This is a rejigged and updated version of an earlier article. Latest update: 29/1/2021.
- The FDA in the US has issued emergency use authorisations for the Pfizer-BioNTech and Moderna vaccines.
- The Pfizer-BioNTech vaccine is being given to members of the public in the UK under an emergency use authorisation.
- The European Commission has granted conditional marketing authorisations for the Pfizer-BioNTech, Astra-Zeneca-Oxford, and Moderna vaccines.
- The Therapeutic Goods Administration in Australia has granted provisional approval for the Pfizer-BioNTech vaccine.
- AstraZeneca’s Covid-19 vaccine has been approved for emergency use in the UK.
- China’s top drug regulator has granted the Beijing Institute of Biological Product’s vaccine, BBIBP-CorV, conditional marketing approval.
- In India, two Covid vaccines have been approved for restricted emergency use.
- Pfizer and BioNTech say their vaccine has been shown to be 95% effective.
- Moderna has announced 94.1%. efficacy for its vaccine.
- AstraZeneca said its vaccine was 90% effective when given as a half dose followed by a full dose at least one month later.
- The developers of Russia’s Sputnik V vaccine report more than 95% efficacy 42 days after the first dose.
- There are concerns that there may be disease enhancement with some vaccines.
- Vaccination could be required to fly, cross borders, and use public transportation.
Two of the front runners in the Covid vaccine race have obtained emergency use authorisations (EUAs) for their vaccines in the US and a mass vaccination drive has begun in the UK, with the elderly being prioritised.
The Food and Drug Administration (FDA) has issued EUAs for 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.
Pfizer and BioNTech announced on December 2 that the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK had granted a temporary authorisation for emergency use for their vaccine.
AstraZeneca announced on December 30 that the MHRA had approved its Covid-19 vaccine for emergency use for individuals aged 18 years and above.
The vaccine was co-invented by the University of Oxford and its spin-out company, Vaccitech.
AstraZeneca, which is now referring to its vaccine as Covid-19 Vaccine AstraZeneca, formerly AZD1222, said the first doses were being released immediately so that vaccinations would begin early in 2021.
“The company aims to supply millions of doses in the first quarter as part of an agreement with the government to supply up to 100 million doses in total,” AstraZeneca said.
“AstraZeneca is working with its global partners to continue building manufacturing capacity of up to three billion doses of the vaccine globally in 2021 on a rolling basis, pending regulatory approvals.”
The company said that additional safety and efficacy data for the vaccine would continue to accumulate from ongoing clinical trials.
The MHRA’s authorisation recommends two doses of the vaccine, administered with an interval of between four and 12 weeks.
AstraZeneca said the company was continuing to work with regulatory authorities around the world to support their ongoing rolling reviews for emergency supply or conditional marketing authorisation.
On January 29, the European Commission granted a conditional marketing authorisation for the AstraZeneca-Oxford vaccine. This followed a recommendation from the 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.
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.
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.
The CEO of BioNTech, Ugur Sahin, added that there would be future testing of the vaccine against any additional virus mutations that might occur.
The Therapeutic Goods Administration (TGA) in Australia announced on January 25 that it had granted provisional approval for the Pfizer-BioNTech vaccine for use for individuals aged 16 and older. The provisional approval is valid for two years.
BNT162b2 (Cominarty), is the first Covid vaccine to receive regulatory approval in Australia.
“The approval is subject to certain strict conditions, such as the requirement for Pfizer to continue providing information to the TGA on longer term efficacy and safety from ongoing clinical trials and post-market assessment,” the TGA said. “Cominarty has been shown to prevent Covid-19 however it is not yet known whether it prevents 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 EUA for 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.
The Moderna vaccine is administered as a series of two doses, one month apart.
The then US President Donald Trump charged in ahead of the official authorisation announcement from the FDA, saying in a tweet that Moderna’s vaccine had been approved and would ship immediately.
Moderna vaccine overwhelmingly approved. Distribution to start immediately.
— Donald J. Trump (@realDonaldTrump) December 18, 2020
On December 12, the Centers for Disease Control and Prevention’s Advisory Committee on Immunisation Practices (ACIP) issued an interim recommendation for use of the Pfizer-BioNTech vaccine in people aged 16 years and above. The first doses were administered on December 14.
The FDA said it had determined that BNT162b2a had met the statutory criteria for issuance of an EUA. “The totality of the available data provides clear evidence that the Pfizer-BioNTech Covid vaccine may be effective in preventing Covid-19,” it added. The data provided by Pfizer indicated that the known and potential benefits of the vaccine outweighed the known and potential risks, the FDA said.
The data provided by Pfizer relates to an analysis of 36,523 participants in the international trial, the majority of whom are US participants, who did not have evidence of SARS-CoV-2 infection seven days after the second vaccine dose. Among these participants, 18,198 received the vaccine and 18,325 received a placebo.
The FDA’s authorisation for BNT162b2a came just a day after members of the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted by 17 votes to four, with one abstention, in favour of the emergency use of the vaccine for people aged 16 years and older.
The FDA’s authorisation for mRNA-1273 came just a day after twenty members of the VRBPAC voted in favour of granting an EUA for the vaccine. No members voted against, and one abstained.
Moderna said that delivery of the vaccine to the US government would begin immediately and the company would continue to gather additional data and planned to file a biologics licence application with the FDA requesting full licensure in 2021.
The company said that a total 200 million doses of the vaccine had been ordered by the US government to date and the government retained the option to purchase up to an additional 300 million doses
Moderna said that, under Operation Warp Speed, the Department of Defence, in partnership with the Department of Health and Human Services and the Centers for Disease Control and Prevention would manage allocation and distribution of the vaccine in the US.
“Allocation and distribution will be prioritised according to populations identified by the CDC’s Advisory Committee on Immunisation Practices,” Moderna said.
“Approximately 20 million doses will be delivered to the US government by the end of December 2020. The company expects to have between 100 million and 125 million doses available globally in the first quarter of 2021, with 85-100 million of those available in the US.”
The FDA said it had determined that the Moderna vaccine had met the statutory criteria for issuance of an EUA.
“The totality of the available data provides clear evidence that the Moderna Covid-19 vaccine may be effective in preventing Covid-19,” the FDA added. “The data also show that the known and potential benefits outweigh the known and potential risks – supporting the company’s request for the vaccine’s use in people 18 years of age and older.
“In making this determination, the FDA can assure the public and medical community that it has conducted a thorough evaluation of the available safety, effectiveness, and manufacturing quality information.”
The director of the FDA’s Center for Biologics Evaluation and Research, Peter Marks, said that, although the EUA was not an FDA approval, the FDA’s expectations described in its June and October guidance documents had been met.
The scientific evidence Moderna presented to the VRBPAC includes a data analysis from the Phase 3 COVE clinical study that the company announced on November 30.
A total 30,351 participants have been enrolled in the COVE trial, which was conducted in the US. Of these participants, 15,185 received the mRNA-1273 vaccine and 15,166 of received a saline placebo.
The effectiveness data presented by Moderna to support its EUA application include an analysis of 28,207 participants in the COVE study who did not have evidence of SARS-CoV-2 infection prior to the first dose of vaccine. Among these participants, 14,134 received the vaccine and 14,073 received placebo.
Moderna announced that its data analysis relating to 196 cases of Covid-19 that occurred during its vaccine trial indicated 94.1% efficacy.
Thirty of the Covid-19 cases were severe, and all were among participants who were in the placebo group. According to Moderna, this means that mRNA-1273 has been shown to have 100% efficacy against severe Covid-19.
There was one Covid-19-related death during the trial, which occurred in the placebo group, Moderna said.
The FDA said on December 18 that at the time of the analysis of the 196 COVID-19 cases, none in the vaccine group were classified as severe. “After the analysis of these 196 cases was completed, one severe case in the vaccine group was identified and is awaiting confirmation,” the FDA added.
“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.”
Moderna told the FDA that the most common solicited adverse reactions after two doses of its vaccine included injection site pain (88.2%), skin redness (8.6%), swelling (12.2%), and ipsilateral lymphadenopathy, which is an enlargement of nodes in the groin, (14.2%).
While the majority of these adverse reactions were mild or moderate, there was a higher occurrence of severe reactions in the mRNA-1273 group and after the second injection, Moderna reported.
Moderna says most of the adverse reactions occurred within the first one to two days after vaccination and generally persisted for a median of one to two days.
Safety data continued to accrue, the company said, and the study continued to be monitored by an independent data safety monitoring board appointed by the National Institutes of Health. All participants in the COVE study would be monitored for two years to assess long-term protection and safety.
The FDA said in its briefing document for the VRBPAC meeting about the Moderna vaccine: “Throughout the safety follow-up period to date, there were three reports of facial paralysis (Bell’s palsy) in the vaccine group and one in the placebo group. Currently available information is insufficient to determine a causal relationship with the vaccine.
“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.”
The FDA states in the briefing document: “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 adds: “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 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 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 to 170 during the trial of the Pfizer-BioNTech vaccine.
Referring to the efficacy data provided by Pfizer, which the company says shows the BNT162b2a vaccine to be 95% effective in preventing Covid-19 disease, 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.”
In a briefing document released on December 8 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”.
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 Albert Bourla said that the company was not certain about this and it was something that needed to be examined.
The Commissioner of Food and Drugs for the FDA, Stephen Hahn, said the FDA’s decision to issue an EUA for BNT162b2 vaccine followed “an open and transparent review process that included input from independent scientific and public health experts and a thorough evaluation by the agency’s career scientists to ensure this vaccine met FDA’s rigorous, scientific standards for safety, effectiveness, and manufacturing quality needed to support emergency use authorisation”.
He added: “The tireless work to develop a new vaccine to prevent this novel, serious, and life-threatening disease in an expedited timeframe after its emergence is a true testament to scientific innovation and public-private collaboration worldwide.”
Peter Marks said on December 11: “While not an FDA approval, today’s emergency use authorisation of the Pfizer-BioNTech Covid-19 vaccine holds the promise to alter the course of this pandemic in the United States.”
Marks said the data provided by Pfizer had met the FDA’s expectations as conveyed in their June and October guidance documents. “Efforts to speed vaccine development have not sacrificed scientific standards or the integrity of our vaccine evaluation process,” he said.
The FDA said the EUA application was supported by safety data relating to 37,586 of the participants enrolled in the ongoing randomised, placebo-controlled international study, the majority of whom are US participants. A total 18,801 participants received the vaccine and 18,785 received a saline placebo.
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 the Medicines and Healthcare Products Regulatory Agency issued a warning that people with a history of allergic reactions should not be given it.
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.
Covid vaccination at the Advocate Condell Medical Centre in Libertyville, Illinois, in the US has been 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 total 3,000 Advocate Aurora Health employees have so far received Covid vaccinations.
Pfizer says, meanwhile, that available data “are insufficient to inform vaccine-associated risks in pregnancy”.
In its authorisation letter to Pfizer, the FDA says the company will conduct a post-authorisation observational study (or studies) to evaluate the association between the BNT162b2a vaccine and “a pre-specified list of adverse events of special interest, along with deaths and hospitalisations, and severe Covid-19”.
The FDA adds: “The study population should include individuals administered the authorised Pfizer-BioNTech Covid-19 Vaccine under this EUA in the general US population (16 years of age and older), populations of interest such as healthcare workers, pregnant women, immunocompromised individuals, subpopulations with specific comorbidities.”
The study or studies should be conducted in large scale databases with an active comparator, the FDA says.
After the VRBPAC recommended the issuance of an FDA for Pfizer, Donald Trump weighed in heavily in a series of tweets. He accused FDA officials of “playing games” and demanded that they get the Covid vaccines out immediately.
While my pushing the money drenched but heavily bureaucratic @US_FDA saved five years in the approval of NUMEROUS great new vaccines, it is still a big, old, slow turtle. Get the dam vaccines out NOW, Dr. Hahn @SteveFDA. Stop playing games and start saving lives!!!
— Donald J. Trump (@realDonaldTrump) December 11, 2020
BNT162b2 has already been authorised or approved for emergency use in Bahrain, Saudi Arabia, and Canada. On December 14, Singapore became the first Asian country to approve the vaccine.
Phase 3 clinical trials of BNT162b2 began on July 27 and are ongoing. More than 43,000 participants have been enrolled in 150 sites in the US, Germany, Turkey, South Africa, Brazil, and Argentina and most of them have received a second vaccine dose.
Pfizer and BioNTech say they expect to file a biologics licence application for possible full regulatory approval of their vaccine in 2021.
China’s top drug regulator, the National Medical Products Administration (NMPA), has granted the Beijing Institute of Biological Product’s inactivated virus vaccine, BBIBP-CorV, conditional marketing approval. It was the first NMPA approval for a Covid-19 vaccine.
The institute is a unit of the China National Biotec Group, which is the vaccine and bioscience arm of the company Sinopharm.
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 December 13, the National Health Regulatory Authority (NHRA) in Bahrain announced that it had approved the registration of BBIBP-CorV.
In August, Russia became the first country to register a Covid vaccine and the first batch of the Sputnik V adenovirus vector-based vaccine was released into civil circulation.
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.
The British-Swedish pharmaceutical giant AstraZeneca announced on December 11 that it plans to start a clinical trial combining its AZD1222 vaccine with Sputnik V to assess the safety and immunogenicity of the combination. Volunteers aged 18 and older will be enrolled.
“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 vaccine task force in the UK has said that it plans to test a combination of the AstraZeneca and Pfizer-BioNTech vaccines next year.
The Chinese authorities have authorised three vaccines for limited or emergency use without Phase 3 trials having being conducted.
The Ad5-nCoV 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.
Ad5-nCoV is one of eight SARS-CoV-2 vaccines being developed in China that have been approved for human trials at home and abroad, Reuters reported. Five of the vaccine projects are already at the stage of human trials.
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 the AstraZeneca-Oxford vaccine, which is branded as Covishield in India and 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.
Euphoria and disquiet
There was widespread media euphoria over the first Pfizer-BioNTech vaccination outside of the official clinical trials – that of 90-year-old Margaret Keenan in Coventry – and excitement, with accompanying jokes, about the next BNT162b2 vaccinee being a man called William Shakespeare.
While there are many who believe the vaccine rollouts herald the end of the Covid-19 pandemic, there are dissenting voices: those who say the fast-tracked vaccines have been inadequately tested, the vaccinees are guinea pigs, and long-term effects are unknown.
Most of the recent vaccine trial announcements in the US, Britain, and Russia were made in press releases, not medical journals.
The editor-in-chief of The Lancet, Richard Horton, tweeted:
On the Pfizer COVID-19 vaccine: publishing interim results through a press release is neither good scientific practice nor does it help to build public trust in vaccines. An announcement should come with full publication of a peer-reviewed research paper in a scientific journal.
— richard horton (@richardhorton1) November 10, 2020
The editor-in-chief of the BMJ, Fiona Godlee, said in an article published on November 12: “’Science by press release’ is just one of many flaws in the way new treatments are evaluated, brought into stark relief by the pandemic.”
Even the ardent and vocal advocate of vaccination Peter Hotez has spoken out about giving emergency use authorisation for a vaccine against SARS-CoV-2.
“I would be very worried about using an EUA mechanism for something like a vaccine. It’s very different from plasma therapy,” Hotez told Reuters.
Five scientists from the WHO’s Solidarity Vaccines Trial Expert Group said in a commentary published in The Lancet on August 27 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 scientists added: “Deployment of a marginally effective vaccine could also interfere with the evaluation of other vaccines, as subsequent vaccines would then have to be compared with it rather than with a placebo.”
They said that the criteria used to define a successful vaccine in the initial clinical trials of vaccination versus placebo should be strict enough to protect against the risk of a weakly effective vaccine being deployed, “especially since there are already many candidate vaccines against Covid-19 to be tested, providing many chances to overestimate efficacy”.
The initial trials comparing Covid-19 vaccines to a placebo should seek reliable evidence not only of some efficacy, but of worthwhile efficacy, the scientists said.
The five researchers say 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%.
“This means that the 95% CI [confidence interval] for the trial result should exclude efficacy less than 30%. Current US Food and Drug Administration guidance includes this lower limit of 30% as a criterion for vaccine licensure,” they said.
The scientists also said that, in comparison with individual trials for each of the many different vaccines, a global multi-vaccine trial with a shared control group could provide more rapid and reliable results.
There is particular disquiet about DNA and mRNA vaccines, which have never previously been approved for human use.
There is concern that, with spike protein vaccines, there may be 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.
Two of the biggest vaccine manufacturers – AstraZeneca and the American multinational corporation Johnson & Johnson – have had to halt trials of their Covid vaccines because of the illness of participants.
As pharmaceutical companies rush to get their vaccines onto the market there is also a groundswell of protest over plans by some governments to make the vaccines mandatory.
There are fears 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.
The CEO of the Australian airline Qantas, Alan Joyce, has already 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 Joyce’s stance was a “bit premature” and that testing was more critical than vaccines.
There is already a petition on change.org against mandatory vaccination for international travel, which has been signed by nearly 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.”
Development of CSL vaccine stops because of false HIV positives
The Australian government announced on September 7 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 AZD1222. 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 Oxford-AstraZeneca 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.
Pfizer and BioNTech vaunt results, but FDA points to adverse events
Pfizer and BioNTech said in their authorisation announcement on December 2: “This constitutes the first emergency use authorisation following a worldwide Phase 3 trial of a vaccine to help fight the pandemic. Pfizer and BioNTech are anticipating further regulatory decisions across the globe in the coming days and weeks and are ready to deliver vaccine doses following potential regulatory authorisations or approvals.”
In July 2020, Pfizer and BioNTech announced an agreement with the UK to supply 30 million doses of the BNT162b2 vaccine once it was authorised for emergency use. That agreement was increased to 40 million doses in early October. The delivery of the 40 million doses will occur in stages in 2020 and 2021.
In the briefing document the FDA released on December 8 it reports that two trial participants who received the BNT162b2 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.
The FDA document also refers to four cases of Bell’s palsy that occurred in the vaccine group. No cases occurred in the placebo group. The FDA says it will recommend surveillance for cases of Bell’s palsy among those vaccinated.
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.
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.”
Pfizer and BioNTech had announced on November 18 that they had met all the primary efficacy endpoints necessary to apply to the FDA for emergency use authorisation for BNT162b2, which they say has been shown to be 95% effective.
They said: “170 confirmed cases of Covid-19 were evaluated, with 162 observed in the placebo group versus eight in the vaccine group.
“Analysis of the data indicates a vaccine efficacy rate of 95% (p<0.0001) in participants without prior SARS-CoV-2 infection (first primary objective) and also in participants with and without prior SARS-CoV-2 infection (second primary objective), in each case measured from seven days after the second dose.”
They added: “Efficacy was consistent across age, gender, race and ethnicity demographics; observed efficacy in adults over 65 years of age was over 94%.”
Pfizer and BioNTech said there were ten severe cases of Covid-19 observed in the trial, with nine of the cases occurring in the placebo group and one in the group vaccinated with BNT162b2.
More complete results of the trial of the Pfizer-BioNTech vaccine were published in the New England Journal of Medicine on December 10. Fernando P. Polack et al. provide clarity about the efficacy statistics announced earlier.
Polack et al. report on the deaths referred to in the FDA briefing document. They note that two BNT162b2 recipients died (one from arteriosclerosis and one from cardiac arrest), as did four placebo recipients, “two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction”.
The researchers say that no deaths were considered by the investigators to be related to the vaccine or placebo and no Covid-19–associated deaths were observed.
Polack et al. specify that a total of 43,548 participants were involved in the trial, of whom 43,448 received injections. A total 21,720 participants received the BNT162b2 vaccine and 21,728 were given a placebo.
The researchers give details about the 170 cases of Covid-19 referred to by Pfizer and BioNTech in earlier announcements.
“Among 36,523 participants who had no evidence of existing or prior SARS-CoV-2 infection, eight cases of Covid-19 with onset at least seven days after the second dose were observed among vaccine recipients and 162 among placebo recipients,” Polack et al. report.
Among participants with and without evidence of prior SARS-CoV-2 infection, nine cases of Covid-19 with onset at least seven days after the second dose were observed among vaccine recipients and 169 cases were observed among placebo recipients.
“BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6),” the researchers write.
“Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions.”
The researchers specify that the companies’ prespecified success criteria was to establish a probability above 98.6% of true vaccine efficacy being greater than 30%.
“The vaccine met both primary efficacy end points, with more than a 99.99% probability of a true vaccine efficacy greater than 30%. These results met our and greatly exceeded the minimum FDA criteria for authorisation.”
A two-dose regimen of BNT162b2 (30 μg per dose, given 21 days apart) was found to be 95% effective against Covid-19, the researchers state.
“For all analysed subgroups in which more than ten cases of Covid-19 occurred, the lower limit of the 95% confidence interval for efficacy was more than 30%.”
Polack et al. say the cumulative incidence of Covid-19 cases over time among placebo and vaccine recipients begins to diverge by 12 days after the first dose (seven days after the estimated median viral incubation period of five days), “indicating the early onset of a partially protective effect of immunisation”.
They add that, in the interval between the first and second doses, the observed vaccine efficacy against Covid-19 was 52%, and in the first seven days after the second dose, it was 91%, “reaching full efficacy against disease with onset at least seven days after dose two”.
Between the first and second doses, 39 cases of Covid-19 were diagnosed in the BNT162b2 group and 82 cases in the placebo group.
The researchers say that the severe split in the ten cases of severe Covid-19 that occurred after the first vaccine dose (only one occurring in the vaccine group) “provides preliminary evidence of vaccine-mediated protection against severe disease, alleviating many of the theoretical concerns over vaccine-mediated disease enhancement”.
They add: “The safety profile of BNT162b2 was characterised by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.”
More BNT162b2 recipients than placebo recipients reported adverse events. Sixty-four vaccine recipients (0.3%) and six placebo recipients (<0.1%) reported lymphadenopathy (an enlargement of lymph nodes).
Four serious, related adverse events were reported among BNT162b2 recipients: a shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia (an abnormal heart rhythm), and right leg paresthesia (a burning or prickling sensation that is usually felt in the hands, arms, legs, or feet, but can also occur in other parts of the body).
Polack et al. point out that adverse reactions were less common and milder in the older trial participants than in the younger adults.
“Systemic reactogenicity was more common and severe after the second dose than after the first dose, although local reactogenicity was similar after the two doses,” the researchers add.
“Severe fatigue was observed in approximately 4% of BNT162b2 recipients, which is higher than that observed in recipients of some vaccines recommended for older adults. This rate of severe fatigue is also lower than that observed in recipients of another approved viral vaccine for older adults.
“Overall, reactogenicity events were transient and resolved within a couple of days after onset. Lymphadenopathy, which generally resolved within ten days, is likely to have resulted from a robust vaccine-elicited immune response.”
Fever (a temperature of 38°C or higher) was reported after the second dose by 16% of younger vaccine recipients and 11% of older recipients. Only 0.2% of vaccine recipients and 0.1% of placebo recipients reported fever (a temperature of 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1% respectively after the second dose. Two participants in the vaccine group and two in the placebo group reported fevers above 40°C.
The researchers said that the main safety subset, with a median of two months of follow-up as of October 9, consisted of 37,706 people.
“Among these 37,706 participants, 49% were female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index … of at least 30.0), and 21% had at least one coexisting condition. The median age was 52 years, and 42% of participants were older than 55 years of age,” Polack et al. write.
The number of people who could be evaluated for efficacy seven days after the second dose, and who had no evidence of prior SARS-CoV-2 infection, was 36,523, and the number of participants with or without evidence of prior infection who could be evaluated seven days after the second dose was 40,137, Polack et al. say.
The researchers admit that the vaccine trial and the preliminary report have several limitations. “With approximately 19,000 participants per group in the subset of participants with a median follow-up time of two months after the second dose, the study has more than 83% probability of detecting at least one adverse event, if the true incidence is 0.01%, but it is not large enough to detect less common adverse events reliably.”
Given that the report includes two months of follow-up after the second vaccine dose for half the trial participants and up to 14 weeks’ maximum follow-up for a smaller subset, both the occurrence of adverse events more than two to 3.5 months after the second dose and more comprehensive information on the duration of protection remain to be determined, Polack et al. state.
The researchers point out that their report does not address the prevention of Covid-19 in younger adolescents, children, and pregnant women.
“Safety and immune response data from this trial after immunisation of adolescents 12 to 15 years of age will be reported subsequently, and additional studies are planned to evaluate BNT162b2 in pregnant women, children younger than 12 years, and those in special risk groups, such as immunocompromised persons,” they write.
BNT162b2 needs to be kept at a very low temperature. Pfizer and BioNTech have developed temperature-controlled thermal shippers utilising dry ice to maintain temperatures of -70°C±10°C.
“They can be used be as temporary storage units for 15 days by refilling with dry ice. Each shipper contains a GPS-enabled thermal sensor to track the location and temperature of each vaccine shipment across their pre-set routes,” the companies said in November.
Polack et al. say in their report that, although the BNT162b2 vaccine can be stored for up to five days at standard refrigerator temperatures once ready for use, very cold temperatures are required for shipping and longer storage. They say the current cold storage requirement may be alleviated by ongoing stability studies and “formulation optimisation”.
Pfizer CEO Albert Bourla said on November 20: “It is with great pride and joy – and even a little relief – that I can say that our request for emergency use authorisation for our potential Covid-19 vaccine is now in the FDA’s hands.
“It took just 248 days to get from the day we announced our plans to collaborate with BioNTech to our FDA submission date.”
Bourla said the company had operated at “extraordinary speed” in its clinical development programme, “from concept to regulatory filing”.
He said the intention was to start shipping the vaccine immediately after authorisation or approval.
“Based on current projections, we expect to produce globally up to 50 million doses in 2020 – and up to 1.3 billion doses by the end of 2021.”
Pfizer had already initiated rolling submissions in Australia, Canada, Europe, Japan and the UK, and planned to make immediate submissions to other regulatory agencies around the world, Bourla said.
Pfizer says its EUA submission is supported by solicited safety data from a randomised subset of approximately 8,000 participants ≥18 years of age and unsolicited safety data from about 38,000 trial participants who have been followed for a median of two months after the second vaccine dose.
“The submission also includes solicited safety data on approximately 100 children 12-15 years of age,” the company added.
The November 18 announcement came after one on November 9 in which the companies stated that a first interim analysis showed that BNT162b2 was more than 90% effective in preventing Covid-19 in Phase 3 trial participants who had no prior evidence of SARS-CoV-2 infection.
The interim analysis was conducted on November 8 by an external, independent data monitoring committee.
The results relate to the analysis of just 94 confirmed cases of Covid-19 that occurred among trial participants.
The companies said: “The case split between vaccinated individuals and those who received the placebo indicates a vaccine efficacy rate above 90%, at seven days after the second dose. This means that protection is achieved 28 days after the initiation of the vaccination, which consists of a two-dose schedule. As the study continues, the final vaccine efficacy percentage may vary.”
The companies said that the monitoring committee had not reported any serious safety concerns and recommended that the collection of additional safety and efficacy data should continue as planned.
Questions remain about how long immunity would last and the companies have not presented a breakdown of the vaccine’s effectiveness in different age groups.
In the case of RNA vaccines, genetic instructions are injected into the body via messenger RNA (mRNA) molecules and cells are told to recreate the spike protein that is found on the surface of SARS-Cov-2.
The intention is to prompt a person’s immune cells to create antibodies to fight the protein. No virus is needed to make the vaccine so production time is short.
RNA vaccines don’t always produce a strong immune response and may require adjuvants. They also need to be stored and transported at very low temperatures.
Two of the vaccines being developed by Pfizer and BioNTech – BNT162b1 and BNT162b2 – received fast-track designation from the FDA on the basis of preliminary data from Phase 1/2 studies in the US and Germany and animal immunogenicity studies.
On July 27, the companies announced that they had selected the BNT162b2 vaccine to move forward into a Phase 2/3 study.
BNT162b2 encodes an optimised SARS-CoV-2 full length spike glycoprotein.
Albert Bourla, sold nearly 62% of his stock for a total US$5.56 million on the same day the company made its announcement about the interim results of its vaccine trial.
Bourla sold 132,508 shares at an average price of $41.94 a share, according to US Securities and Exchange Commission records. This is close to the highest Pfizer stock price this year. He still owns 81,812 Pfizer shares.
According to the details filed, the sale was part of a predetermined trading plan that was adopted on August 19, 2020.
Pfizer’s executive vice-president Sally Susman sold 43,662 shares (nearly 29 per cent of her holding) on the same day, at the same price, netting her about US$1.83 million. Susman’s transaction was part of a predetermined trading plan that was adopted on November 14, 2019.
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 says he has asked a number of his colleagues, who include resident physicians and faculty physicians who work with Covid patients on a daily basis. whether they will be first in line for the new vaccine and he has yet to hear any of my them respond affirmatively.
“The reasons for hesitancy are that the uncertainties about safety exceed what they perceive to be a small benefit,” Berdine writes. “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.”
Associate editor at The BMJ Peter Doshi writes 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 are 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 writes.
Pfizer, he says, has already sent trial participants a letter discussing “crossing over” from placebo to vaccine.
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.
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
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 says the vaccine trials have not been designed to answer those questions, which, Demasi says, has sparked criticism that vaccine manufacturers have set themselves a low bar for success.
“That’s because trials conducted by Pfizer, Moderna and AstraZeneca only require that their vaccine prevents moderate symptoms of COVID-19 which may be as mild as cough, or headache,” Demasi writes.
In the BMJ article Doshi writes: “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 writes: “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.”
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.
There has been an outcry in the UK over the government’s decision to delay the administration of second doses of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines.
The government has followed the advice of the 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 National Health Service across the UK will now prioritise giving the first dose of the vaccines to those in the most high-risk groups. “With two vaccines now approved, we will be able to vaccinate a greater number of people who are at highest risk, protecting them from the disease and reducing mortality and hospitalisation,” the government said.
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.”
The chairman of the BMA, Richard Vautrey, said: “The BMA believes the existing commitment made to these patients by the NHS and local clinicians should be respected and if GPs decide to honour these booked appointments in January the BMA will support them.”
He added: “The decision to ask GPs, at such short notice, to rebook patients for three months hence, will cause huge logistical problems for almost all vaccination sites and practices.
“For example, to make contact with even just two thousand elderly or vulnerable patients will take a team of five staff at a practice about a week, and that’s simply untenable.”
AZD1222 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.
AstraZeneca announced on November 23 that AZD1222 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 AZD1222.
“More data will continue to accumulate and additional analysis will be conducted, refining the efficacy reading and establishing the duration of protection,” the company said.
“An independent Data Safety Monitoring Board determined that the analysis met its primary endpoint showing protection from Covid-19 occurring 14 days or more after receiving two doses of the vaccine. No serious safety events related to the vaccine have been confirmed. AZD1222 was well tolerated across both dosing regimens.”
Oxford University stated: “Phase 3 interim analysis including 131 Covid-19 cases indicates that the vaccine is 70.4% effective when combining data from two dosing regimens. In the two different dose regimens vaccine efficacy was 90% in one and 62% in the other.”
AstraZeneca said it would immediately prepare submission of the data to regulatory authorities around the world that have a framework in place for conditional or early approval.
“The company will seek an emergency use listing from the World Health Organisation for an accelerated pathway to vaccine availability in low-income countries. In parallel, the full analysis of the interim results is being submitted for publication in a peer-reviewed journal.”
In an interview with Bloomberg, published on November 26, AstraZeneca’s CEO, Pascal Soriot, said that a new study was now needed to evaluate the lower dosage that showed the highest efficacy.
“Now that we’ve found what looks like a better efficacy we have to validate this, so we need to do an additional study,” Soriot said.
It would probably be another international study, Soriot added. ”This one could be faster because we know the efficacy is high so we need smaller number of patients,” he said.
Soriot told Bloomberg he didn’t expect the additional trial to hold up regulatory approvals in the UK and European Union.
Clearance from the FDA in the US might take longer because the FDA is unlikely to approve the vaccine on the basis of studies conducted elsewhere, especially given the questions over the results, Soriot told Bloomberg.
Clinical trials of AZD1222 are also being conducted in Japan, Russia, South Africa, Kenya, and Latin America and are planned in other European and Asian countries.
On December 8, the researchers involved in studying AZD1222 published the first full results of the interim analysis of four trials.
The efficacy analysis presented in the new, peer-reviewed paper, which was published in The Lancet, relates to trials in the UK (Phase 2 and 3) and Brazil (Phase 3) involving 11,636 people and the safety data is from four trials in the UK, Brazil, and South Africa involving 23,745 participants.
The paper’s authors state that the pooled results confirm that AZD1222 “has an acceptable safety profile and is efficacious against symptomatic Covid-19 disease, with no hospitalisations or severe disease reported in the Covid-19 vaccine group so far”.
They report that only three out of the 23,745 trial participants experienced serious adverse events that were possibly related to a vaccine and all of them had recovered or were recovering, and remained in the trial. Safety was monitored for a median of 3.4 months.
“Out of 23,745 participants, 168 experienced a total of 175 severe adverse events over the period, but 172 events were unrelated to the Covid-19 or control vaccines,” the researchers state.
“One event was in the control group (a case of haemolytic anaemia), one event was in the Covid-19 vaccine group (a case of transverse myelitis considered possibly related to the vaccine), and a case of severe fever (> 40oC) was reported in South Africa in a participant who remains masked to group allocation and recovered rapidly without an alternative diagnosis and was not hospitalised.”
Giving additional data about the cases of Covid-19 that occurred among 11,636 participants in the trials in the UK and Brazil, the researchers state: “There were 131 cases of symptomatic Covid-19 disease more than 14 days after the second vaccine dose in these 11,636 people. This included 30/5,807 (0.5%) cases in the vaccine group and 101/5,829 (1.7%) cases in the control group, which equates to a vaccine efficacy of 70%.”
The researchers report that among those who received two standard doses of the vaccine there was an efficacy of 62% – based on 27/4,440 (0.6%) Covid-19 cases in the vaccine group and 71/4,455 (1.6%) cases in the control group – and the low-dose/standard-dose group vaccine efficacy was 90% – based on 3/1,367 (0.2%) cases in the vaccine group and 30/1,374 (2.2%) cases in the control group.
Five cases of symptomatic Covid-19 disease occurred in people aged over 55 years old, but the researchers said that vaccine efficacy in older age groups could not be assessed as there were too few cases. The researchers say that this analysis will be completed in the future.
Study author Merryn Voysey, from the University of Oxford, said: “In order to assess vaccine efficacy, we need to have a sufficient number of Covid-19 cases among participants to indicate that the vaccine is protecting them from disease.
“Since recruitment of older adults started later than in younger adults there has been less follow-up time for these cohorts and less time to accrue Covid-19 cases. This means we have to wait longer to have sufficient data to provide good vaccine efficacy estimates in smaller subgroups.”
Voysey added: “In future analyses, with more data included as it becomes available, we will investigate differences in key subgroups such as older adults, various ethnicities, doses, timing of booster vaccines, and we will determine which immune responses equate to protection from infection or disease.”
Further evidence will be required to determine the duration of protection accorded by the vaccine and the need for additional booster doses, the researchers say.
The researchers report on the cases of severe disease and hospitalisation that occurred among the 23,745 trial participants. From 21 days after the first vaccine dose ten people diagnosed with Covid-19 were hospitalised, all of whom were in the control arm of the trials. Two cases were classified as severe, and one of those participants died. These are secondary outcomes and will require additional confirmation, the researchers point out.
The new report also includes data about asymptomatic infection, but this also relates to secondary outcomes and the findings need to be confirmed when more information is available.
In the UK, 6,638 trial participants were asked to provide a weekly, self-administered nose and throat swab for SARS-CoV-2 testing from one week after the first vaccine dose and the researchers say that 69 cases of asymptomatic infection were identified. “This included 29/3,288 (0.9%) cases in the vaccine group, and 40/3,350 (1.2%) cases in the control group, leading to a vaccine efficacy against asymptomatic transmission of 27%,” the report authors state.
“In the low-dose/standard-dose group, there were 7/1,120 (0.6%) cases in the vaccine group and 17/1,127 (1.5%) cases in the control group, resulting in a vaccine efficacy against asymptomatic transmission of 59%.
“In people given two standard doses, there were 22/2,168 (1%) cases in the vaccine group and 23/2,223 (1%) in the control group, which equates to a vaccine efficacy against asymptomatic transmission of 4%.”
Participants in the Covid-19 vaccine group received two doses of AZD1222, each containing approximately 5×1010 viral particles (a standard dose). 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,” the researchers stated. “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.”
Overall, most participants were aged 18-55 years (82%,19,588/23,745) as people aged 56 years and older were recruited later and will be studied in future analyses.
In an article in WIRED, Hilda Bastian points to numerous flaws in the analysis presented by AstraZeneca and Oxford University on November 23. The claims they made were based on very shaky science, Bastian wrote, and the analysis was patched together.
The Oxford-AstraZeneca data came out of two very different studies (one in Brazil and one in the UK), Bastian pointed out. There wasn’t standardised dosing across the trials, the cohorts in the various dosage groups had different demographics, and the ‘control’ injections were not the same in both trials (in the UK, the MenACWY was the ‘control’ and, in Brazil, it was a saline injection).
Oxford-AstraZeneca reported only the results for certain subgroups of people within each trial, Bastian said.
The half-dose/full-dose option started out as a mistake, which was only spotted when some people in the study didn’t have the expected number of adverse effects, she pointed out.
“Oxford-AstraZeneca reports that two of the dosing regimens ‘demonstrated efficacy’. Presumably, none of the others did, but they didn’t give specifics,” Bastian wrote.
As regards the efficacy percentages, “we only have numbers on these two regimens, as opposed to everyone in the trials – and how they arrived at those percentages isn’t explained”, she added. And overall, the Oxford-AstraZeneca trials appeared to include relatively few participants over the age of 55, even though this group is especially vulnerable to Covid-19.
Trials halted twice because of illness
On September 6, 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 AZD1222 in the US, the UK, Brazil, South Africa, India, and Japan.
AstraZeneca said that suspension of the AZD1222 trials 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 AZD1222 trials 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 AZD1222, 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 AZD1222 had resumed across the world. The company gave no explanation about the illness that triggered the halt in the trials.
AstraZeneca had earlier announced that the AZD1222 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.
AstraZeneca and scientists at the University of Oxford’s Jenner Institute collaborated to produce AZD1222, which will be known as Covishield in India, and is a non-replicating viral vector vaccine.
The company has already concluded agreements with numerous countries, and the European Commission, for the supply of billions of doses of AZD1222.
In its statement about the suspension of the AZD1222 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 AZD1222 trial 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.
“Following consultation with the US Food and Drug Administration, preparations to resume the trial in the United States, including submissions for approval by the Institutional Review Boards, are now underway.
Discussions with other regulators around the world to resume the clinical trial programme are progressing.”
The ENSEMBLE trial is a randomised, double-blind, placebo-controlled study of the JNJ-78436735 vaccine, set to involve 60,000 participants in Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa, and the US.
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.
Johnson & Johnson says the results of the Phase 1/2a clinical study of JNJ-78436735 have been submitted to the medRxiv preprint platform and are due to be published online imminently.
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 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.”
A regulatory hold of a clinical trial is a requirement by a regulatory health authority such as the FDA. “We proactively disclose any regulatory hold of a pivotal clinical trial,” Johnson & Johnson said.
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 its announcement on November 30 Moderna said the primary endpoint of the Phase 3 COVE study was based on the analysis of Covid-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine.
“Today’s primary analysis was based on 196 cases, of which 185 cases of Covid-19 were observed in the placebo group versus 11 cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.1%,” the company said.
The vaccine continued to be generally well tolerated, with “no serious safety concerns identified to date”, Moderna said. The company said, however, that solicited adverse reactions increased in frequency and severity in the mRNA-1273 group after the second dose.
The Phase 3 COVE Study had exceeded two months of median follow-up post vaccination, as required by the FDA for emergency use authorisation, the company added.
Moderna said efficacy was consistent across age, race and ethnicity, and gender demographics.
“The 196 Covid-19 cases included 33 older adults (ages 65+) and 42 participants identifying as being from diverse communities (including 29 Hispanic or LatinX, six Black or African Americans, four Asian Americans and three multiracial participants).”
Moderna said it planned to immediately request an EUA from the FDA and to apply for a conditional marketing authorisation from the European Medicines Agency (EMA), and to progress with rolling reviews by international regulatory agencies.
The company said it had already initiated the rolling review process with the EMA, Health Canada, SwissMedic, the United Kingdom Medicines and Healthcare products Regulatory Agency, the Ministry of Health in Israel, and the Health Sciences Authority in Singapore and intended to seek prequalification and/or emergency use listing from the World Health Organisation (WHO).
Moderna had announced on November 16 that a first interim analysis of trials of its mRNA-1273 vaccine had shown it to be 94.5% effective. The results relate to 95 people who developed Covid-19 during the trial.
“The independent, NIH-appointed Data Safety Monitoring Board (DSMB) for the Phase 3 study of mRNA-1273 … has informed Moderna that the trial has met the statistical criteria pre-specified in the study protocol for efficacy, with a vaccine efficacy of 94.5%,” Moderna said.
Of the 95 cases analysed, ninety cases of Covid-19 were observed in the placebo group versus five cases observed in the mRNA-1273 group.
A secondary endpoint was used in the analysis of severe cases of Covid-19 and included 11 cases, which all occurred in the placebo group.
The interim analysis included a review of Phase 3 study safety data by the DSMB, which Moderna says showed no significant safety concerns.
“The majority of adverse events were mild or moderate in severity. Grade 3 (severe) events greater than or equal to 2% in frequency after the first dose included injection site pain (2.7%), and after the second dose included fatigue (9.7%), myalgia (8.9%), arthralgia (5.2%), headache (4.5%), pain (4.1%) and erythema/redness at the injection site (2.0%),” Moderna said.
“These solicited adverse events were generally short-lived. These data are subject to change based on ongoing analysis of further Phase 3 COVE study data and final analysis.”
The COVE study is being conducted in collaboration with the National Institute of Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Authority.
Moderna said: “The COVE study includes more than 7,000 Americans over the age of 65. It also includes more than 5,000 Americans who are under the age of 65, but have high-risk chronic diseases that put them at increased risk of severe Covid-19, such as diabetes, severe obesity, and cardiac disease.
“The study also included communities that have historically been underrepresented in clinical research and have been disproportionately impacted by Covid-19. The study includes more than 11,000 participants from communities of colour, representing 37% of the study population, which is similar to the diversity of the US at large.
“This includes more than 6,000 participants who identify as Hispanic or LatinX, and more than 3,000 participants who identify as Black or African American.”
The mRNA-1273 vaccine underwent a Phase 1 trial in the US that was sponsored by the National institute of Allergy and Infectious diseases (NIAID) and Lonza. Ten, 25, 50, 100 and 250 microgramme doses were tested and there will be a 12-month follow-up.
Three of the 15 people in the high dose (250 microgrammes) cohort of the mRNA-1273 Phase 1 trial suffered adverse effects within 43 days of receiving Moderna’s vaccine.
Moderna described the effects as “grade 3 systemic symptoms, only following the second dose”.
The company said the 250-microgramme dose was being eliminated from future studies, “not so much because of the side effects, but because the lower doses appeared to work so well that the high dose is not needed”.
Moderna said its findings were based on results from the first eight people who each received two doses of the mRNA-1273 vaccine, starting in March.
The company announced on December 10 that the first adolescent trial participants had received vaccinations in the Phase 2/3 study of mRNA-1273.
The study will evaluate the safety, reactogenicity, and immunogenicity of two mRNA-1273 vaccinations given 28 days apart. Moderna intends to enroll 3,000 adolescent participants in the US who are at least 12 years old and aged under 18. Each participant will receive either 100-microgramme doses of mRNA-1273 or a placebo.
Critics of the way Moderna has presented its trial information point out that the company has not released its clinical trial study or raw data.
The chairman and president of the non-profit organisation ACCESS Health International, William Haseltine, criticised Moderna for putting out a press release without adequate data, and affecting its share prices. Moderna’s announcement, he says, was premature as only eight people had been studied. “It was not impressive and it was opaque,” Haseltine told CNBC television.
On August 11, Moderna announced that the US government had awarded the company up to $1.525 billion for the initial manufacture and delivery of 100 million doses of mRNA-1273.
Under the terms of the agreement, the US government will also have the option to purchase up to an additional 400 million doses of mRNA-1273 from Moderna.
“With the previous award of up to $955 million from BARDA for the development of mRNA-1273 to licensure, today’s announcement brings the U.S. government commitments for early access to mRNA-1273 to up to $2.48 billion,” Moderna said.
On August 28, Moderna confirmed that the company was engaged in discussions with the Ministry of Health, Labour and Welfare in Japan to potentially supply 40 million or more doses of mRNA-1273.
Under the terms of this arrangement, if the vaccine receives regulatory approval, it will be distributed in Japan by the Takeda Pharmaceutical Company, beginning in the first half of 2021.
Moderna announced on November 17 that it had signed an agreement with the UK government to supply mRNA-1273 from March 2021 if the vaccine is approved for use by the UK regulatory authorities.
Moderna aims to deliver about 500 million doses of mRNA-1273 globally per year and possibly increase this to one billion doses annually, beginning in 2021.
The company says its vaccine remains stable at 2° to 8°C (36° to 46°F) – the temperature of a standard home or medical refrigerator – for 30 days.
“Stability testing supports this extension from an earlier estimate of seven days. mRNA-1273 remains stable at -20° C (-4°F) for up to six months, at refrigerated conditions for up to 30 days, and at room temperature for up to 12 hours,” Moderna added.
There was massive share dumping by Moderna’s chief medical officer, Tal Zaks, and other top executives in the company before Moderna released a press release about its Covid vaccine on May 18.
The non-profit organisation the Informed Consent Action Network (ICAN) in the United States accuses Moderna of rigging the clinical trial of mRNA-1273 to avoid capturing adverse reactions that could prevent licensure of the vaccine.
“Their trick is to only capture adverse reactions that occur more than 28 days after injection if the participant withdraws from the clinical trial,” ICAN said. This, ICAN says, is nonsensical. “Once a participant has received both doses, if anything, a participant would have an incentive to remain part of the follow-up check-ups to address any adverse effects.”
There could be many autoimmune, neurological, and chronic health disorders that have a major impact on the quality of life that the vaccine could cause and may only arise more than 28 days after the injection, ICAN says.
“As long as the participant does not withdraw from the clinical trial, these will nonsensically be ignored as if they did not occur,” ICAN said. “This is unethical and renders vacuous any claim of safety for this product based on this trial.”
ICAN’s legal team has filed a citizen petition and an emergency stay petition demanding that the clinical trial design for Moderna’s vaccine be updated to require that all adverse reactions for the entire period of the clinical trial be tracked.
The petitions also demand that the number of participants in the Moderna trial be increased and that participants are tested before and after vaccination for any T-cell reactions to SARS-CoV-2.
There are currently more than 180 Covid vaccines being developed around the world. About fifty of them are in clinical or pre-clinical trials.
The main types being developed include vaccines that are viral vector based, virus based, nucleic acid based, and protein based.
The viruses used by Covid vaccine developers include adenoviruses, modified vaccinia ankara, which is a weakened pox virus, the parainfluenza virus, and rabies.
The British conglomerate GlaxoSmithKline (GSK) and the French multinational Sanofi Pasteur are developing a SARS-CoV-2 vaccine using insect cells, and incorporating a squalene adjuvant.
DNA vaccines also require adjuvants to enable a good immune response, but don’t have to be frozen for storage or transportation.
In the case of DNA vaccines, a plasmid containing the DNA sequence encoding the antigen(s) against which an immune response is sought is injected into the body.
DNA vaccines are being developed by the Indian company Zydus Cadila, also known as Cadila Healthcare; a consortium led by the Korean company Genexine; the American biotechnology company Inovio Pharmaceuticals, working in collaboration with the International Vaccine Institute and the Korea National Institute of Health; and Osaka University working in collaboration with the Japanese biopharmaceutical company AnGes and Takara Bio, which is headquartered in Japan.
The global Coalition for Epidemic Preparedness Innovations (CEPI) granted $6.9 million in funding to Inovio and its partners to finance Phase 1 and 2 clinical trials of the INO-4800 vaccine.
The Genexine-led consortium is developing the GX-19 vaccine, which was approved in June for Phase 1 and 2 clinical trials in South Korea.
The Canadian genetic medicine company Mediphage Bioceuticals has been collaborating with the University of Waterloo in Ontario to develop a DNA vaccine that would be administered as a nasal spray.
Another Canadian company, Entos Pharmaceuticals, has been working on two potential DNA vaccines against SARS-CoV-2.
Viral vector vaccines
CanSino Biologics is developing a non-replicating adenovirus type 5 vector-based vaccine in collaboration with the Beijing Institute of Biotechnology. An adenovirus has been used as a vector to deliver the DNA for the coronavirus protein. The coronavirus protein is expression based, i.e. it is produced by a gene. The idea is to generate protein antigens that will call up antigens to SARS-CoV-2.
Viral vectors are genetically engineered to carry a piece of a virus. They are then further modified to produce a protein such as the SARS-CoV-2 spike protein that can then be recognised by the immune system to elicit an immune response.
In a comprehensive ‘vaccine tracker’ report, Emily Chung from CBC News in Canada lays out the pros and cons of the various vaccines being developed.
She says that non-replicating viral vector vaccines generate a more powerful immune response than subunit vaccines, in which only fragments of a virus are used. Some non-replicating viral vector vaccines don’t have to be stored at very low temperatures.
However, Chung reports, people who have already been exposed to the viral vector may be resistant. Also, large quantities of the virus need to be grown, which adds to production time.
Writing for GlobalData Healthcare on June 23, Reynald Castaneda said that CanSino Biologics’ Ad5-nCoV and Johnson & Johnson’s vaccine use a human adenovirus vector, “but a significant chunk of people may already have neutralising antibodies against the vector, decreasing efficacy prospects”.
He added that “Phase 1 Ad5-nCoV data is also underwhelming, adding credence to the issue of pre-existing antibodies”.
AstraZeneca’s AZD1222 and Rome-based ReiThera’s SARS-CoV-2 vaccines are also adenovirus vectored but use nonhuman vectors, Castaneda reported.
“However, AZD1222’s recent animal data also leave questions about its utility to prevent virus spread. A possible way to improve efficacy is to add a booster shot down the line, perhaps using a different adenovirus vector or even a different vaccine technology. Perhaps AZD1222 only carrying SARS-CoV-2’s spike protein may not be enough.”
Johnson & Johnson is developing a non-replicating viral vector vaccine with BioNtech. BioNtech and the American multinational Pfizer are meanwhile developing an RNA vaccine.
The American company Novavax is producing a protein-based subunit vaccine, NVX-CoV2373, which is engineered from the genetic sequence of SARS‑CoV‑2. Antigens have been derived from the coronavirus spike protein.
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 the UK, India, the Czech Republic, South Africa, and Japan.
NVX-CoV2373 is currently in Phase 2 clinical trials that began in August in the US and Australia and in which about half of the participants are between sixty and 84 years of age.
In addition, a Phase 2b clinical trial to assess efficacy began in South Africa in August.
Novavax said on August 4 that the results of its small Phase 1 trial, conducted in Australia, were promising and that higher levels of antibodies had been produced in healthy volunteers after two doses than those found in recovered Covid-19 patients.
There were just 131 participants in the Phase 1 trial. All were healthy adults ages 18-59 years. Novavax said the vaccine induced neutralising titers in all participants
Novavax’s vaccine is one of about a dozen that the US government is funding under its ‘Warp Speed’ operation.
Disease enhancement and other vaccine risks
There are concerns that there will, with spike protein vaccines against SARS-CoV-2, be pathogenic priming, also known as disease enhancement. This happened with vaccines against SARS.
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%.”
Andre Watson, who is the founder and CEO of the regenerative medicine and pandemic defence biotechnology company Ligandal, which is based in San Francisco, also says that 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) are a concern with SARS-Cov-2 and Covid-19.
“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.”
Watson says that, in the case of SARS-CoV-2, there are about 100 spikes per virus. “The latest mutant has an even higher density. Each of the spikes is pointing in a very specific direction and only the very tip of the spike sticks to the ACE2 receptor and should be bound by neutralising antibodies.
“If you cut off the spike and just throw it into circulation, it will face random directions and you may develop many of the wrong antibodies preferentially. The neutralising ones may decline disproportionately to other epitopic, or immune binding, sites.”
Watson’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 AZD1222 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 AZD1222 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.”
With regard to the new SARS-CoV-2 mutation that is circulating in the UK and numerous other countries, and the ones that have been identified in South Africa and Nigeria, Watson says 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.”
Watson added: “Still early to say for certain with respect to the #SARSCoV2 N501Y mutant’s effect on neutralising antibody responses, reinfection, and vaccine efficacy. This mutant causes enhanced ACE2 receptor binding, though is unlikely to significantly affect antibody binding by itself.
“This is not to say that the enhanced ACE2 binding couldn’t contribute to antibody escape and inefficacy of neutralising antibodies against this virus in the presence of ACE2, which already competes with neutralising antibodies with similar binding strength.”
In 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.
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.
Emily Chung from CBC News points out that live attenuated vaccines may not be suitable for people with weakened immune systems or long-term health problems, or for people who’ve had organ transplants.
Live viruses, she says, need to be refrigerated, making them more difficult to transport and unusable in countries without access to refrigeration. The virus must be grown in large quantities, Chung adds.
Chung adds that Covid-19 vaccines made from an inactivated virus can be given to people with weakened immune systems.
In this case, she says, the virus is grown in large quantities in cells, and is then killed, often with a chemical, which is usually formaldehyde. Heat or radiation can also be used.
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. Again, 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; the Indian company Bharat Biotech; the Chinese company Sinovac Biotech; and the Beijing Institute of Biological Products are all developing vaccines made from an inactivated virus.
Liability in the EU
The European Union has announced that it is only offering vaccine manufacturers partial protection against any legal actions that might result if people suffer adverse effects after vaccination against SARS-CoV-2.
An EU official said EU governments were ready to financially cover certain elements of the companies’ risks.
Under EU rules, other than in certain exceptional circumstances, vaccine manufacturers are liable for products they sell in the EU.
In 2017, the EU’s top court ruled that those vaccinated were entitled to compensation if they could prove that a vaccine caused an adverse effect, even when there was no scientific consensus on the matter.
AstraZeneca has already concluded an agreement with the European Commission to supply up to 400 million doses of its AZD1222 vaccine. The agreement allows EU member states to redirect doses to other European countries.
The company has also said it would supply Russia, South Korea, Japan, China, and Brazil with an estimated three billion doses of the vaccine in total.
CEO Pascal Soriot said the company hoped that the first doses of AZD1222 would be delivered by the end of 2020.
Moderna announced on August 24 that it had concluded advanced exploratory talks with the European Commission to supply 80 million doses of its mRNA-1273 vaccine.
The potential purchase agreement provides for an option for EU member states to purchase additional doses, up to 160 million in total.
For manufacturing in Europe, Moderna is working with the Swiss-based multinational chemicals and biotechnology company Lonza and the Spanish pharmaceutical company ROVI.
Pfizer, Sanofi Pasteur, GlaxoSmithKline, and the German company CureVac, which is developing an RNA vaccine, have all reportedly been involved in talks with the EU about supplying Covid vaccines to EU countries.
A randomised, double-blind, placebo-controlled Phase 3 trial of the Sputnik V vaccine, which was developed by the Gamaleya National Research Centre for Epidemiology and Microbiology, is continuing in Russia. It involves 40,000 participants in more than 45 medical centres.
A Phase 3 trial has also commenced in the United Arab Emirates (UAE).
The developers of the Sputnik V vaccine announced on November 24 that the vaccine had been shown to be 91.4% effective 28 days after the first dose and more than 95% effective 42 days after the initial dose.
The calculation was based on the second interim analysis of data and related to 39 confirmed cases of Covid-19 among 18,794 volunteers who received both doses of Sputnik V or a placebo.
Preliminary data obtained 42 days after the first dose (21 days after the second dose) indicated an efficacy above 95%, the vaccine developers reported.
Efficacy of 91.4% was indicated 28 days after the first dose (7 days after the second dose).
“The interim research data will be published by the Gamaleya Centre team in one of the leading international peer-reviewed medical journals,” the vaccine developers said. After completion of Phase 3 clinical trials, the centre will provide access to the full clinical trial report.
A total of 40,000 volunteers are taking part in the Phase 3 double-blind, randomised, placebo-controlled, post-registration study of the Sputnik V vaccine.
The vaccine developers said there had been no unexpected adverse events among trial participants and monitoring was ongoing.
The director of the Gamaleya Centre, Alexander Gintsburg, stressed that the second interim analysis was conducted a week after volunteers received their second vaccine dose, meaning that their bodies had partially reacted to both doses.
“We expect the efficacy rate to be even higher based on the data three weeks after the second immunisation when the body’s strongest and most stable response is achieved,” he said.
“We plan to conduct the third interim data analysis after 78 confirmed coronavirus cases among volunteers and we have every reason to believe that the results will exceed our initial expectations. The drug’s final efficacy assessment will be made available after Phase 3 clinical trials are concluded.”
Russia’s sovereign wealth fund, the Russian Direct Investment Fund (RDIF) announced that the cost of the Sputnik V vaccine for international markets would be less than $10 per dose, starting from February 2021.
Russia’s Association of Clinical Trials Organisations urged the country’s government to postpone approving the Sputnik V vaccine before advanced trials were completed.
“Fast-tracked approval will not make Russia the leader in the race, it will just expose consumers of the vaccine to unnecessary danger,” the association said.
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.
Sputnik V: Phase 1 and 2 trials
The Sputnik V vaccine was given to workers at the Gamaleya research centre and then to volunteer soldiers. The researchers says no substantial adverse effects were reported and participants showed strong antibody and cellular immune responses.
On September 8, the Russian 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 trials were conducted by researchers from Russia’s health and defence ministries.
Only 76 participants were enrolled in the two studies (38 in each). They were aged 18–60 years.
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.
The report by Denis Y. Logunov et al. states that the two formulations of the vaccine had a good safety profile with no serious adverse events detected over 42 days and antibody responses induced in all participants within 21 days.
The researchers say that the trials suggest that the vaccines also produce a T-cell response within 28 days.
The Russians are using two different vectors in their vaccine: 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.
In each study, nine volunteers received rAd26-S in Phase 1, nine received rAd5-S in Phase 1, and twenty received rAd26-S and rAd5-S in Phase 2 (rAd26-S was given first, then rAd5-S was given 21 days later).
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 most common adverse events were pain at the injection site (58%), hyperthermia (50%), headache (42%), asthenia, which is abnormal physical weakness or lack of energy (28%), and muscle and joint pain (24%). The report states that most adverse events were mild and all participants produced antibodies to the SARS-CoV-2 glycoprotein.
The report’s authors say that, when the antibody responses from the vaccination were compared with those from infection (using convalescent plasma samples), the antibody responses from vaccination appeared to be higher.
They say that vaccination elicited the same level of SARS-CoV-2 neutralising antibodies as were produced in people who had recovered from Covid-19.
They added that T-cell responses occurred in all participants in the phase 2 trials within 28 days of vaccination. This included the formation of T-helper (CD4) cells and T-killer (CD8) cells. The number of T-helper cells increased by 2.5% and the number of T-killer cells increased by 1.3% after vaccination with the frozen formulation. The percentage increases were 1.3 and 1.1 respectively after vaccination with the freeze-dried formulation.
The researchers state that large, long-term trials including a placebo comparison and further monitoring are needed to establish the long-term safety and effectiveness of the Sputnik V vaccine.
The authors of the report about the vaccine trials say that, despite there being neutralising antibody responses against the adenovirus vectors, the antibody response to the SARS-CoV-2 spike protein was not affected.
“In addition, the neutralising antibodies against rAd26 did not interfere with rAd5, or vice versa,” they said.
The researchers say this suggests that using different adenovirus vectors is an effective approach “to elicit a robust immune response and to overcome the immune reaction to the first viral vector”, but note that more research will be needed to confirm this.
The scientists note that study limitations include the short 42-day follow-up. They also note that the study was small, some parts of the Phase 1 trials included only male volunteers, and there was no placebo or control vaccine.
Also, despite plans to recruit healthy volunteers aged 18–60 years, the study included fairly young volunteers who were, on average, in their 20s and 30s.
The scientists say more research is needed to evaluate the Sputnik V vaccine in different populations, including older age groups, individuals with underlying medical conditions, and people in at-risk groups.
One of the report’s authors, Alexander Gintsburg, said that the provisional licensure of the Sputnik V vaccine required a large-scale study, “allows vaccination in a consented general population in the context of a Phase 3 trial” and “allows the vaccine to be brought into use in a population under strict pharmacovigilance, and to provide vaccination of risk groups”.
He said the Phase 3 clinical trial was approved on August 26. “It is planned to include 40,000 volunteers from different age and risk groups, and will be undertaken with constant monitoring of volunteers through an online application.”
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 in The Lancet. 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.”
Bar-Zeev and Inglesby said that safety outcomes up to now were reassuring, but studies to date were too small to address less common or rare serious adverse events.
“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.
“Safety assurance will then require further large-scale surveillance after licensure. Such surveillance is not well established in many settings, and rapid efforts need to be made by governments, regulators, and global research funders to get those systems in place.
“Surveillance will also be vital for showing transmission reduction, which is to come from Phase 3 trials since these are powered to detect Covid-19 disease outcomes and not asymptomatic SARS-CoV-2 infection.”
The two scientists added 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,” they 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 human clinical trial for the Sputnik V vaccine in India.
The trial will be a multi-centre, randomised, controlled study, which will assess safety and immunogenicity.
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.
On October 2, the RDIF announced that the first batch of Sputnik V had been delivered to the Bolivarian Republic of Venezuela for use in clinical trials there.
Trials of the Sputnik V vaccine are also being carried out in Belarus. One hundred people will participate in the study, which will be conducted in eight medical institutions.
The RDIF and one of the leading pharmaceutical groups in Egypt, Pharco (acting through its key operational subsidiary, Biogeneric Pharma), have meanwhile 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.
Fourteen Covid-19 vaccines developed in China are now undergoing clinical trials, including five that are at Phase-3 stage.
In July, the Chinese authorities cleared CoronaVac and other Covid vaccines, including Sinopharm’s BBIBP-CorV, for emergency use for specific groups deemed to be at high risk of exposure, including medical personnel and border officials.
Millions of doses have been used for priority groups such as frontline medical workers and people going overseas to work, and the safety and efficacy of the vaccines have been proved, the vice-minister in charge of the National Health Commission, Zeng Yixin, said.
When announcing the approval of the Sinopharm vaccine at a press conference on December 31, the deputy head of the National Medical Products Administration, Chen Shifei, said that the vaccine was generally safe and, according to clinical results released by Sinopharm on December 30, had a 79.34% efficacy rate.
Strict supervision would continue to be carried out after the vaccine’s approval to ensure its safety and quality, Chen said.
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 BIBP’s vaccine emergency use authorisation in September so that it could be given to frontline workers most at risk of contracting Covid-19.
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.
The Reuters news agency has quoted the CEO of Sinovac, Yin Weidong, as saying that about 90 per cent of the company’s employees and their family members had agreed to receive doses of Sinovac Biotech’s CoronaVac vaccine under the country’s emergency use scheme.
Tens of thousands of people in Beijing have been given the Sinovac vaccine. However, Phase 3 trials of CoronaVac, which are being conducted in Brazil and Indonesia, only started in August. Sinovac said it also expected to test CoronaVac in Bangladesh. The company says it will be able to produce 300 million doses of CoronaVac annually.
In Brazil, Anvisa said on November 9 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 is 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.
In a report published in The Lancet on October 15, Xiaoming Yang et al. said that Phase 1/2 trials in China of BBIBP-CorV, which is being jointly developed by the Beijing Institute of Biological Products and the China Centres for Disease Control and Prevention, indicated that the vaccine 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.
The two-dose vaccinations at all dosages in the two age groups induced neutralising antibodies in 100% of vaccine recipients, Yang et al. reported.
“Humoral responses against SARS-CoV-2 were induced in all vaccine recipients on day 42,” the researchers wrote. “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.”
Humoral immune responses are mediated by antibodies produced by B cells whereas cell-mediated immune responses do not involve antibodies.
Yang et al. reported that “mild adverse reactions, including pain and fever” were observed “but no severe adverse reaction was reported in all groups”.
In Phase 1, at least one adverse reaction was reported within the first seven days of vaccination in 42 of the 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 7 days was reported in 76 of 336 vaccine recipients.
“The most common systematic adverse reaction was fever (one [1%], 8 μg day 0; one [1%], 4 μg days 0 and 14; three [4%], 4 μg days 0 and 21; two [2%], 4 μg days 0 and 28),” Yang et al. wrote.
In a comment that was also published in The Lancet on October 15, 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 say that more studies are needed to establish whether the inactivated SARS-CoV-2 vaccines are 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”.
The BBIBP-CorV vaccine was derived from a SARS-CoV-2 strain isolated from a hospitalised patient and has aluminium hydroxide as the adjuvant. The researchers isolated three SARS-CoV-2 strains from three patients and selected strain 19nCoV-CDC-Tan-HB02 to develop the vaccine “because of its optimal replication and high virus yields in Vero cells, when compared with the other two strains”.
Phase 3 trials of the vaccine have begun in the United Arab Emirates.
India has bought 1.6 billion doses of Covid-19 vaccines, which is more than any other country in the world, according to the US-based Duke University Global Health Innovation Centre.
The country is reported to have purchased 500 million doses of the AstraZeneca-Oxford University vaccine, one billion vaccine doses from Novavax, and 100 million doses of Sputnik V.
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 Phase 3 efficacy trial involved 25,800 volunteers in India, the ministry added, and 22,500 participants had been vaccinated to date.
The 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 has been 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.”
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, which is responsible for testing and manufacturing Covishield in India, says the allegations made by the trial participant are “malicious and misconceived” and will 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 risks of fast tracking
Even the director of NIAID, Anthony Fauci (pictured left), who is the target of vilification by supporters of Donald Trump who say he is mobilising to undermine the US president, and is disliked by most anti-vaccination activists, has spoken out against distributing a Covid vaccine under special emergency use guidelines before large-scale trials have been carried out.
“The one thing that you would not want to see with a vaccine is getting an EUA before you have a signal of efficacy,” Fauci told Reuters in a phone interview.
“One of the potential dangers if you prematurely let a vaccine out is that it would make it difficult, if not impossible, for the other vaccines to enrol people in their trial.”
The CEO of Merck, Ken Frazier has also spoken out against those who are hyping up the possibility of a vaccine against SARS-CoV-2 being made available to the American public by the end of 2020.
Merck has itself been accused of fast tracking its HPV vaccination Gardasil, particularly for its introduction into Australia and China, and the company is the target of class actions in numerous countries over Gardasil injury.
In an interview with the Naylor Fitzhugh professor of business administration at the Harvard Business School, Tsedal Neeley, Frazier said officials were doing a “grave disservice” to the public when they told people that a Covid-19 vaccine would be available to them later this year. He said there were massive scientific and logistical obstacles to achieving such a feat.
“What worries me the most is that the public is so hungry, so desperate to go back to normalcy, that they are pushing us to move things faster and faster. But ultimately, if you’re going to use a vaccine in billions of people, you better know what that vaccine does,” Frazier told Neeley.
“There are a lot of examples of vaccines in the past that have stimulated the immune system, but ultimately didn’t confer protection. And unfortunately, there are some cases where it stimulated the immune system and not only it didn’t confer protection, but actually helped the virus invade the cell because it was incomplete in terms of its immunogenic properties. We have to be very careful.”
Frazier added: “I think at the end of the day, we don’t want to rush the vaccine before we’ve done rigorous science. We’ve seen in the past, for example, with the swine flu, that that vaccine did more harm than good. We don’t have a great history of introducing vaccines quickly in the middle of a pandemic. We want to keep that in mind.”
He said that when the public were told that a vaccine is coming right away, politicians were then allowed to tell the public not to do the things that they need to be doing, like wearing a mask.
In the case of SARS-CoV-2, Merck is moving at a much slower pace than the other big vaccine manufacturers. It is working on two vaccines that are both at the pre-clinical stage of development. The conglomerate recently acquired the Austrian company Themis Bioscience and is working with Themis on the V591 vaccine against SARS-CoV-2 that uses a measles virus vector.
In addition, Merck is collaborating with the International AIDS Vaccine Initiative on development of the V590 vaccine, which uses a recombinant vesicular stomatitis virus (rVSV) platform and could be administered orally.
On September 8, nine pharmaceutical firms involved in developing SARS-CoV-2 vaccines signed a letter in which they pledged to “continue to make the safety and well-being of vaccinated individuals the top priority in development of the first Covid-19 vaccines”.
The signatories were AstraZeneca, BioNTech and Pfizer, GlaxoSmithKline and Sanofi, Johnson & Johnson, Merck, Moderna, and Novavax.
Physician-scientist Hooman Noorchashm from Pennsylvania in the US wrote a ‘public letter of warning’ to the medical director of The Massachusetts Department of Public Health, Larry Madoff, about what he described as “a potentially high immunological risk to asymptomatic SARS-CoV-2 carriers who non-selectively receive the 2020 influenza vaccine (or any other vaccine)”.
Noorchashm, who makes clear that he is not taking an anti-vaccination stance, was responding to the public health department’s announcement that, except in the case of specific exemptions, vaccination against influenza would be required for all children aged six months or older who were attending Massachusetts childcare or pre-school establishments, primary and secondary schools, and colleges and universities.
He said that activation or hyper-activation of an immune response to SARS-CoV-2 in asymptomatic carriers, in whom the virus was present but latent, was a real and present danger that every government and institutional leader must take seriously.
It was, Noorchashm said, a known immunological fact that vaccines could trigger and activate latent immune responses in a “bystander” fashion.
Addressing Madoff, Noorchashm said: “With potentially millions of Americans being asymptomatic/tolerant carriers of the SARS-CoV-2 virus in the coming months, all public health agencies, including yours, ought to consider whether the flu vaccine might incite a pathogenic immune response to SARS-CoV-2 in a bystander fashion leading to Covid-19 disease.”
Noorchashm added: “Your state of MA is now one of the first to mandate all school children to undergo vaccination against the influenza virus … it is also a fact that this subset of the population contains the largest frequency of asymptomatic SARS-CoV-2 carriers.
“I ask that you and your colleagues imagine the scenario in which this concentrated wave of influenza vaccinations drives asymptomatic carriers of the SARS-CoV-2 virus to lose their immunological ‘tolerance’ to the virus and mount a pathogenic inflammatory response following vaccination.
“Such an iatrogenic trigger would translate into many seriously ill members within the paediatric community in the state of MA (and elsewhere). In this risk scenario, Covid-19 disease will have been triggered iatrogenically by a non-selective vaccination strategy.”
Noorchashm urged the Massachusetts Department of Public Health to take every possible step towards mitigating against this potential risk.
He said he was not advocating for complete avoidance of the 2020 influenza vaccine, but was suggesting that the vaccine only be administered to people who have been screened and shown not to be asymptomatic carriers of SARS-CoV-2.
“Those who are asymptomatic carriers ought to be vaccinated only after their antigen test converts to negative,” he said.
“I am respectfully alerting you that non-selective vaccination of the paediatric and young adult populations, a fraction of whom are certainly going to be asymptomatic SARS-CoV-2 carriers, could have a catastrophic consequence to your population’s health.”
Pharmacovigilance expert Rebecca Chandler from the Uppsala Monitoring Centre in Sweden has tweeted about the difference in people’s immune systems: “The number of rare immune-linked disorders is large and various because of this, and that means that the response to any new vaccine could show some oddities as you start heading out into millions of people.”
Andre Watson is concerned about the social requirements that will come once Covid vaccines are made available.
“Credit scores, housing rental availability, the availability of a driver’s licence, and potentially even the ability to get on public transit could readily be dictated by whether or not you’ve already been infected, and whether or not you’ve received a vaccine,” he said.
Objections to mandatory Covid vaccination have – in Europe, Australia, and the US – become incorporated into wider demonstrations about mask wearing and lockdowns and what the protesters consider to be a general assault on people’s human rights and freedoms.
Those who wish to hone in on the threat of mandatory vaccination say the generalisation of the protests to include objections to all government restrictions weakens the message about the dangers of fast-tracked vaccine development and the very real threat of Covid vaccination being made mandatory.
It has been suggested that part of the reason why there is such a campaign against the use of hydroxychloroquine as a treatment for Covd-19, and a prophylactic, is that, if there is an effective treatment, then the argument for vaccination is weakened.
There have been criticisms of the massive protest in Berlin on August 29 – and similar, but smaller, demonstrations in Dublin and London – because of the visible involvement of far-right groups including the Islamophobic political party Alternative for Germany.
The chairwoman of the far-right Irish Freedom Party, Dolores Cahill, who is against all anti-Covid restrictions, underplays the death toll in Ireland, and claims that SARS-CoV-2 is no longer circulating in the country, has spoken at rallies in Ireland and Britain and at the launch in Germany of the World Doctors Alliance, whose members say there is no Covid-19 pandemic.
Violence by far-right militants has erupted at several of the Dublin protests. The gardaí (police) have had to intervene on several occasions and numerous arrests have been made for breaches of Covid-19 restrictions.
In one case, a man has been charged with assaulting an anti-fascism protester on September 12. Michael Quinn, aged 29, from Ardee, County Louth, is accused of attacking Ruth O’Rourke, who is known as Izzy Kamikaze, with a plank of wood wrapped in an Irish flag, causing O’Rourke a serious head wound.
The lawyer and environmentalist Robert F. Kennedy Jr spoke at the Berlin protest and voiced objection to the media focus on far-right involvement.
“I look at this crowd and I see the opposite of Nazism,” he said. “I see people who love democracy; people who want open government; people who want leaders that are not going to lie to them.”
However, during the demonstration, far-right radicals waving nationalist flags did break through police barriers to storm the parliamentary building, the Reichstag.
There is now division among those who would previously have been allies in their stance against mandatory vaccination and their concerns about vaccine injury.
One concerned, vaccine-aware parent, living in Ireland, who is in favour of wearing face coverings as a protection during the current pandemic, says he is now being blocked by as many anti-vaccination activists as he previously was by those who are pro-vaccination.
The parent, who would prefer to remain anonymous, but posts about health issues on Twitter under the handle @silversynergy, said: “I find myself agreeing with the same people I was arguing with last year. Covid has turned everything on its head.”
Anti-mask activists say that accepting face coverings is a slippery slope to accepting mandatory vaccination; they say mask are muzzles, don’t protect people against viruses, and are even dangerous to people’s health.
@silversynergy said: “There is a well-planned and highly sophisticated form of counter-revolutionary disinformation and deception going on, very similar to what happened in the 1930s, but now they have a lot more powerful tools at their disposal.
“People are distracted and confused. Things are being all mixed up on purpose to divide people and draw attention away from the real villains and what is truly important.”
Nicole Tucker, who is from Spokane in the US, has chosen to no longer vaccinate her children and is against mandatory vaccination, but she is in favour of wearing face masks as a protection against SARS-CoV-2, not least as she has a vulnerable daughter who has Down syndrome.
“For 19 years I have aligned myself with people who are against mandatory vaccines, but I have realised that I can’t do this anymore as almost all of those I was in agreement with on this issue are against wearing masks,’ Tucker said.
“This is such a disappointment to me. I am feeling a real loss of community.”
It is clear that several governments are aiming to introduce mandatory Covid vaccination. 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.
The Oxford vaccine; earlier results
AstraZeneca says that interim results from the Phase 1 and 2 trials showed that AZD1222 generated robust immune responses against the SARS-CoV-2 virus in all evaluated participants.
William Haseltine, points out, however, that, in the animal trials of the Oxford vaccine, none of the monkeys who were vaccinated were protected against SARS-CoV-2. He told CNBC television: “They didn’t have as much virus in their lungs, but they still had a nasal infection. A hundred percent of the vaccinated monkeys got infected.”
The Informed Consent Action Network says AstraZeneca and the University of Oxford have rigged the clinical trial of AZD1222 “to avoid capturing many potential life-altering adverse reactions that may occur from this experimental vaccine”. Despite reviewing efficacy for at least two years, the manufacturers of AZD1222 would only capture adverse events for one month and “serious adverse events” for just six months after each dose, ICAN said.
ICAN’s legal team has filed a citizen petition and an emergency stay petition demanding that the clinical trial design for the AZD1222 vaccine be updated to require that all adverse reactions for the entire period of the clinical trial be tracked against a placebo control group.
The petitions also demand that the number of participants in the trial be increased and that they be tested before and after injection for any T cell immunity to SARS-CoV-2.
Scientists from the Oxford Vaccine Group and Oxford University’s Jenner Institute published the results of the first human trials of ChAdOx1 nCoV-19 in The Lancet on July 20.
The researchers said the vaccine was “safe and tolerated, with reduced reactogenicity when paracetamol was used prophylactically for the first 24 hours after vaccination”.
They said reactogenicity was reduced after a second dose and the strongest immune response was seen in the ten participants who received two doses. The booster vaccine was administered 28 days after the first dose.
“Neutralising antibodies were induced in all participants after a second vaccine dose. After two doses, potent cellular and humoral immunogenicity was present in all participants studied,” they said.
The researchers said the vaccine provoked a T cell response within 14 days of vaccination and an antibody response within 28 days.
Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in a microneutralisation assay (MNA) and in 35 (100%) participants when measured in a plaque reduction neutralisation assay (PRNT).
After a booster dose, all participants had neutralising activity by day 56.
No participants were exposed to SARS-CoV-2 after vaccination, so, the researchers pointed out, it was not possible for the study to determine whether AZD1222 effectively protects against SARS-CoV-2 infection.
The Oxford researchers said the trial findings were not easily generalisable, “as this was a first-in-human study of fairly young and healthy volunteers, the majority of whom were white”.
They added: “Further studies are required to assess the vaccine in various population groups including older age groups, those with comorbidities, and in ethnically and geographically diverse populations.”
The Oxford researchers used the MenACWY meningitis vaccine, Nimenrix, as a “control”, not a saline placebo.
Adverse effects, which included headaches and fatigue, were greater in the group given AZD1222 than in the group given the meningitis vaccine. Other adverse effects included muscle aches, malaise, and chills.
The Oxford group’s vaccine trial involved 1,077 healthy adults aged 18-55 years with no history of Covid-19, and took place in five UK hospitals between April 23 and May 21. The data included in the paper in The Lancet covered the first 56 days of the trial.
A total of 543 people were given ChAdOx1 nCoV-19 and 543 were given the meningococcal conjugate vaccine. A total of 113 participants (56 who were given ChAdOx1 nCoV-19, and 57 in the control group) were asked to take paracetamol before and for 24 hours after their vaccination.
In the group given ChAdOx1 nCoV-19 and no paracetamol, 60% of participants suffered muscle aches as compared with 48% of those who took paracetamol.
Malaise was suffered by 61% of those not taking paracetamol and 48% of those who took paracetamol. The statistics for chills were 56% and 27% and fever 51% and 36%.
Eight patients in the group vaccinated with ChAdOx1 nCoV-19, and not given paracetamol, had a temperature of at least 39°C.
The researchers say that, in the first two days after vaccination with ChAdOx1 nCoV-19, prophylactic paracetamol reduced pain, fever, chills, muscle ache, headache, and malaise.
Writing in a linked comment about the Oxford vaccine trial and a vaccine trial in China, also reported upon in The Lancet, Naor Bar-Zeev and William J. Moss from the Johns Hopkins Bloomberg School of Public Health in the US, who were not involved in the two studies, said the vaccine trials were small so inferential caution was warranted, “but the explorations are laudable”.
Bar-Zeev and Moss said: “Ethnic diversity in both these trials was very limited. Both trials used adenovirus vectors to deliver and study the Covid-19 vaccine, an innovative and efficient means of vaccine development in the midst of a pandemic.
“Capable of generating humoral, cellular, and innate responses, adenovirus-vectored vaccines have much potential.”
The scientists added, however: “The platform [adenovirus vectored vaccines] only achieved European Commission regulatory licensure on July 1, 2020, with the Ebola vaccine.”
They said that much remained unknown about these and other Covid-19 vaccines in development, including longevity of response and immunogenicity in older adults or other specific groups, such as those with comorbidities who are often excluded from clinical trials, or ethnic or racial groups more severely affected by Covid-19.
“Hand in hand with the trajectory of vaccine study, pharmacovigilance infrastructure is urgently needed, including surveillance for asymptomatic infection among vaccinated and unvaccinated persons if both absolute and relative risk of adverse vaccine outcomes, such as enhanced disease, are to be determined.”
Phase 2 trial results were published in The Lancet on November 18. The researchers stated that ChAdOx1 nCoV-19 appeared to be better tolerated in older adults than in younger adults and had similar immunogenicity across all age groups after a booster dose.
“Most of the reported local and systemic adverse events were mild to moderate in severity, in line with our previous phase 1 study of the ChAdOx1 nCoV-19 vaccine and previously reported studies of ChAdOx1-vectored vaccines,” the researchers stated.
“Fewer adverse events were reported after the boost vaccination than after the prime vaccination and reactogenicity reduced with increasing age. The lower dose of vaccine was less reactogenic than the standard dose of vaccine across all age groups.”
AstraZeneca has already entered into agreements with the CEPI; Gavi, the Vaccine Alliance (GAVI); and the SII.
The company said on June 4 that it had reached a $750 million agreement with the CEPI and GAVI to support the manufacturing, procurement, and distribution of 300 million doses of the vaccine, with delivery starting by the end of the year.
“In addition, AstraZeneca reached a licensing agreement with SII to supply one billion doses for low and middle-income countries, with a commitment to provide 400 million before the end of 2020,” the company added.
Pfizer and BioNTech: engagements with governments
Pfizer and BioNTech announced on August 5 that, subject to clinical success and Health Canada approval, they had reached an agreement with the Canadian government to supply their vaccine against SARS-CoV2.
In addition to engagements with governments, Pfizer and BioNTech have expressed interest in supplying to the COVAX Facility, a mechanism established by GAVI, the CEPI, and the WHO that aims to provide governments with early access to Covid vaccines produced by multiple manufacturers.
The Informed Consent Action Network accuses Pfizer and BioNTech of rigging the clinical trial of BNT162b to avoid capturing many potential life-altering adverse reactions that may occur.
ICAN says that although Pfizer and BioNTech have now included a placebo control group in their clinical trials they are avoiding capturing safety issues that could prevent licensure of BNT162b.
The clinical trial for BNT162b provides for reviewing efficacy for at least two years, but adverse events will only be captured for one month and “serious adverse events” for only six months after each vaccination, ICAN adds.
ICAN says the adverse events captured beyond a month after vaccination should not be limited to “serious adverse events”. There are many autoimmune, neurological, and chronic health disorders that have a major impact on quality of life, yet are categorised by the FDA as “adverse reactions” and not as “serious adverse reactions”, ICAN says.
“These artificial limitations are unethical and make any claim of safety for this product based on this trial specious at best.
“There are a myriad of post-licensure adverse reactions reported by consumers and physicians, and which are also listed in vaccine package inserts, that any individual living with them would categorise as ‘serious’; yet the FDA, under its current guidelines, may not.”
These include, but are not limited to, alopecia, autoimmune disease, lupus erythematosus, vasculitis (nflammation of the blood vessels), Bell’s Palsy, hypotonia (decreased muscle tone), migraine, myelitis, neuropathy, seizures, mental disorders, rhinitis, and vertigo, ICAN says.
Given that the effectiveness of BNT162b will be tracked for two years, the only reason to not track safety for this same duration is to avoid detecting any safety issues that would prevent licensure, the non-profit adds.
ICAN’s legal team has filed a citizen petition and an emergency-stay petition demanding that the clinical trial design for BNT162b be updated to require that all adverse reactions for the entire period of the trial be tracked.
The non-profit’s petitions also demand that the number of participants in the trial be increased and that participants are tested before and after vaccination for any T-cell immunity to SARS-CoV-2.
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