letter sent to the European Commission 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.
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.
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.
The European Commission has granted conditional marketing authorisations for the Pfizer-BioNTech, AstraZeneca-Oxford, and Moderna vaccines.
The Therapeutic Goods Administration (TGA) in Australia announced on January 25 that it had granted provisional approval for the Pfizer-BioNTech vaccine BNT162b2 (Cominarty) for use for individuals aged 16 and older. 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 single-dose Covid vaccine developed by the Johnson & Johnson subsidiary Janssen Biotech. 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.
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 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 (the virus’s entry portal into human cells) 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 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.”
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.
South Africa has put use of AstraZeneca’s vaccine on hold. Health Minister Zweli Mkhize that the government would await advice from scientists on how best to proceed, given that research has indicated that the vaccine does 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 Serum Institute of India (SII), which is responsible for testing and manufacturing the AstraZeneca vaccine in India under the brand name 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 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.
Vaccine efficacy studies
Pfizer and BioNTech say their Covid-19 vaccine is effective against virus variants detected in the UK and South Africa but there is reduced efficacy against the South Africa variant.
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.
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 viral vector 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 Institute of Biological Products. 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.”
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 (CHM) 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 agency adds: “The MHRA has received 130 UK spontaneous adverse reactions associated with anaphylaxis or anaphylactoid reactions with the Pfizer/BioNTech vaccination. All patients have recovered from the anaphylaxis episode. Thirty reports of anaphylaxis have been received for the Covid-19 Oxford University/AstraZeneca vaccine to date.”
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 Russia’s sovereign wealth fund, the Russian Direct Investment Fund (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 Gamaleya institute’s director, 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.
Dangers of vaccinating SARS-CoV-2 carriers
Physician-scientist 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 the Covid vaccination Covishield.
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.
Other adverse effects
A total 9,845 total adverse events after Covid vaccination had been reported to VAERS As of January 22.
There are 9,277 total reports listed on https://vaxpain.us/ and 11,249 on OpenVAERS.
On February 21, there were 84,489 reports of adverse events after Covid vaccination listed on VigiBase. A total 3,907 of these were reports of cardiac disorders blood and 4,846 were reports of blood and lymphatic system 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.
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 February 11 that since Covid vaccination began in the country on December 26, 2020, there had been 2,140 reports of adverse reactions after vaccination with the Pfizer-BioNTech vaccine.
Between January 22 and February 4, there had been forty reports of adverse reactions after vaccination with the Moderna vaccine, the agency reported.
Between February 6, when vaccination with the AstraZeneca-Oxford vaccine began in France, and February 4 there were 149 adverse event reports in which people spoke of high fevers, aches, and headaches. Over the reporting period, about 10,000 people were vaccinated.
Frequency of grade 3 adverse events ‘higher than for most vaccines’
Associate editor of The BMJ Peter Doshi notes 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 – is higher than it is 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
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.
The trial involves about 4,000 healthy women who are being vaccinated when they are 24 to 34 weeks pregnant. The trial participants will receive two doses of BNT162b2 or a placebo, administered 21 days apart.
Each woman will participate in the study for approximately seven to ten months, depending on whether she was randomised to receive the vaccine or placebo.
The study will study the infants of the vaccinated women to assess vaccine safety and examine whether the women transfered 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 receive 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 have found that one dose of the Pfizer-BioNTech vaccine appears 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.”
Contradictory data in Israel
Twenty-nine percent of Israelis have received at least one dose of the Pfizer-BioNTech Covid vaccine and 80% of them are over-60s. The vaccination drive began on December 19.
According to Our World in Data, 5.38 million vaccine doses had been administered as of February 5.
While researchers report 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.
Various studies give different results to those reported by the Clalit Research Institute on January 12.
Hilla De-Leon et al. reported in a preprint published on medRxiv on February 3 that the Pfizer-BioNTech vaccine may curb cases of Covid-19 by about 50 percent 14 days after the first of two doses is administered.
The researchers admit, 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 on 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 provides 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.
Full details of the study aren’t yet publicly available, and the research hasn’t yet been peer reviewed.
A limitation of the study is that it is observational research, not a randomised controlled trial.
It’s being reported in the Israeli media that demand for Covid vaccination has 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.”
The Brazilian health authority 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.”
In a report published in The Lancet on February 2, 2021, Denis Y Logunov et al. said that, in an interim analysis of a Phase 3 clinical trial, Sputnik V had 91.6% efficacy against Covid-19.
The percentage is slightly higher than the 91.4% announced by the Gamaleya National Research Centre for Epidemiology and Microbiology and the RDIF on December 14.
Both calculations are based on an analysis of 78 confirmed cases of Covid-19 (62 cases in the placebo group and 16 in the vaccinated group).
The most recent data 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 centigrade.
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 Drug Control General of India 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.
Dr Reddy’s officials said they hoped to launch Sputnik V in India in March this year.
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.
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.
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.
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.
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.
[UPDATE] 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. [ENDS UPDATE]
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.”
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.
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.
The Brazilian health regulator, 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 European Commission granted a conditional marketing authorisation for the AstraZeneca-Oxford vaccine. This followed a recommendation from the European Medicines Agency (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 European Commission (EC) granted a conditional marketing authorisation (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 European Commission. 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 conditional marketing authorisation for use of the Moderna Covid vaccine for people aged 18 years and above.
On March 4, the EMA’s Committee for Medicinal Products for Human Use (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.
DONATE TO CHANGING TIMES VIA SIMPLE PAYMENTS
1= 5 euro, x 2 = 10 euro, X 3 =15 euro, etc.