Brown et al. added: “Findings from this investigation suggest that even jurisdictions without substantial or high Covid-19 transmission might consider expanding prevention strategies, including masking in indoor public settings regardless of vaccination status, given the potential risk of infection during attendance at large public gatherings that include travellers from many areas with differing levels of transmission.”

Walensky said the CDC’s masking recommendation was updated “to ensure the vaccinated public would not unknowingly transmit virus to others, including their unvaccinated or immunocompromised loved ones”.

In earlier updates about quarantine recommendations, the CDC had said that fully vaccinated people “who meet criteria” would no longer be required to quarantine following exposure to someone with Covid-19.

“Additional considerations for patients and residents in healthcare settings are provided,” the CDC added.

According to CNN, the “criteria” were that the person must be fully vaccinated and at least two weeks must have passed since the second dose (in cases where two doses are required).

CNN quoted the CDC as saying it was not known how long protection lasted, so people who had their last vaccine dose three months or more earlier should still quarantine if they were exposed to a case of Covid-19.

“They also should quarantine if they show symptoms,” CNN quoted the CDC as saying.

The recommendation was criticised as being ill thought out and premature.

@Reuters @CDCDirector @CDCgov THIS IS INADVISABLE AND PREMATURE POLICY:
• New strains will quickly become predominant and lead to increased disease severity
• There is an absence of evidence that vaccines protect from transmission
• We are nowhere near herd immunity pic.twitter.com/o9938sTVIq

— Andre Watson 🧬💊💉🎹 (@nanogenomic) February 11, 2021

On March 8, the CDC had updated its guidelines about what people could and could not do after vaccination.

The guidelines stated at that time that people who had been fully vaccinated could do the following:

• gather indoors with fully vaccinated people without wearing a mask.
• gather indoors with unvaccinated people from one other household (for example, visiting with relatives who all live together) without masks, unless any of those people or anyone they live with has an increased risk for severe illness from Covid-19.

They added that, if a person was around someone with Covid-19, they did not need to stay away from other people or get tested unless they had symptoms. “However, if you live in a group setting (like a correctional or detention facility or group home) and are around someone who has Covid-19, you should still stay away from others for 14 days and get tested, even if you don’t have symptoms,” the CDC added.

While there was literal jubilation in many quarters about the new guidelines, there were also many people who were shocked at the separation of people according to their vaccination status.

One person tweeted: “Vaccinated people can gather, no restrictions. But if you are around unvaccinated, all have to mask & SD. This causes a wedge, leads to division, fear, anger, resentment, and lastly compliance/acceptance.”

The CDC issued its new guidelines despite admitting that they were still learning how effective the Covid vaccines were against SARS-CoV-2 variants, how well the vaccines prevented people from spreading the virus, and how long any protection they offered might last.

On May 1, the CDC transitioned from monitoring all reported Covid-19 vaccine breakthrough infections to investigating only those in patients who are hospitalised or die. It says this is “to help maximise the quality of the data collected on cases of greatest clinical and public health importance”.

The CDC said it would continue to lead studies in multiple US sites “to evaluate vaccine effectiveness and collect information on all Covid-19 vaccine breakthrough infections regardless of clinical status”.

The CDC defines a breakthrough case as “a person who has SARS-CoV-2 RNA or antigen detected on a respiratory specimen collected ≥14 days after completing the primary series of a US Food and Drug Administration (FDA)-authorised Covid-19 vaccine”.

Andre Watson tweeted in response to the CDC’s decision:

The CDC said that, as of October 12, 2021, more than 187 million people in the US had been fully vaccinated against Covid-19 and that, up to that date, it had received reports from 50 US states and territories of 31,895 patients with Covid-19 vaccine breakthrough infection who were hospitalised or died.

In an internal CDC presentation, first reported on by the Washington Post on July 29, 2021, the CDC estimated that there were 35,000 symptomatic breakthrough infections per week among fully vaccinated adults in the US.

The CDC says the number of reports of Covid-19 vaccine breakthrough infections it receives are likely to be an undercount of all SARS-CoV-2 infections among fully vaccinated people. “National surveillance relies on passive and voluntary reporting, and data might not be complete or representative,” the CDC said.

Data on patients with vaccine breakthrough infection who were hospitalised or died will be updated regularly. Studies are being conducted in multiple U.S. sites that will include information on all vaccine breakthrough infections regardless of clinical status to supplement the national surveillance.

There was controversy over a statement made in a CDC Morbidity and Mortality Weekly Report that people were considered to be unvaccinated when it had been fewer than 14 days since they received the first dose of a two-dose Covid vaccine series or one dose of a single-dose vaccine, or if no vaccination registry data were available.

This meant that if someone was infected by SARS-CoV-2, was hospitalised, or died within those 14 days they were categorised as unvaccinated. This categorisation had serious implications for cases in which death or illness was caused by a Covid vaccine.

In a report entitled ‘SARS-CoV-2 Infections and Hospitalizations Among Persons Aged ≥16 Years, by Vaccination Status – Los Angeles County, California, May 1–July 25, 2021’ by Jennifer B. Griffin et al., published on August 27, it is stated: “Persons were considered fully vaccinated ≥14 days after receipt of the second dose in a 2-dose series (Pfizer-BioNTech or Moderna Covid-19 vaccines) or after 1 dose of the single-dose Janssen (Johnson & Johnson) Covid-19 vaccine; partially vaccinated ≥14 days after receipt of the first dose and <14 days after the second dose in a 2-dose series; and unvaccinated <14 days receipt of the first dose of a 2-dose series or 1 dose of the single-dose vaccine or if no vaccination registry data were available.”

In its Morbidity and Mortality Weekly Report posted online on May 25, 2021, and providing data up to April 30, 2021, the CDC said it had received more than 10,000 reports of SARS-CoV-2 infection among people who were fully vaccinated with a Covid-19 vaccine.

As of April 30, 10,262 breakthrough infections were reported to the CDC from 46 US states and territories. A total 6,446 of the cases (63%) occurred in women and the median age of those infected was 58.

Based on preliminary data, 2,725 (27%) vaccine breakthrough infections were asymptomatic, 995 (10%) of the patients were known to be hospitalised, and 160 (2%) of the patients died. Among the 995 hospitalised patients, 289 (29%) were asymptomatic or hospitalised for a reason unrelated to Covid-19. The median age of patients who died was 82 years.

The CDC said that 28 (18%) of those who died were asymptomatic or died from a cause unrelated to Covid-19.

Sequence data were available from 555 reported cases, the CDC said. In 356 cases (64%) the viruses were identified as SARS-CoV-2 Variants of Concern. This included 199 variants (56%) identified as B.1.1.7, 88 (25%) identified as B.1.429, 28 (8%) identified as B.1.427, 28 identified as P.1, and 13 (4%) identified as B.1.351.

The CDC said that, during the surveillance period, SARS-CoV-2 transmission continued at high levels in many parts of the US, with about 355,000 Covid-19 cases reported nationally during the week of April 24–30, 2021.

“Even though FDA-authorised vaccines are highly effective, breakthrough cases are expected, especially before population immunity reaches sufficient levels to further decrease transmission,” the CDC said.

“However, vaccine breakthrough infections occur in only a small fraction of all vaccinated persons and account for a small percentage of all Covid-19 cases (5–8).

“The number of Covid-19 cases, hospitalisations, and deaths that will be prevented among vaccinated persons will far exceed the number of vaccine breakthrough cases.”

The CDC says its findings about breakthrough infections are subject to at least two limitations. “First, the number of reported Covid-19 vaccine breakthrough cases is likely a substantial undercount of all SARS-CoV-2 infections among fully vaccinated persons,” it said.

“The national surveillance system relies on passive and voluntary reporting, and data might not be complete or representative. Many persons with vaccine breakthrough infections, especially those who are asymptomatic or who experience mild illness, might not seek testing.”

Secondly, the CDC said, SARS-CoV-2 sequence data were available for only a small proportion of the reported cases.

In Illinois in the US the Department of Public Health said that, as of July 28, 169 fully vaccinated people had died from Covid-19 or Covid-19 complications and 644 had been hospitalised with the disease. A total 51.13% of the Illinois population had been fully vacccinated, the health department added.

In April, 2021, the CDC issued new guidance to laboratories in which it recommended reducing the RT-PCR cycle threshold (Ct) value to 28 cycles for fully vaccinated people being tested for SARS-CoV-2 infection.

In a reverse transcriptase–polymerase chain reaction (RT-PCR) test RNA is converted to complementary DNA (cDNA) by reverse transcription, then the cDNA is amplified (copied) by the polymerase chain reaction.

The result of one PCR cycle is two double-stranded sequences of target DNA, each containing one newly made strand and one original strand. The cycle is repeated numerous times (usually 20–30) as most processes using PCR need large quantities of DNA.

Globally, the accepted cut-off level for the Ct value for SARS-CoV-2 ranges between 35 and 40, depending on instructions from the manufacturers of testing equipment. If the virus is detected at a low Ct value, this means that the viral load is high.

In discussions in India between the Maharashtra government and the Indian Council of Medical Research (ICMR) the ICMR said that lowering the Ct threshold might lead to infections being missed. A benchmark of 35, for instance, meant that more patients would be considered positive than if the benchmark were 24, the ICMR said.

The argument in favour of lowering the Ct threshold was that there would be fewer false positives, but the CDC was accused of making the change so that there would be fewer reports of vaccine breakthrough cases in the US.

It was possible, however, that the lower threshold would not influence the number of infections detected using nasal swabs. This was borne out by research conducted by Wenling Wang et al. about the detection of SARS-CoV-2 in different types of clinical specimens.

Wang et al. reported on their research in a letter published on March 11, 2020, on the JAMA Network, published by the American Medical Association.

The researchers found that higher viral loads were found in nasal swab testing than in testing of other specimen types so infections were detected at the lower Ct threshold.

They wrote: “The mean cycle threshold values of all specimen types were more than 30 (<2.6 × 10⁴ copies/mL) except for nasal swabs with a mean cycle threshold value of 24.3 (1.4 × 10⁶ copies/mL), indicating higher viral loads.”

UK study finds high virus levels in vaccinated people infected with Delta

Findings from a study conducted in the UK indicated that, if fully vaccinated people were infected with the Delta variant, they could harbour SARS-CoV-2 virus levels that were as high as those in unvaccinated people infected with Delta.

The study, which was released as a pre-print and had not been peer reviewed, was conducted by researchers from several universities and organisations, including Oxford University, the UK’s Office for National Statistics, and the Department of Health and Social Care. The vaccines studied were the Pfizer-BioNTech, AstraZeneca-Oxford, and Moderna vaccines.

The researchers compared the protection provided by Covid-19 vaccines before and after May 17, 2021, when Delta became the predominant variant in the UK.

Referring to the Pfizer-BioNTech and AstraZeneca-Oxford vaccines, the researchers said that Delta infections after two vaccine doses had similar peak levels of virus to those in unvaccinated people. With the Alpha variant, they said, peak virus levels in those infected post-vaccination were much lower.

“With Delta, infections occurring following two vaccinations had similar peak viral burden to those in unvaccinated individuals,” Koen B. Pouwels et al. wrote. “SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with Delta.”

The researchers said their findings had potential implications for onward transmission risk, “given the strong association between peak Ct and infectivity”. The impact on infectivity to others was unknown, they said, but required urgent investigation.

“A greater percentage of virus may be non-viable in those vaccinated, and/or their viral loads may also decline faster as suggested by a recent study of patients hospitalised with Delta,” they said.

Pouwels said that whilst vaccinations reduced the chance of getting Covid-19, they did not eliminate it. “More importantly, our data shows the potential for vaccinated individuals to still pass Covid-19 onto others, and the importance of testing and self-isolation to reduce transmission risk,” he said.

The researchers analysed 2,580,021 test results from nose and throat swabs taken from more than 384,543 people aged 18 years or older between December 1, 2020, and May 16, 2021, and 811,624 test results from 358,983 people between May 17, 2021, and August 1, 2021.

They said their findings indicated that a single dose of the Moderna vaccine had similar or greater effectiveness against the Delta variant compared to a single dose of the Pfizer-BioNTech or AstraZeneca-Oxford vaccine.

They added that two doses of the Pfizer-BioNTech vaccine were shown to have greater initial effectiveness against new SARS-CoV-2 infections, but this declined faster compared with two doses of the AstraZeneca-Oxford vaccine.

The time between doses was not shown to affect effectiveness in preventing new infections, they added, but younger people were shown to be more protected by vaccination than older people.

The researchers also said that two doses of the Pfizer-BioNTech or AstraZeneca-Oxford vaccine provided at least the same level of protection as having developed Covid-19 through natural infection.

People who were vaccinated after being infected with SARS-CoV-2 had more protection than vaccinated individuals who had not previously contracted Covid-19, they said.

Israeli researchers from Maccabi Healthcare Services and Tel Aviv University published a preprint on medRxiv on August 25 in which they report about natural immunity against SARS-CoV-2 compared to vaccine-induced immunity.

They reported that those studied who had recovered from Covid-19 had superior protection against the Delta variant compared to those who received the Pfizer-BioNTech vaccine.

“This study demonstrated that natural immunity confers longer lasting and stronger protection against infection, symptomatic disease and hospitalisation caused by the Delta variant of SARS-CoV-2, compared to the BNT162b2 two-dose vaccine-induced immunity,” Sivan Gazit et al. wrote.

“Individuals who were both previously infected with SARS-CoV-2 and given a single dose of the vaccine gained additional protection against the Delta variant.”

The researchers conducted a retrospective observational study comparing three groups of people: SARS-CoV-2-naïve individuals who received a two-dose regimen of the Pfizer-BioNTech vaccine, previously infected individuals who had not been vaccinated, and previously infected individuals who had received a single dose of the Pfizer-BioNTech vaccine.

They found that vaccinees who had not been infected with SARS-CoV-2 before vaccination had a 13.06-fold increased risk for breakthrough infection with the Delta variant compared to those previously infected, when the first event (infection or vaccination) occurred during January and February of 2021.

Gazit et al. also found that the increased risk of developing symptomatic Covid-19 disease was also significant.

When infection occurred at any time before vaccination (from March 2020 to February 2021), evidence of waning natural immunity was demonstrated, the researchers said.

They added that, with this timescale, vaccinees who had not been infected with SARS-CoV-2 before vaccination had a 5.96-fold increased risk for breakthrough infection and a 7.13-fold increased risk of developing symptomatic Covid-19 disease.

SARS-CoV-2-naïve vaccinees were also at a greater risk for Covid-19-related hospitalisations compared to those that were previously infected, Gazit et al. said.

They said that the advantageous protection afforded by natural immunity that their analysis demonstrated could be explained by the more extensive immune response to the SARS-CoV-2 proteins than that generated by the anti-spike protein immune activation conferred by the vaccine.

“However, as a correlate of protection is yet to be proven, including the role of B-cell and T-cell immunity, this remains a hypothesis,” they added.

The researchers said their study had several limitations. “First, as the Delta variant was the dominant strain in Israel during the outcome period, the decreased long-term protection of the vaccine compared to that afforded by previous infection cannot be ascertained against other strains,” they wrote.

Secondly, they said, their analysis addressed protection afforded solely by the Pfizer- BioNTech. It did not address other vaccines or long-term protection following a third dose.

“Additionally, as this is an observational real-world study, where PCR screening was not performed by protocol, we might be underestimating asymptomatic infections, as these individuals often do not get tested,” they added.

“Lastly, although we controlled for age, sex, and region of residence, our results might be affected by differences between the groups in terms of health behaviours (such as social distancing and mask wearing), a possible confounder that was not assessed.”

Gazit et al. said that their finding that individuals who were previously infected with SARS-CoV-2 seemed to gain additional protection from a subsequent single-dose vaccine regimen corresponded to previous reports, but they could not demonstrate significance in their cohort.

Brazil postpones Sputnik V importation approval

On April 26, the National Health Surveillance Agency (Anvisa) in Brazil decided not to approve the importation of Sputnik V, which had been requested by ten states.

Anvisa said that replication-competent adenovirus (RCA) was found in batches of the vaccine.

Replication-competent virus particles are capable of infecting cells and replicating to produce additional infectious particles.

The RDIF and the Gamaleya research centre said Anvisa’s decision was “of a political nature and has nothing to do with the regulator’s access to information or science”.

The Sputnik V team said the existing quality controls ensured that no RCA could exist in its vaccine.

On April 30, the Gamaleya institute issued a statement to clarify issues related to what it describes as “the ongoing disinformation campaign against Sputnik V”.

The institute described allegations by Anvisa that it had detected RCA in Sputnik V as “inaccurate and misleading”.

The Gamaleya institute says Anvisa has now admitted that it did not undertake any tests of the Sputnik V vaccine “and was referring to a regulatory limit in Russia on potential RCA presence”.

It said that no RCA was detected in any of the batches of the Sputnik V vaccine and add that this information was sent to Anvisa on March 26.

The institute sent an official letter dated March 26, 2021, that stated: “In addition, we would like to inform you that during the release of the vaccine product at the centre site and at the contract site of JBC Generium, not a single batch containing RCA was recorded.”

The institute said it had clarified to Anvisa that the limit used for quality control of the Sputnik V vaccine was much stricter than the allowed regulatory limit in Russia and corresponded to the strictest standards of world regulators.

“That strict limit has been confirmed by 64 of the world’s regulators that authorised Sputnik V,” the institute said.

The institute says that Anvisa did not attempt to clarify any of these issues after its visit “and their inaccurate statements could have been avoided simply by asking for the Gamaleya institute to comment”.

It added: “The Gamaleya institute regrets that unethical forces continuously attack the Sputnik V vaccine for competitive and political reasons costing lives and undermining the world vaccination programme.”

Anvisa said that that the presence of RCA could lead to infections in humans and “can cause damage and death, especially in people with low immunity and respiratory problems, among other health problems”.

The agency said that consistent and reliable data about Sputnik V was lacking and the evaluation of available data pointed to “flaws in the development and production of the vaccine”.

Anvisa added: “There is an absence or insufficiency of data on quality control, safety, and efficacy of the product.”

According to Brazil’s General Management of Medicines and Biological Products (GGMED), flaws in the development of Sputnik V were identified in all stages of the clinical studies (phases 1, 2, and 3), Anvisa said.

“Inadequate characterisation studies of the vaccine were detected, including with regard to the analysis of impurities and contaminating viruses during the manufacturing process,” the agency said.

Anvisa also said that there was a lack of toxicity testing to see if the vaccine might be harmful to reproductive cells.

The agency also says too little is known about short-, medium-, and long- term adverse effects resulting from use of the Sputnik V vaccine.

To date, 14 states have sent import orders for the Sputnik V vaccine to Anvisa.

The Sputnik V team said the Brazilian regulator’s decision contradicted a previous decision by the Ministry of Science, Technology and Innovation, “which recognised the Sputnik V vaccine as safe and allowed its production in Brazil”.

The team added: “The Gamaleya centre, which carries out strict quality control of all Sputnik V production sites, confirmed that no replication-competent adenovirus was found in any of the Sputnik V vaccine batches that were produced.”

The Sputnik V team said: “The quality and safety of Sputnik V are, among other things, guaranteed by the fact that, unlike other vaccines, it uses a four-stage purification technology that includes two chromatography stages and two tangential flow filtration stages.

“Only non-replicating adenoviral vectors of type E1 and E3, which are harmless to the human body, are used in the production of the Sputnik V vaccine.”

The Federal Supreme Court in Brazil will review Anvisa’s decision and hear a motion from seven Brazilian states whose governments want to accelerate their vaccination programmes.

It’s been reported that Anvisa’s decision doesn’t affect a separate request from the Brazilian company União Química for emergency use authorisation of Sputnik V that is produced locally.

On March 29, Brazil’s General Manager of Sanitary Inspection and Inspection denied a request from the Indian company Bharat Biotech for certification of good manufacturing practices for its vaccine Covaxin.

The step is a prerequisite for drug manufacturers to receive authorisation for the emergency use of a vaccine, or for definitive registration. Anvisa carried out an inspection of Bharat Biotech’s factory in India in early March.

Mix-and-match studies

In May, Spanish researchers gave a presentation about the CombivacS trial, in which participants were given one dose of the AstraZeneca-Oxford vaccine followed at least eight weeks later by a dose of the Pfizer-BioNTech vaccine.

The team, led by researchers from the from the Carlos III Health Institute said that the preliminary findings from the trial, which involved 673 people, indicated that there was a potent immune response.

They wrote: “The first results indicate that this heterologous vaccination regimen is highly immunogenic and does not present problems of post-vaccination reactogenicity different from those already reported in the homologous use (alone) of these same vaccines; that is, the response of the immune system is greatly enhanced after the second dose of the Comirnaty [Pfizer-BioNTech] vaccine, while the observed adverse effects are within what is expected, are mild or moderate and are mostly restricted to the first two–three days after receiving the vaccine.

“In no case has a hospital admission secondary to the use of this vaccination regimen been reported within this clinical trial.”

The researchers said their findings needed to be treated with caution, but the immune response observed in the CombivacS trial was in the same range as that occurring when two doses of the same vaccine were administered.

A total 441 people received the Pfizer-BioNTech vaccine and there were 232 people in the control group who didn’t receive it. The increase in the levels of antibodies and neutralising antibodies was analysed in 663 people.

Researchers at the University of Oxford have been conducting a trial in the UK in which eight different combinations are being tested, including single-vaccine, two-dose regimens with different time intervals and mix-and-match combinations of one dose of the Pfizer-BioNTech vaccine and one dose of the AstraZeneca-Oxford vaccine (referred to in the study as prime and boost doses).

The researchers have been gathering data about the effects of different intervals between the first and second doses in a mixed-vaccine regimen compared with control groups in which the same vaccine is used for both doses.

The 13-month Com-COV study, partly funded with £7 million from the UK government, was announced by the UK’S Department of Health and Social Care on February 4, 2021.

The UK minister for Covid-19 vaccine deployment, Nadhim Zahawi, said: “Nothing will be approved for use more widely than the study, or as part of our vaccine deployment programme, until researchers and the regulator are absolutely confident the approach is safe and effective.”

Robert H. Shaw et al. reported on the Com-COV study in an article in The Lancet, published on May 12, 2021.

During a trial conducted in February 2021, 463 participants were randomly assigned to four groups with a 28-day prime-boost interval, and 367 participants were randomised to groups with a 12-week prime-boost interval.

All 463 participants in the 28-day prime-boost interval group received their prime vaccine, and 461 participants received their boost vaccine.

The participants are aged 50 years and older, with no or mild-to-moderate, well controlled comorbidity. They were recruited across eight sites.

Shaw et al. presented initial reactogenicity and safety data ahead of publication of the primary immunological findings.

They found that people in the mix-and-match groups experienced higher rates of vaccine-related adverse effects, such as fever, than those who received two doses of the same vaccine.

“We found an increase in systemic reactogenicity after the boost dose reported by participants in heterologous vaccine schedules in comparison to homologous vaccine schedules, and this was accompanied by increased paracetamol usage,” Shaw et al. reported.

The researchers said that feverishness was reported by 37 (34%) of 110 recipients of the AstraZeneca-Oxford vaccine as a prime dose and the Pfizer-BioNTech vaccine as a booster compared with 11 (10%) of 112 recipients of the AstraZeneca-Oxford vaccine for both prime and booster doses.

Feverishness was reported by 47 (41%) of 114 recipients of the Pfizer-BioNTech vaccine as a prime dose and the AstraZeneca-Oxford vaccine as a booster compared with 24 (21%) of 112 recipients of the Pfizer-BioNTech vaccine for both prime and booster doses, Shaw et al. said.

Similar increases were observed for chills, fatigue, headache, joint pain, malaise, and muscle ache, the researchers added. “There were no hospitalisations due to solicited symptoms, and most of this increase in reactogenicity was observed in the 48 h after immunisation.” they said.

Shaw et al. noted that the data were obtained in participants aged 50 years and older, and reactogenicity might be higher in younger age groups.

They added that a mixed vaccination schedule was being advocated in Germany, France, Sweden, Norway, and Denmark for people who had received a first dose of the AstraZeneca-Oxford vaccine. This was in light of concerns about thrombotic thrombocytopenia.

“Pending availability of a more complete safety dataset and immunogenicity results for heterologous prime-boost schedules (to be reported shortly), these data suggest that the two heterologous vaccine schedules in this trial might have some short-term disadvantages,” Shaw et al. said.

It was reassuring that all reactogenicity symptoms were short lived, and there were no concerns from the limited haematology and biochemistry data available, they added.

“Further studies evaluating heterologous prime-boost schedules, incorporating vaccines manufactured by Moderna and Novavax, are ongoing, and are crucial to informing the appropriateness of mixed Covid-19 vaccine schedules,” they wrote.

Shaw et al. reported again on the study in a preprint published in The Lancet on June 25. They reported on the results of the trial involving 463 participants in the 28-day prime-boost interval group.

They said that the regimen in which a Pfizer-BioNTech dose was followed by an AstraZeneca-Oxford dose did not meet “non-inferiority criteria”.

They added, however, that the geometric mean concentrations (GMCs) of both heterologous schedules (a dose of the AstraZeneca-Oxford vaccine followed by a dose of the Pfizer-BioNTech vaccine and vice versa) were higher than that of a licensed vaccine schedule (two doses of the AstraZeneca-Oxford vaccine) “with proven efficacy against Covid-19 disease and hospitalisation”.

The researchers explained that the GMC of post-boost SARS-CoV-2 anti-spike IgG (the immunoglobulin G antibody) on day 28 was “non-inferior” to that in those who had received two doses of the AstraZeneca- Oxford vaccine.

They said that, in the case of participants primed with the Pfizer-BioNTech vaccine, they failed to show non-inferiority of the heterologous schedule (a Pfizer-BioNTech dose followed by a dose of the AstraZeneca-Oxford vaccine) as against two doses of the Pfizer-BioNTech vaccine.

The researchers said their data supported flexibility in the use of heterologous prime-boost vaccination using the AstraZeneca-Oxford and Pfizer-BioNTech vaccines.

They said there were four serious adverse events across all groups, but none of them were considered to be related to immunisation.

Scientists at the University of Oxford and Imperial College London reported that combining an RNA-based vaccine and a viral-vector vaccine generated a strong immune response in mice.

“We demonstrate that antibody responses are higher in two dose heterologous vaccination regimens than single dose regimens, with high titre neutralising antibodies induced,” the researchers said in a preprint published on bioRxiv on January 29.

“Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1⁺ CD4 T cells which is superior to the response induced in homologous vaccination regimens in mice.”

The University of Oxford is meanwhile launching a study that will investigate the delivery of the AstraZeneca-Oxford vaccine using a nasal spray. It will involve thirty volunteers aged 18 to forty years.

All of the volunteers will receive the same vaccine that is currently being delivered by intramuscular injection and will be followed for four months.

The study’s chief investigator, Sandy Douglas, said: “Some immunologists believe that delivering the vaccine to the site of infection may achieve enhanced protection, especially against transmission, and mild disease.”

He added: “There are a variety of people who will find an intranasal delivery system more appealing, which may mean vaccine uptake is higher in those groups.”

Dangers of vaccinating SARS-CoV-2 carriers

On January 26, 2021, Hooman Noorchashm wrote a ‘letter of warning’ to the FDA And Pfizer about “the immunological danger of Covid-19 vaccination in the recently convalescent and asymptomatic carriers”.

He had earlier written a ‘public letter of warning’ to the medical director of The Massachusetts Department of Public Health, Larry Madoff, about what he described as “a potentially high immunological risk to asymptomatic SARS-CoV-2 carriers who non-selectively receive the 2020 influenza vaccine (or any other vaccine)”.

Noorchashm, who makes clear that he is not taking an anti-vaccination stance, says no one who has natural immunity from a prior SARS-CoV-2 infection should receive a Covid vaccination. He has described the vaccination of already immune children as an “intolerable act of public health negligence”.

He says it is his sincere hope that his most recent emailed letter “might stimulate FDA, Pfizer and Moderna leaders to think critically and quickly about the immunological danger the Covid-19 vaccine might pose to the recently convalescent or asymptomatic carriers of SARS-CoV-2 –most especially to those who are elderly, frail or have significant cardiovascular risk factors”.

He says he wants to make clear that his warning is based on a “near definitive scientific immunological prognostication” that he has put forth “in the absence of clear ‘evidence’ of it being a material risk”. He says he is “an ardent supporter of President Biden’s plan to vaccinate 150 million Americans in 100 days”.

Noorchashm points out that the SARS-CoV-2 virus has tropism for the vascular endothelium, among other tissues and organs.

It seems that endothelial injury from the virus or from the inflammatory reaction it incites is the reason why many Covid-19 patients experience thromboembolic complications, Noorchashm writes.

“So it is a matter of certainty that viral antigens are present in the endothelial lining of blood vessels in all persons with active or recent SARS-CoV-2 infection – irrespective of whether they are symptomatic or convalescent.”

Noorchashm warns that “it is an almost certain immunological prognostication that, if viral antigens are present in the tissues of subjects who undergo vaccination, the antigen-specific immune response triggered by the vaccine will target those tissues and cause tissue inflammation and damage”.

When viral antigens are present in the vascular endothelium, and especially in elderly and frail people with cardiovascular disease, the antigen-specific immune response incited by the vaccine is almost certain to do damage to the vascular endothelium, Noorchashm says.

“Such vaccine-directed endothelial inflammation is certain to cause blood clot formation with the potential for major thromboembolic complications, at least in a subset of such patients.

“If a majority of younger more robust patients might tolerate such vascular injury from a vaccine immune response, many elderly and frail patients with cardiovascular disease will not.”

Noorchashm asks the FDA, in collaboration with Pfizer and Moderna, to immediately, “and at the very minimum”, issue clear recommendations to clinicians to delay vaccinating any recently convalescent Covid patients as well as any known symptomatic or asymptomatic carriers and to actively screen as many patients with high cardiovascular risk as is reasonably possible in order to detect the presence of SARS-CoV-2 prior to vaccinating them.

Noorchashm also highlights the case of Hank Aaron, “a giant in the black American struggle and a hero to America’s civil rights movement”, who died, aged 86, of a massive stroke on January 22, 2021, 17 days after receiving the Moderna Covid vaccine.

Aaron (pictured left), who is regarded as one of the greatest baseball players of all time, had medical co-morbidities and likely met the medical definition of “frailty”, Noorchashm wrote in an article on Medium.

Noorchashm says he doesn’t personally believe that the Moderna vaccine caused Aaron’s death. “It is entirely likely that Hank Aaron’s death from a massive stroke has nothing to do with his vaccine dose,” he said. “86-year-olds with his health profile have massive strokes every day across the country.”

He adds, however: “I do believe that we ought to take Mr Aaron’s death following Covid-19 vaccination very seriously – and to do our best to help the public make sense of it.

“We do this through logical, respectful and scientifically based discourse – not just with experts, but even more importantly, with the general public. And in the case of Mr Aaron’s death, with the black community in America.”

It is an immunological possibility, Noorchashm says, that Aaron was an asymptomatic carrier of SARS-CoV-2, and that the vaccine may have exacerbated a local vasculitis that led to an acute thrombotic event, i.e. a blood clot in the blood vessels to or in his brain that led to his stroke.

“I do think there is a reasonable scientific rationale for screening older and frail patients or those with co-morbidities (i.e. obesity, diabetes, hypertension, high cholesterol or history of cardiovascular disease), like Mr Aaron, for Covid-19 prior to vaccinating them.

“If folks in these categories do turn out to be asymptomatic carriers, I would advocate for delaying their vaccination by 3–4 weeks with good social isolation instructions – followed by vaccination.

It would be reasonable for Aaron’s family and community to ask his local health authorities, the FDA and Moderna to perform assays on his remaining tissues and see if he was a carrier of SARS-CoV-2, Noorchashm says.

“In general, I believe that it is logical and safest to delay vaccination in any known asymptomatic carriers of the virus by a few months, especially if they are found to have antibodies – and, certainly, I would screen all frail patients or those with cardiovascular co-morbidities for Covid-19, before vaccinating them.

“Based on emerging data, I would even go as far as to say that asymptomatic carriers may be better candidates for the Regeneron or Eli Lilly antibodies, instead of the Covid-19 vaccine.”

Frequency of grade 3 adverse events ‘higher than for most vaccines’

Peter Doshi noted in an article published in the New York Times on January 7, 2021, that, with the Moderna vaccine, the frequency of grade 3 adverse events – those severe enough to prevent daily activity – was higher than it was for most vaccines: 17.4 percent, or nearly one in five 18-to-64-year-olds who received two doses of the vaccine in the company’s trial.

FDA briefing document about the Moderna vaccine

Cell signalling

On January 11, 2021, Yuichiro J. Suzuki from the Georgetown University Medical Centre, Washington, DC, in the US and Sergiy G. Gychka from Bogomolets National Medical University, Kiev, in Ukraine published an article entitled ‘SARS-CoV-2 Spike Protein Elicits Cell Signalling in Human Host Cells: Implications for Possible Consequences of Covid-19 Vaccines’.

They proposed that the SARS-CoV-2 spike protein (without the rest of the viral components) triggers cell signalling events “that may promote pulmonary vascular remodelling and PAH [pulmonary arterial hypertension] as well as possibly other cardiovascular complications”.

The two researchers said the advancement in spike protein-based Covid-19 vaccine development was exciting and had “shed light on how to end the current pandemic” and the vaccines “should benefit elderly people with underlying conditions if they do not exhibit any acute adverse events”.

They added, however: “We need to consider their long-term consequences carefully, especially when they are administered to otherwise healthy individuals as well as young adults and children.”

Suzuki and Gychka cite research by Kuba et al. that showed that the injection of mice with recombinant SARS-CoV-1 spike protein reduced ACE2 expression and worsened acid-induced lung injury.

“In mice with an acid-induced lung injury, the recombinant SARS-CoV-1 spike protein dramatically increased angiotensin II, and the angiotensin receptor inhibitor losartan attenuated the spike protein-induced enhancement of lung injury,” Suzuki and Gychka wrote.

“Thus, these in vivo studies demonstrated that the spike protein of SARS-CoV-1 (without the rest of the virus) reduces the ACE2 expression, increases the level of angiotensin II, and exacerbates the lung injury.”

Suzuki and Gychka also refer to research by Patra et al. who show that the SARS-CoV-2 spike protein without the rest of the viral components activates cell signalling.

“This cell signalling cascade was found to be triggered by the SARS-CoV-2 spike protein downregulating the ACE2 protein expression, subsequently activating the angiotensin II type 1 receptor,” Suzuki and Gychka wrote.

“These experiments using transient transfection may reflect the intracellular effects of the spike protein that could be triggered by the RNA- and viral vector-based vaccines.”

The two researchers say their results “collectively reinforce the idea that human cells are sensitively affected by the extracellular and/or intracellular spike proteins though the activation of cell signal transduction”.

They said they found that, in contrast to the full-length spike protein or the full-length SARS-CoV-2 spike protein S1 subunit, protein that only contained the RBD did not promote cell signalling.

“It is generally thought that the sole function of viral membrane fusion proteins is to allow the viruses to bind to the host cells for the purpose of viral entry into the cells, so that the genetic materials can be released and the viral replication and amplification can take place,” Suzuki and Gychka wrote.

“However, recent observations suggest that the SARS-CoV-2 spike protein can by itself trigger cell signalling that can lead to various biological processes.”

Suzuki and Gychka only tested the effects of the SARS-CoV-2 spike protein in lung vascular cells and those implicated in the development of PAH. However, they said, the spike protein may also affect the cells of systemic and coronary vasculatures, eliciting other cardiovascular diseases such as coronary artery disease, systemic hypertension, and stroke.

“In addition to cardiovascular cells, other cells that express ACE2 have the potential to be affected by the SARS-CoV-2 spike protein, which may cause adverse pathological events,” the researchers wrote.

“Thus, it is important to consider the possibility that the SARS-CoV-2 spike protein produced by the new Covid-19 vaccines triggers cell signalling events that promote PAH, other cardiovascular complications, and/or complications in other tissues/organs in certain individuals.”

The researchers added: “While human data on the possible long-term consequences of spike protein-based Covid-19 vaccines will not be available soon, it is imperative that appropriate experimental animal models are employed as soon as possible to ensure that the SARS-CoV-2 spike protein does not elicit any signs of the pathogenesis of PAH or any other chronic pathological conditions.”

Researchers at the Old Dominion University in Norfolk, Virginia, in the US have meanwhile discovered that the SARS-CoV-2 spike protein alone is enough to induce Covid-like symptoms in mice, including severe inflammation of the lungs.

Pavel Solopov, who is an assistant professor at the Frank Reidy Research Center for Bioelectrics at the university, said the researchers’ findings showed that the SARS-CoV-2 spike protein caused lung injury even without the presence of the intact virus

“This previously unknown mechanism could cause symptoms before substantial viral replication occurs,” Solopov said.

Solopov is presenting the new research at the annual meeting of the American Society for Pharmacology and Experimental Therapeutics during the virtual Experimental Biology 2021 meeting, being held from April 27–30.

Solopov explained that studying SARS-CoV-2 could be challenging because experiments involving the intact virus requires a Biosafety Level 3 laboratory. The researchers therefore used transgenic mice that expressed the human receptor for SARS-CoV-2 in their lungs.

“Our mouse model dramatically reduces the danger of doing this type of research by allowing Covid-19 lung injury to be studied without using the intact, live virus,” Solopov said.

The researchers injected the genetically modified mice with a segment of the spike protein and analysed their response 72 hours later. Another group of mice received only saline as as a control.

The scientists found that the genetically modified mice injected with the spike protein exhibited Covid-19-like symptoms that included severe inflammation, an influx of white blood cells into their lungs, and evidence of a cytokine storm. The mice that only received saline remained normal.

Vaccination during pregnancy

On January 25, 2021, the WHO issued interim guidance for use of the Moderna mRNA-1273 vaccine. It recommended that mRNA-1273 not be used during pregnancy, “unless the benefit of vaccinating a pregnant woman outweighs the potential vaccine risks, such as in health workers at high risk of exposure and pregnant women with comorbidities placing them in a high-risk group for severe Covid-19”.

On November 29 it did an about-turn and said that, while very little data were available to assess vaccine safety in pregnancy, “based on what we know about this kind of vaccine, we don’t have any specific reason to believe there will be specific risks that would outweigh the benefits of vaccination for pregnant women”.

The WHO later said that those pregnant women at high risk of exposure to SARS-CoV-2 (e.g. health workers) or who had comorbidities that added to their risk of severe disease “may be vaccinated in consultation with their health care provider”.

In the guidance it issued on January 25, 2021, the WHO said: “The available data on mRNA-1273 vaccination of pregnant women are insufficient to assess vaccine efficacy or vaccine-associated risks in pregnancy.

“However, it should be noted that the mRNA-1273 vaccine is not a live virus vaccine, and the mRNA does not enter the nucleus of the cell and is degraded quickly. Developmental and reproductive toxicology (DART) studies in animals have not shown harmful effects in pregnancy. Further studies are planned in pregnant women in the coming months.”

The EMA stated: “There is limited experience with use of Covid-19 Vaccine Moderna in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or post-natal development. Administration of Covid-19 Vaccine Moderna in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and foetus.”

Neither Moderna nor Pfizer enrolled pregnant women in their Covid-19 vaccine trials. Moderna says it plans to establish a registry to study pregnancy outcomes in mothers and infants.

Pfizer and BioNTech announced on February 18, 2021, that the first participants in a Phase 2/3 study to evaluate the safety, tolerability, and immunogenicity of their Covid vaccine for pregnant women had received their initial vaccine dose.

Participants were vaccinated when they were 24 to 34 weeks pregnant. They received two doses of BNT162b2 or a placebo, administered 21 days apart.

About 4,000 participants were enrolled at more than 130 sites in the US, Canada, Brazil, Chile, Mozambique, South Africa, the UK, and Spain.

Each woman participated in the study for approximately seven to ten months, depending on whether she was randomised to receive the vaccine or a placebo.

The infants of the vaccinated women were studied to assess vaccine safety and examine whether the women transferred antibodies to their babies.

The infants were monitored until they were about six months old. After a trial participant’s infant was born, she was be unblinded and those who were in the placebo group were offered the vaccine.

Pfizer and BioNTech said that, prior to conducting their trial involving pregnant women, they completed a developmental and reproductive toxicity (DART) study of BNT162b2, which they say “showed no evidence of fertility or reproductive toxicity in animals”.

Pfizer says that, currently, available data “are insufficient to inform vaccine-associated risks in pregnancy”.

Doctor calls for a halt to Covid vaccination

In June 2021, the director of the Evidence-based Medicine Consultancy (E-BMC) and the crowdfunded community interest company EbMC Squared CiC, Dr Tess Lawrie, wrote to June Raine calling for an immediate halt to the Covid vaccination programme in the UK.

She also asked Raine to give EbMC Squared CiC full access to the Yellow Card adverse reactions database so that researchers there can conduct a “comprehensive, independent and accurate evaluation” of the data in collaboration with clinical experts.

Lawrie, who is based in Bath, said the MHRA had more than enough evidence via the Yellow Card system to declare the Covid-19 vaccines unsafe for use in humans.

“Preparation should be made to scale up humanitarian efforts to assist those harmed by the Covid-19 vaccines and to anticipate and ameliorate medium to longer term effects,” Lawrie wrote.

“As the mechanism for harms from the vaccines appears to be similar to Covid-19 itself, this includes engaging with numerous international doctors and scientists with expertise in successfully treating Covid-19.”

There are at least three urgent questions that the MHRA needs to answer, Lawrie says:

• How many people have died within 28 days of Covid vaccination?
• How many people have been hospitalised within 28 days of Covid vaccination?
• How many people have been disabled by Covid vaccination?

Lawrie says the nature and variety of adverse reactions reported via the Yellow Card System are “supported by other recent scientific papers on vaccine-induced harms, which are mediated through the vaccine spike protein product”.

It was now apparent, Lawrie said, that these products in the blood stream are toxic to humans.

“An immediate halt to the vaccination programme is required whilst a full and independent safety analysis is undertaken to investigate the full extent of the harms, which the UK Yellow Card data suggest include thromboembolism, multisystem inflammatory disease, immune suppression, autoimmunity and anaphylaxis, as well as antibody dependent enhancement,” Lawrie wrote.

Researchers at EbMC Squared CiC studied the adverse event data published by the MHRA and grouped it into four categories: bleeding, clotting and ischaemic adverse reactions; immune system adverse reactions; ‘pain’ adverse reactions; neurological adverse reactions; adverse reactions involving the loss of sight, hearing, speech, or smell; and adverse reactions related to pregnancy.

Working with data up to May 26, 2021, the researchers identified 13,766 bleeding, clotting and ischaemic adverse reactions, 856 of which were fatal.

“Government reports have highlighted the occurrence of cerebral venous sinus thrombosis, apparently accounting for 24 fatalities and 226 ADRs [adverse drug reactions] up to the 26th May 2021,” Lawrie wrote.

“However, our analysis indicates that thromboembolic ADRs have been reported in almost every vein and artery, including large vessels like the aorta, and in every organ including other parts of the brain, lungs, heart, spleen, kidneys, ovaries and liver, with life-threatening and life-changing consequences.”

The most common Yellow Card categories in which these sorts of ADRs were reported were the nervous system category (152 fatalities, mainly from brain bleeds and clots), and the respiratory and cardiac categories (with 103 fatalities, mainly from pulmonary thromboembolism, in the former and 81 fatalities in the latter), Lawrie adds.

Lawrie said that, as of May 26, 2021, there were 54,870 ADRs and 171 fatalities in the ‘immune system’ category.

She said the second highest number of fatalities were in this category, but only four associated deaths were reported in the Yellow Card ‘immune disorders’ category (as of May 26).

The majority (141 fatalities associated with 19,474 ADRs) were reported in the ‘Infections’ category. Among 1,187 people for whom post-vaccination Covid-19 infection was reported, there were 72 fatalities, Lawrie noted.

Lawrie added that many adverse reactions in the ‘infections’ category indicated a reactivation of latent viruses, including herpes zoster (1,827 ADRs), herpes simplex (943 ADRs, including one that was fatal), and rabies (one fatal reaction).

“This is strongly suggestive of vaccine-induced immune compromise,” Lawrie wrote.

Lawrie also noted that Bell’s palsy, which she says is also associated with latent virus reactivation, is reported in the neurological adverse reaction section of her report.

“Also suggestive of vaccine-induced immunocompromise was the high number of immune-mediated conditions reported, including Guillain-Barré syndrome (280 ADRs, including six deaths), Crohn’s and non-infective colitis (231 ADRs, including two deaths) and multiple sclerosis (113 ADRs),” she said.

Under the ‘pain’ category, the EbMC Squared CiC researchers identified at least 157,579 ADRs.

Lawrie noted that a large number of these were arthralgias (24,902 reports of joint pain) and myalgias (31,168 reports of muscle pain), including 270 reports of fibromyalgia, a long-term condition that causes pain all over the body.

Among reported congenital disorders (conditions that are usually present from birth) there were 11 reports of paroxysmal extreme pain disorder (PEPD), which is an extremely rare inherited disease caused by a genetic mutation leading to dysfunction of voltage-gated sodium channels.

“The head was the most common location for pain, but abdominal pain, eye pain, chest pain, pain in extremities, and anywhere else that pain can be imagined was reported,” Lawrie wrote.

“Headaches were reported more than 90,000 times and were associated with death in four people (excluding deaths reported to be from other causes, that may also have involved headache).”

The EbMC Squared CiC researchers noted that 21% percent (185,474) of ADRs were categorised as nervous system disorders in the Yellow Card system.

“A wide variety of neurological ADRs were noted, including 1,992 ADRs involving seizures and 2,357 ADRs involving some form of paralysis, including Bell’s palsy (626 ADRs),” Lawrie noted.

“Other ADRs involving encephalopathy (18), dementia (33), ataxia (34), spinal muscular atrophy (1), Parkinson’s (18) and delirium (504) may reflect post-vaccination neurodegenerative pathology.”

Lawrie said that most of the fatalities associated with nervous system ADRs occurred as a result of central nervous system haemorrhages (127 of the 186 fatalities reported as nervous system fatalities). The EbMC Squared CiC researchers counted these 127 deaths in the bleeding, clotting and ischaemic category.

In the ‘loss of sight, hearing, speech or smell’ category the EbMC Squared CiC researchers identified 4,771 reports of visual impairment including blindness, 130 reports of speech impairment, 4,108 reports of taste impairment, 354 reports of olfactory impairment, and 704 reports of hearing impairment.

In relation to pregnancy, Lawrie wrote: “Given that vaccinated pregnant women comprise a small proportion of the vaccinated population in the UK up to 26th May, 2021, there appear to be a high number of pregnancy ADRs.”

The 307 ADRs included one maternal death, 12 stillbirths (reported as six stillbirths and six foetal deaths, but only three listed as fatal), Lawrie adds.

There was also one newborn death following preterm birth, and 150 spontaneous abortions, she said.

“We have submitted a Freedom of Information request as to the cause of the maternal death and will look into pregnancy and congenital ADRs in more detail in our next report,” she added.

“Due to the need for expedience, we have not detailed all ADRs in this preliminary report. The existing Yellow Card data covering just under a five-month period indicate that the extent of morbidity and mortality associated with the Covid-19 vaccines is unprecedented.

“Age and gender specific data, as well as the time from vaccination, are required to further our analysis of these data and we have sent Freedom of Information requests to the MHRA in this regard.”

Lawrie said that urgent independent expert evaluation and discussion was required to assess whether Covid vaccines might be causing gene mutations among recipients, “as suggested by the occurrence of usually extremely rare genetic disorders, such as PEPD”.

In addition to the 11 cases of PEPD reported via the Yellow Card system, there were 12 reports of this extremely rare condition on the WHO’s VigiBase and ten on EudraVigilance, Lawrie said.

“Are these ADRs occurring in babies of vaccinated pregnant women, or spuriously among vaccinated adults? she wrote. “This question needs urgent attention.”

Lawrie added: “As pharmacovigilance data are known to be substantially under-reported, we recommend that the MHRA urgently publicises these ADR data and assists people with their ADR reporting, to facilitate full elucidation and clarification of the extent of the problem.”

Data from Israel

Israel’s vaccination drive began on December 19, 2020. While researchers reported indications of decreased SARS-CoV-2 infection and fewer Covid-19 cases after vaccination, the number of severe Covid-19 cases, daily SARS-CoV-2 infections, and total active Covid-19 cases reached all-time peaks in Israel in January.

Vaccinations with the Pfizer-BioNTech vaccine began amid a surge of infections that led to a national lockdown on December 27, 2020. Daily infections peaked at 10,213 cases on January 20, 2021, and lockdown was lifted on March 7.

By April 3, 72% of people aged over 16 years (4,714,932 of 6,538,911) and 90% of those over 65 years (1,015,620 of 1,127,965) had received two doses of the Pfizer-BioNTech vaccine.

In a report published in The Lancet on May 5, 2021, Eric J. Haas et al. said nationwide data in Israel showed that two doses of the Pfizer-BioNTech vaccine were more than 95% effective against infection, hospitalisation, and death from Covid-19, including among the elderly, at a time when the B.1.1.7 variant was the dominant strain.

Israel is the country with the second highest proportion of its population vaccinated in the world. According to the Bloomberg vaccine tracker, 57.9% of the vaccine-eligible population in Israel has been vaccinated, as compared with 66.5% in the Seychelles. (Bloomberg calculates vaccine coverage by dividing the number of doses administered for each vaccine type by the number of doses required for full vaccination.)

The researchers’ analysis indicated that the vaccine provided 95.3% protection against infection and 96.7% protection against death seven days after the second dose. Protection against symptomatic and asymptomatic infection was 97.0% and 91.5%, respectively, they said.

The vaccine was shown to provide 97.2% protection against hospitalisation overall and 97.5% protection against severe and critical hospitalisation, they added.

By 14 days after vaccination, the protection conferred by a second dose increased to 96.5% against infection, 98.0% against hospitalisation, and 98.1% against death, Eric J. Haas et al. reported.

Eric J. Haas et al. reported that protection was considerably lower between seven and 14 days after administration of the first vaccine dose: 57.7% protection against infection, 75.7% protection against hospitalisation, and 77.0% protection against death.

The observational study was conducted by researchers from Israel’s Ministry of Health, Pfizer Pharmaceuticals Israel, and Pfizer USA.

Eight of the 15 authors of the report declared that they held stock and stock options in Pfizer.

Haas et al. said that, while their findings were encouraging, challenges to controlling the Covid-19 pandemic remained.

They said that, despite indications of at least partial effectiveness after one dose of BNT162b2, relying on protection against Covid-19 from a single dose might not be prudent.

“BNT162b2 was developed and evaluated in the RCT [randomised controlled trial] as a two-dose schedule, and substantially lower levels of neutralising antibodies were observed after one dose compared with after two doses,” the researchers wrote.

“Additionally, little is known about the duration of protection of one dose and how it compares with the durability after two doses. It is possible that one dose will provide a shorter duration of protection than two doses, particularly in an environment where new SARS-CoV-2 variants continue to emerge.”

Haas et al. used national pandemic surveillance data recorded by Israel’s Ministry of Health to calculate adjusted vaccine effectiveness.

Data was analysed in groups based on age. The average follow-up time for people who received two vaccine doses was 48 days.

During the analysis period, there were 232,268 confirmed SARS-CoV-2 infections in the country. B.1.1.7 accounted for 94.5% of specimens tested (8,006 of 8,472 specimens).

A total 66.6% of the infections were in people aged over 16 years. There were 7,694 hospitalisations (in 4,481cases, the illness was severe and, in 188 cases, the patient’s condition was critical). There were 1,113 deaths.

Haas et al. say that protection among the elderly was as strong as that for younger people, with analysis indicating that people aged over 85 years had 94.1% protection against infection, 96.9% protection against hospitalisation, and 97% protection against death seven days after the second vaccine dose.

They said that people aged between 16 and 44 years had 96.1% protection against infection, 98.1% protection against hospitalisation, and 100% protection against death.

Haas et al. say that declines in SARS-CoV-2 infections for each age group corresponded with achieving high vaccine coverage in that age group rather than initiation of the nationwide lockdown.

“These findings suggest that the primary driver of reductions in the incidence of SARS-CoV-2 infections was high vaccine coverage, not implementation of the lockdown,” they wrote. “Furthermore, even after reopenings occurred, SARS-CoV-2 incidence remained low, suggesting that high vaccine coverage might provide a sustainable path towards resuming normal activity.”

The report’s authors say that, given the differences in the way vaccines are rolled out in different countries, and how the pandemic evolves, caution should be used in extrapolating their findings to other nations.

They say their study has some limitations. “In the absence of randomisation, there could have been unmeasured differences between vaccinated and unvaccinated persons (e.g. different test-seeking behaviours or levels of adherence to non-pharmaceutical interventions) which might have confounded our vaccine effectiveness estimates,” they wrote.

“Although we adjusted our estimates for age, sex, and calendar week, the effect of additional covariates such as location, comorbidities, race or ethnicity, socioeconomic status, and likelihood of seeking SARS-CoV-2 testing should be evaluated in future studies.

“Preliminary findings from a study in Israel, for example, indicate that neighbourhood might be an important confounder.”

The researchers also note the possibility that some people who had SARS-CoV-2 infection and reported being asymptomatic at the time they were interviewed may in fact have been presymptomatic.

“Further studies are needed to confirm the magnitude of BNT162b2 protection against asymptomatic infection that we observed,” they wrote. “Specifically, studies are needed to evaluate testing behaviour of vaccinated and unvaccinated people and to determine the extent to which prevention of asymptomatic infection leads to interruption of transmission.”

In a linked comment, Eyal Leshem from the Chaim Sheba Medical Centre in Israel and Annelies Wilder-Smith from the London School of Hygiene and Tropical Medicine, who were not involved in the study, wrote: “Haas and colleagues’ findings from Israel suggest that high vaccine coverage rates could offer a way out of the pandemic. Regrettably, rapid population-level coverage cannot be easily replicated in many other countries. The global use of BNT162b2 vaccine is limited by supply issues, high costs, and ultra-cold chain storage requirements.”

Haas et al. said that, among 154,648 SARS-CoV-2 infections in those aged 16 years and older, 109,876 (71%) were unvaccinated and 6,266 (4.1%) were fully vaccinated (with ≥7 days after the second dose).

Among the 54,677 people aged 16 years and older who had symptomatic Covid-19, 39,065 (71.4%) were unvaccinated and 1,692 (3.1%) received two doses (with ≥7 days after the second dose).

Among the 7,694 people aged 16 years and older who were hospitalised with Covid-19, 5,526 (71.8%) were unvaccinated and 596 (7.7%) received two vaccine doses with ≥7 days after the second dose.

Of the 4,481 severe or critical hospitalisations related to Covid-19 that occurred in people aged 16 years and above, 3,201 (71.4%) people were unvaccinated and 364 (8.1%) were fully vaccinated.

Of the 1,113 people aged 16 years and older who died from Covid-19, 715 (64.2%) were unvaccinated and 138 (12.4%) were fully vaccinated.

In a blog post entitled ‘Is the Pfizer vaccine as effective as claimed?’, published on May 17, 2021, professor in risk information management Norman Fenton and professor in computer science and statistics Martin Neil gave their analysis of the report by Haas et al..

They said that the 95% effectiveness measure was exaggerated. They referred to an article by Will Jones, who stated that Haas et al. did not adjust for the declining infection rate during the study period. When this adjustment was made, Jones said, effectiveness dropped to 74% in the over 65s.

Fenton and Neil noted that Haas et al. stated the following; “Israel’s SARS-CoV-2 testing policy was different for unvaccinated and vaccinated individuals during the study period. At seven days after the second dose, vaccinated individuals were exempt from the SARS-CoV-2 testing required of individuals who either had contact with a laboratory-confirmed case or returned from travel abroad.

“This testing policy might have resulted in a differential bias that would cause overestimation of vaccine effectiveness against asymptomatic infection (i.e., asymptomatic people who received two doses were less likely to be tested than unvaccinated asymptomatic people).”

Fenton and Neil explained: “What this is saying is that, whereas unvaccinated people continued to be regularly and routinely subject to PCR tests, vaccinated people no longer had to be.”

They added: “If you stop testing vaccinated people then you are not going to find any ‘cases’ among them.”

Haas et al. stated that 19% of the 4.4 million PCR tests conducted during the study period were done on exempted (vaccinated) individuals.

However, Fenton and Neil say, “this still means unvaccinated people were much more likely to be tested than vaccinated people, so we have to take account of the absolute number of tests performed on both vaccinated and unvaccinated”.

Fenton and Neil noted that the number of ‘cases’ per 1,000 tests was as follows:

• 30.8 for unvaccinated people (109,876 divided by 3,564,000 times 1,000), and
• 7.5 for vaccinated people (6,266 divided by 836,000 times 1000).

They based this calculation on the conclusion that there 836,000 tests on vaccinated people and 3,564,000 tests on unvaccinated people.

“Using the simple ‘cases per 1,000 tests’ (rather than the biased ‘incident rate per 100,000 person days’) results in an approximate ‘vaccine effectiveness’ measure of 75.7%,” Fenton and Neil said.

“While this is much less than the 95% headline figure, it is still impressive, so it is strange why the study failed to account for the difference in proportions tested.”

Hilla De-Leon et al. had reported in a preprint published on medRxiv on February 3 that the Pfizer-BioNTech vaccine might curb cases of Covid-19 by about 50 percent 14 days after the first of two doses is administered.

The researchers admitted, however, that their study had numerous limitations. They used data analysis tools and simulations to model epidemic dynamics in Israel, comparing different scenarios of lockdown duration and effectiveness. Each scenario was modelled with and without up-to-date vaccine coverage.

“While our study cannot accurately estimate the effectiveness of the Pfizer-BioNTech vaccine, it suggests that the effectiveness is greater than 50% and that there is a considerable level of prevention of transmission following vaccinations,” Hilla De-Leon et al. said.

Statistics reported by the Maccabi health fund indicated that vaccination with the Pfizer-BioNTech vaccine led to a 51% drop in SARS-CoV-2 infection two weeks after an initial vaccine dose.

Researchers from the Maccabi research and innovation centre, the KSM, and Tel Aviv University conducted a retrospective study using data from all Maccabi members aged 16 years or above who were vaccinated with BNT162b2 between December 19, 2020, and January 15, 2021. Daily and cumulative infection rates on days 13–24 after the first dose were compared with those on days 1–12.

Data from 503,875 individuals, of whom 351,897 had 13–24 days of follow-up after the first dose, were analysed.

“Our findings showed that the first dose of the vaccine is associated with an approximately 51% reduction in the incidence of PCR-confirmed SARS-CoV-2 infections at 13 to 24 days after immunisation compared to the rate during the first 12 days,” Gabriel Chodick et al. said. “Similar levels of effectiveness were found across age groups …

“Our findings … might be an underestimation of the vaccine effectiveness against Covid-19. Nonetheless, our study provides critically needed evidence on the early performance of BNT162b2 vaccine in real life.”

Maccabi said that when researchers analysed the first 430,000 Covid vaccinations received by its members the rate of SARS-CoV-2 infection dropped by 60% after the 12th day post-vaccination.

“The rate of infection decreased from about 40 per 100,000 persons per day in the first 12 days to about 15 per 100,000 persons on days 13 to 21, indicating an efficiency of about 60% in reducing the infection,” Maccabi said.

“Despite the encouraging findings, there were still cases of people being infected after 13 days had already passed since the first dose. The researchers emphasise that, even after receiving the first dose, the rules of social distancing must be maintained.”

In a separate analysis, Maccabi researchers, in collaboration with scientists from the KI Institute, studied a group of 50,777 over-60s vaccinated in late December and mid-January. They found that, two days after the second dose, the number of new infections and hospitalisations were both down about 60% from their peak.

The researchers found that the rate of hospitalisation started to fall sharply from Day 18 after the first dose.

Until Day 13, the vaccinated cohort had similar infection rates as the overall population of over-60s. By Day 23, there were 18 daily infections among the total cohort of 50,777 people, but just six among those vaccinated.

The head of infectious diseases at the Sheba Medical Centre, Galia Rahav, told The Times of Israel that some of the decrease might be due to a tendency of newly vaccinated people to adhere to lockdown rules, which caused a drop in infection and hospitalisation.

On February 1, Maccabi published data about 132,015 of its members over the age of 60 who received the first dose of BNT162b2 between December 20 and 29, 2020.

Day 10 represented the peak of confirmed SARS-CoV-2 infections and a slight decrease began at day 11. There was a peak in Covid-19 related hospitalisations on day 14.

A 55% decrease in average daily infections was seen between the peak point and day 21. In a similar timeframe, a 14% increase in SARS-CoV-2 infections was seen in the general population.

An additional 25% decrease in the number of newly infected members was seen between days 21 and 28 whereas an 18% decrease was seen in the general population.

“The decrease in daily hospitalisation numbers is more significant, though we draw attention to the fact that the numbers are small – and therefore must be cautiously interpreted,” Maccabi said.

“Compared to the peak number of newly vaccinated hospitalised patients on day 14, an 80% decrease is seen on days 27-28.”

Tal Patalon, who is the head of KSM, said: “Though the trend is encouraging, those vaccinated still need to be cautious. We still do not have enough data about hospitalisations among vaccinated individuals – as well as their potential to infect – and not merely be infected.”

In a separate study, reported on in a preprint published on medRxiv on February 8, 2021, researchers from Maccabi and the Israel Institute of Technology found that, after vaccination with the Pfizer-BioNTech vaccine, viral load was reduced fourfold in infections occurring 12–28 days after the first vaccine dose.

“These reduced viral loads hint to lower infectiousness, further contributing to vaccine impact on virus spread,” the researchers said.

The study was based on an analysis of positive post-vaccination samples obtained between December 23, 2020, and January 25. Patients who had a positive test prior to vaccination were excluded as well as patients aged 90 and above.

“Our results show that infections occurring 12 days or longer following vaccination have significantly reduced viral loads, potentially affecting viral shedding and contagiousness as well as severity of the disease,” Idan Yelin et al. wrote.

The researchers pointed to several limitations of their study, which was observational, not a randomised, controlled trial:

• The group of vaccinees may have differed from the demographically matched control group in ways that could affect the observed viral load, such as behaviour, tendency to get tested, and general health status.
• Different viral variants, which could be associated with different viral loads, may affect different parts of the population.
• The oro-nasopharyngeal test does not distinguish the viral load in the nose from the one in the oral cavity, which may be more representative of viral shedding and infectiousness.

The researchers also said that post-vaccination positive tests “may be enriched for long-term, low viral load infections lasting from pre-immunisation transmission events”.

They added: “With the accumulation of additional and longer-term datasets, it will also be important to see how these results vary for other vaccines as well as among viral variants.”

On January 28, The Times of Israel reported that the Pfizer-BioNTech vaccine had been shown to be 92 percent effective.

Thirty-one out of 163,000 Israelis vaccinated by Maccabi Healthcare Services were diagnosed with Covid-19 in the first ten days after the second dose, Maccabi’s top vaccine statistics analyst, Anat Ekka Zohar, told The Times of Israel.

Israel’s health ministry said in January that just 0.04 per cent of Israelis (317 out of 715,425) who had received two doses of the Pfizer/BioNTech vaccine had tested positive for SARS-CoV-2.

Clalit Health Services said on January 14 that a study involving 600,000 people who received two doses of the Pfizer/BioNTech vaccine and 600,000 people who had not been vaccinated indicated that the vaccine provided more than 90% protection against Covid disease.

In the vaccinated group, there was 94% less symptomatic infection and about 92% (between 91 and 99%) fewer cases of serious Covid illness, compared to the non-vaccinated group, Clalit said.

The rate of “efficacy” was the same across all age groups, including those aged 70 years and above, Clalit said.

Those vaccinated were tested at least seven days after their second vaccine dose. The founding director of the Clalit Research Institute, Ran Balicer, said that a preliminary examination of results indicated that the vaccine had even higher efficacy in preventing symptomatic and severe Covid disease 14 days or more post-vaccination.

Each vaccinated person was “paired” for study with a unvaccinated person of a similar age, with a similar health and risk profile.

A limitation of the study is that it is observational research, not a randomised controlled trial.

In a report, published in the New England Journal of Medicine on February 24, 2021, Israeli and American researchers said their study, conducted in Israel, suggested that effectiveness of the Pfizer-BioNTech vaccine was high in preventing hospitalisation, severe illness, and death from Covid-19 and the “estimated benefit” benefit increased in magnitude as time passed.

Noa Dagan et al. assessed estimated vaccine effectiveness in the period from day 14 to day 20 after the first dose and seven or more days after the second dose.

They said that estimated effectiveness in combatting documented infection was 46% and 92% respectively over the studied time periods. They added that estimated effectiveness in combatting symptomatic Covid-19 was shown to be 57% at days 14 to 20 after the first dose, rising to 94% seven or more days after the second dose.

In reducing hospitalisation, estimated effectiveness was seen to be 74%, rising to 87% seven or more days after the second dose. In reducing the incidence of severe disease, estimated effectiveness was 62%, rising to 92% seven or more days after the second dose.

The researchers said the estimated effectiveness in preventing death from Covid-19 was 72% on days 14 to 20 after the first vaccine dose.

Of those study participants who died from Covid-19, nine were fully vaccinated and 32 were unvaccinated.

“Estimated effectiveness in specific subpopulations assessed for documented infection and symptomatic Covid-19 was consistent across age groups, with potentially slightly lower effectiveness in persons with multiple coexisting conditions,” Dagan et al. said.

Each group in the study included 596,618 people. Matched participants in the unvaccinated cohort were younger than the eligible population overall and had a lower prevalence of chronic conditions because there was a smaller pool of potential unvaccinated matches for older vaccine recipients, owing to high vaccination rates in the older population.

The Times of Israel reported on January 15 on a survey conducted by the Maccabi health fund of the first 600 people in the country to get their second vaccine dose.

Seventy percent of those surveyed reported some pain at the injection site or such effects as fever, nausea, or dizziness within the first 72 hours after getting the shot. There were 13 reported cases of Bell’s palsy. Three people reported a bitter metallic taste in the mouth, two had breathing difficulties and one person fainted.

According to statistics released by Israel’s health ministry on January 14, 1,127 of nearly two million people vaccinated filed reports about adverse effects, most of which the ministry described as minor. The most common side effects reported were weakness, dizziness, headaches, and fever, the ministry said.

The health ministry found that 82,567 people were infected with SARS-CoV-2 within a week of getting their first vaccine dose and the number dropped to 4,500 after 15 days, The Times of Israel reported.

Reports of adverse reactions

The Israeli People`s Committee, which is an independent citizens’ group that includes doctors, attorneys, and researchers from various disciplines, said in its report updated with data up to August 5, 2021, that it had received 484 reports of deaths occurring in proximity to Covid vaccination. A total 227 of these reports were of “sudden death”, 170 were from “cardiac arrest/heart attack”, 22 were deaths from a stroke, 19 were deaths from Covid-19 after vaccination, and six were deaths from multi-system failure.

The committee says it has already received reports about deaths occurring very soon after administration of booster (third) vaccine doses.

The people’s committee had said in its report published on April 25 that it had received 309 reports of deaths occurring in proximity to Covid vaccination.

In its previous report, also published in April, in which it cited 288 deaths, the committee said that 90% of those deaths occurred up to 10 days after vaccination and 64% of those who died were men.

“According to the Ministry of Health’s figures: only 45 deaths occurred in proximity to the vaccination,” the committee said.

“According to data from the Central Bureau of Statistics (CBS), during January–February 2021, in the midst of the vaccination operation, there was a 22% increase in overall mortality in Israel compared to the bi-monthly average mortality in the previous year.

“The period of January–February 2021 is the deadliest one in the last decade, with the highest overall mortality rates, when compared to the corresponding months over the last 10 years.”

Among the 20–29 age group, the increase in the mortality rate was even more dramatic, the committee said. “In this group, during the same vaccination period, January–February 2021, there has been a 32% increase in overall mortality compared to the bi-monthly average mortality in 2020,” the committee said.

“A statistical analysis of data from the CBS combined with information from the Ministry of Health leads to the conclusion that the mortality rate amongst the vaccinated is estimated at 1:5,000 (1:13,000 for ages 20–49, 1:6,000 for ages 50–69, 1:1600 for ages 70+).”

The people’s committee has concluded that the risk of death after the second vaccine dose is higher than the risk after the first dose.

In its report updated to include data up to August 5, the committee said it had received 3,754 reports of adverse events after Covid vaccination (3,454 analysed and 300 others received, but not yet analysed).

In its report updated on April 25, the committee had said it had received 2,256 reports of adverse events after Covid vaccination (1,956 analysed and 300 others received, but not yet analysed).

“These reports indicate damage to almost every system in the human body,” the committee stated.

“These figures also highlight the inconceivable gap between official Israeli media reports and what is actually happening, enabling a ‘two worlds’ situation …”

The committee said it had registered a “relatively high” rate of cardiac-related injuries after Covid vaccination.

“Twenty-six percent of all cardiac events occurred in young people below the age of 40, the most common diagnosis in these cases being myocarditis or pericarditis,” the committee said.

The committee also reported a high prevalence of what it describes as “massive vaginal bleeding” and reports of neurological, skeletal, and skin damage.

“It should be noted that a significant number of adverse events reported are related, directly or indirectly, to coagulopathy (myocardial infarction, stroke, miscarriages, disruption of blood flow to the limbs, and pulmonary embolism),” the committee added.

“The reporting of adverse events from hospitals and HMO [health maintenance organisation] clinics has been very low, and there is a tendency for a diagnostic bias that excludes the possibility of a link between the adverse events and the vaccination.”

The committee also listed 178 reports of pain, including 44 reports of extreme headache, and a total 246 reports of lymphadenopathy (swollen or enlarged lymph nodes), syncope (fainting), extreme fatigue, a reduced ability to perform daily activities, or mental disorders.

Vaccination incentives

It was reported in the Israeli media in February 2021 that demand for Covid vaccination had plummeted. The Times of Israelreported on February 9 that the health ministry had been aiming to carry out 200,000 vaccinations per day, but demand was running at barely half that total so the ministry and some companies were looking at ways to incentivise Israelis to get vaccinated.

 

Promising treatment results

The promising results in Israel of small trials of two drugs that combat the immune-cell hyperactivation and inflammatory response (cytokine storm) that can occur in patients with Covid-19 have revived the argument that developing successful treatments is preferable to mass vaccination.

A cytokine storm is an immune response in which the body starts to attack its own cells and tissues rather than just fighting off the virus.

There is also increasing evidence that ivermectin is successful as a treatment, but the results of a Phase 1 trial of the drug EXO-CD24, which has been used to treat moderate-to-serious cases of Covid-19, are a breakthrough that has hit the mainstream headlines. Thirty patients given the treatment all recovered, 29 of them within three to five days..

EXO-CD24 uses exosomes to deliver the CD24 protein called to the lungs. “The preparation is inhaled once a day for a few minutes, for five days,” Nadir Arber from Tel Aviv’s Ichilov Medical Centre told The Times of Israel. “EXO-CD24 is administered locally, works broadly and without side effects.”

There have also been promising results from a small Phase 2 trial of the drug Allocetra, which is also used to combat the cytokine storm in Covid-19 patients. Israel’s Channel 13 reported that 90% of twenty seriously ill patients treated with the drug recovered.

The drug is now entering Phase 3 trials and will be given to more than 100 people.

One patient, 49-year-old Yair Tayeb, who has now been discharged from hospital, told Channel 13: “They gave me the drug. Suddenly after two hours I started feeling something strange in my body. I stopped coughing, my breathing started to come back, I was feeling better. I stopped sweating. I couldn’t believe it. I was afraid to tell people I was okay, I was so excited.”

‘We need the raw data’

In an article published on January 4, 2021, Peter Doshi said he had new concerns about the trustworthiness and meaningfulness of the efficacy results published by Pfizer and Moderna: “We need more details and the raw data,” Doshi wrote.

Doshi noted that two journal publications and about 400 pages of summary data were available in the form of multiple reports presented by and to the FDA. “While some of the additional details are reassuring, some are not,” Doshi said.

Pfizer reported 170 PCR-confirmed Covid-19 cases, split eight to 162 between the vaccine and placebo groups, he notes, but these numbers were dwarfed by cases of “suspected covid-19” – people with symptomatic Covid-19 that was not PCR confirmed.

According to the FDA’s report about the Pfizer vaccine, there were 3,410 total cases of suspected, but unconfirmed Covid-19 in the overall study population. A total 1,594 occurred in the vaccine group and 1,816 in the placebo group.

With twenty times more suspected than confirmed cases, this category of disease cannot be ignored simply because there was no positive PCR test result,” Doshi wrote. “Indeed this makes it all the more urgent to understand.”

“A rough estimate of vaccine efficacy against developing covid-19 symptoms, with or without a positive PCR test result, would be a relative risk reduction of 19% – far below the 50% effectiveness threshold for authorisation set by regulators.

“Even after removing cases occurring within seven days of vaccination (409 on Pfizer’s vaccine vs. 287 on placebo), which should include the majority of symptoms due to short-term vaccine reactogenicity, vaccine efficacy remains low: 29%.”

Doshi said that an analysis of severe disease irrespective of etiologic agent – namely, rates of hospitalisations, ICU cases, and deaths amongst trial participants – seemed warranted, and was “the only way to assess the vaccines’ real ability to take the edge off the pandemic”.

Pfizer didn’t mention the 3,410 suspected Covid-19 cases in its 92-page report or its article in the New England Journal of Medicine, Doshi noted. “The only source that appears to have reported it is FDA’s review of Pfizer’s vaccine.”

Referring to the trial results reported by Pfizer and Moderna, Doshi wrote in his opinion piece published on November 26 that the results referred to the trials’ primary endpoint of Covid-19 of essentially any severity, “and importantly not the vaccine’s ability to save lives, nor the ability to prevent infection, nor the efficacy in important subgroups (e.g. frail elderly)”. Those, Doshi wrote, remained unknown.

He said the results reflected a time point relatively soon after vaccination, adding “we know nothing about vaccine performance at three, six, or 12 months, so cannot compare these efficacy numbers against other vaccines like influenza vaccines (which are judged over a season)”.

Children, adolescents, and immunocompromised individuals were largely excluded from the trials, so data was still lacking about these important populations, Doshi wrote.

Doshi argued that the trials studied the wrong endpoint, and said there was an urgent need to correct course and study more important endpoints like the prevention of severe disease and transmission in high- risk people.

“Yet, despite the existence of regulatory mechanisms for ensuring vaccine access while keeping the authorisation bar high (which would allow placebo-controlled trials to continue long enough to answer the important question), it’s hard to avoid the impression that sponsors are claiming victory and wrapping up their trials,” Doshi wrote.

Doshi also questions the way decisions were taken about which trial participants should be tested for SARS-CoV-2 infection. The trial protocols for Moderna and Pfizer’s studies contain explicit language instructing investigators to use their clinical judgment to decide whether to refer people for testing, he says.

“In a proper trial, all cases of Covid-19 should have been recorded, no matter which arm of the trial the case occurred in. (In epidemiology terms, there should be no ascertainment bias, or differential measurement error.),” Doshi wrote.

”… if referrals for testing were not provided to all individuals with symptoms of Covid-19 – for example because an assumption was made that the symptoms were due to side-effects of the vaccine – cases could go uncounted.”

Also, Doshi says, if people in the vaccine arm of the trials took pain and fever reducing medicines prophylactically more often or for a longer duration of time than those in the placebo arm, this could have led to greater suppression of Covid-19 symptoms following SARS-CoV-2 infection in the vaccine arm, translating into a reduced likelihood of being suspected of having Covid-19, a reduced likelihood of testing, and a reduced likelihood of meeting the primary endpoint.

In an article published on December 11, Maryanne Demasi from The Institute for Scientific Freedom in Denmark said there were also some outstanding unknowns about the Pfizer vaccine.

“How long will immunity last? Is the vaccine safe and efficacious for children under 16 years of age, or for the elderly (the group with the highest fatality risk)? And will the vaccine prevent community transmission of the virus?,” Demasi wrote.

“Those with antibodies to SARS-CoV-2 were excluded from participating in the trial. It is not understood, therefore, how the vaccine might affect people who have already been exposed to Covid-19, which could be substantial.”

In a BMJ article published on October 21, 2020, Doshi wrote: “None of the trials currently under way are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths. Nor are the vaccines being studied to determine whether they can interrupt transmission of the virus.”

Demasi wrote: “The data for the Pfizer vaccine suggests that the benefits outweighs its harms, but this is still short-term data (only two months). On the first day of rolling out the Pfizer vaccine in the UK, two NHS workers experienced an ‘anaphylactoid reaction’ shortly after receiving the jab, causing the UK regulator to issue a warning that people with a history of allergic reactions should not be vaccinated.

“It’s not surprising; people with a history of severe allergic reactions such as anaphylaxis were excluded from the original studies, a common problem when trials do not recruit participants that reflect ‘real world’ populations.”

Writing for the Mises Wire, Gilbert Berdine, who is an associate professor of medicine at the Texas Tech University Health Sciences Centre in the US, talked about “what the Covid vaccine hype fails to mention”.

Commenting about the Pfizer-BioNTech and Moderna trials, he wrote: “There was no information about the cycle number for the PCR tests. There was no information about whether the ‘cases’ had symptoms or not. There was no information about hospitalisations or deaths.”

Berdine added: “The Moderna announcement claimed that eleven cases in the control group were ‘severe’ disease, but ‘severe’ was not defined. If there were any hospitalisations or deaths in either group, the public has not been told.

“When the risks of an event are small, odds ratios can be misleading about absolute risk. A more meaningful measure of efficacy would be the number to vaccinate to prevent one hospitalisation or one death. Those numbers are not available.”

Berdine said he had asked a number of his colleagues, who include resident physicians and faculty physicians who work with Covid patients on a daily basis. whether they would be first in line for the new vaccine and he had yet to hear any of them respond affirmatively.

“The reasons for hesitancy are that the uncertainties about safety exceed what they perceive to be a small benefit,” Berdine wrote. “In other words, my colleagues would prefer to take their chances with Covid rather than beta test the vaccine.

“Many of my colleagues want to see the safety data after a year of use before getting vaccinated; these colleagues are concerned about possible autoimmune side effects that may not appear for months after vaccination.”

Trials halted twice because of illness

On September 6, 2020, AstraZeneca, halted all trials of its AZD1222 vaccine, which was previously designated as ChAdox1 nCoV-19, because one of the participants in the Phase 3 trial in the UK had what was initially described as “an unexplained illness”.

It was later reported that the participant who became ill experienced neurological symptoms consistent with the spinal inflammatory disorder transverse myelitis.

After an investigation, regulators approved the resumption of trials of the AstraZeneca vaccine in the US, the UK, Brazil, South Africa, India, and Japan.

AstraZeneca said that suspension of the trials of its vaccine was a “routine action” that had to happen whenever there was a potentially unexplained illness in one of the trials.

“On 6 September, the standard review process triggered a voluntary pause to vaccination across all global trials to allow review of safety data by independent committees, and international regulators,” the company said.

The American TV station CNN said it obtained an initial internal safety report by AstraZeneca that stated that the study volunteer, a previously healthy 37-year-old woman, “experienced confirmed transverse myelitis” after receiving her second dose of the AZD1222 vaccine, and was hospitalised on September 5.

According to CNN, the document describes how the study participant had trouble walking and suffered weakness and pain in her arms and other symptoms.

The internal safety report is dated September 10, and, on September 11, it was sent out to doctors running the study’s clinical trial sites, CNN reported on September 17.

The news of the suspension of the trials of the AstraZeneca vaccine was first reported on the STAT news website.

STAT journalist Adam Feuerstein reported that the participant who became ill experienced neurological symptoms consistent with transverse myelitis.

Feuerstein said this was revealed by Pascal Soriot during a private conference call with investors.

The journalist said Soriot told investors that the board tasked with overseeing the data and safety components of the AstraZeneca clinical trials confirmed that the participant who became ill was injected with the vaccine, not a placebo.

Soriot also confirmed that the clinical trial was halted once previously, in July, after a participant experienced neurological symptoms, Feuerstein reported. Soriot said that, upon further examination, that participant was diagnosed with multiple sclerosis, deemed to be unrelated to the Covid-19 vaccination, Feuerstein added.

The trial participant information sheet dated July 12, 2020, states that the person who became ill “developed symptoms of transverse myelitis …, which has not required medical treatment and is being investigated, though the cause is uncertain”.

An August update of the information sheet removed the reference to transverse myelitis and said the participant developed neurological symptoms that caused the study to be paused, and that the volunteer was later diagnosed with what was described as “an unrelated neurological illness”.

AstraZeneca said on October 23 that clinical trials of its Covid vaccine had resumed across the world. The company gave no explanation about the illness that triggered the halt in the trials.

The company had earlier announced that the trials had restarted in the UK after the MHRA stated that it was safe to resume the testing.

The UK committee had concluded its investigations and had recommended to the MHRA that it was safe to resume the UK trials, the company said, adding that it could not disclose further medical information relating to the trial participant’s illness.

In its statement about the suspension of the trials, Oxford University said: “We cannot disclose medical information about the illness for reasons of participant confidentiality.”

The university added: “Globally some 18,000 individuals have received study vaccines as part of the trial. In large trials such as this, it is expected that some participants will become unwell and every case must be carefully evaluated to ensure careful assessment of safety.

“The independent review process has concluded and following the recommendations of both the independent safety review committee and the UK regulator, the MHRA, the trials will recommence in the UK.”

Anvisa said on October 21 that a volunteer in the trial of the AstraZeneca vaccine in Brazil had died. Comments reported by the Reuters news agency suggest that the volunteer received the meningitis control vaccine, not AZD1222.

CNN Brasil reported that the volunteer was a 28-year-old man who lived in Rio de Janeiro and died from Covid-19 complications.

An AstraZeneca spokesperson said that all significant medical events were carefully assessed by trial investigators, an independent safety monitoring committee, and regulatory authorities. These assessments had not led to any concerns about continuation of the study in Brazil, the company spokesperson said.

Cases of transverse myelitis, in which an immune-mediated process causes neural injury to the spinal cord, have been triggered by vaccination, but the disorder can also be caused by viral infections.

Johnson & Johnson also paused trials

Johnson & Johnson said it paused trials of its Covid vaccine because of “an unexplained illness in a study participant”.

The company said on October 12: “We have temporarily paused further dosing in all our Covid-19 vaccine candidate clinical trials, including the Phase 3 ENSEMBLE trial, due to an unexplained illness in a study participant.

“Following our guidelines, the participant’s illness is being reviewed and evaluated by the ENSEMBLE independent Data Safety Monitoring Board as well as our internal clinical and safety physicians.”

Johnson & Johnson said on October 23 that, after review, it was preparing to resume recruitment to the Phase 3 ENSEMBLE trial in the US.

“The independent Data Safety and Monitoring Board overseeing the ENSEMBLE study has recommended resuming trial recruitment,” the company said.

Johnson & Johnson said that, “after a thorough evaluation of a serious medical event experienced by one study participant”, no clear cause had been identified.

“There are many possible factors that could have caused the event. Based on the information gathered to date and the input of independent experts, the company has found no evidence that the vaccine candidate caused the event,” Johnson & Johnson added.

The company states that adverse events (“illnesses, accidents, etc.”) – and even those that are serious – “are an expected part of any clinical study, especially large studies”.

It distinguishes between a study pause, which is what is occurring in the case of the the JNJ-78436735 vaccine, and a “regulatory hold”.

In the case of a study pause, recruitment or dosing is paused by the study sponsor, and is a standard component of a clinical trial protocol, Johnson & Johnson says.

“While the company informs all study investigators, we typically do not communicate study pauses publicly.”

The director of the Drug Safety Research Unit (DSRU) in Britain, Saad Shakir, said after the Johnson & Johnson trials were halted that serious adverse events were expected in a clinical trial that included 60,000 vaccinees.

Shakir said that the Data Safety Monitoring Board (DSMB) couldn’t say whether the event occurred in a person who received the active vaccine or the comparator because divulging this would compromise the blinding of the study and it could not announce the clinical details of the adverse event for confidentiality reasons.

“The description of the event as an ‘unexplained illness’ is interesting and somewhat unusual. They are likely to be investigating its nature in detail, in collaboration with the doctors who are treating the patient,” Shakir said. “Given the description ‘unexplained illness’, an educated guess is that it could be an event that affected the nervous system, though this is by no means certain.

“While the monitoring board looks for causality when assessing serious adverse events, it is acknowledged that regulators or members of the DSMB may be forced to act even in the absence of a definite causal relationship.”

Russia

On February 4, 2022, the RDIF announced that the Sputnik V vaccine had been granted full permanent approval by Russia’s health ministry.

It was previously being administered under temporary emergency use authorisation.

Initially registered by the Russian Ministry of Health on August 11, 2020, Sputnik V was the world’s first Covid-19 vaccine to be granted emergency use authorisation. At that time it had only undergone Phase 1 and Phase 2 clinical trials involving just 76 participants in total.

On September 8, the health ministry said the first batch of the vaccine had passed the necessary quality tests in the Roszdravnadzor laboratories and had been released into civil circulation.

Sputnik V has now been authorized in 71 countries and Sputnik Light is authorised in more than 30 countries, both as a standalone vaccine and a booster to other vaccines.

The RIDF said that a comparative study conducted at Lazzaro Spallanzani National Institute for Infectious Diseases in Italy by a team of 12 Italian and nine Russian scientists had shown that Sputnik V demonstrated more than two times higher titers of virus neutralising antibodies to Omicron (B.1.1.529) than two doses of the Pfizer-BioNTech vaccine (2.1 times higher in total and 2.6 times higher three months after vaccination.

“The study was conducted in equal laboratory conditions on comparable sera samples from inpiduals vaccinated with Sputnik V and Pfizer with a similar level of IgG antibodies and virus neutralizing activity against the Wuhan variant,” the RIDF said.

“Sputnik V showed significantly smaller (2.6 times) reduction of virus neutralising activity against Omicron as compared to the reference Wuhan variant than the Pfizer vaccine (8.1-fold reduction for Sputnik V in contrast to 21.4-fold reduction for the Pfizer vaccine).”

The RIDF added that preliminary study by researchers from the Gamaleya centre found that, when used as a booster, Sputnik Light significantly increased virus-neutralising activity against Omicron.

A study in Argentina on heterogeneous regimens combining Sputnik Light and vaccines produced by AstraZeneca, Sinopharm, Moderna, and Cansino had demonstrated that each “vaccine cocktail” combination with Sputnik Light provided higher antibody titers on the 14th day after administering the second dose as compared to the original homogenous regimens (using the same vaccine for the first and second doses) of each of the other vaccines, the RIDF said.

On April 19, 2021, the Gamaleya centre and the RDIF had announced that Sputnik V demonstrated efficacy of 97.6%.

They said the conclusion was based on the analysis of data about the SARS-CoV-2 infection rate among Russians vaccinated with two doses of Sputnik V.

According to the data from 3.8 million Russians vaccinated with two doses of Sputnik V between December 5, 2020, and March 31, 2021, the infection rate starting from the 35th day from the date of the first injection was 0.027%.

Over the same period, and starting from the 35th day after the launch of mass vaccination in Russia, the infection rate among the unvaccinated adult population was reported to be 1.1%.

The following formula was used to calculate the vaccine’s efficacy:

Alexander Gintsburg, said: “The actual efficacy of the Sputnik V vaccine may be even higher than the results of our analysis demonstrate since the data on the case registration system allows a time lag between the collection of the sample (the actual date of the disease) and the diagnosis.”

In a report published in The Lancet on February 2, 2021, Denis Y. Logunov et al. had said that, in an interim analysis of a Phase 3 clinical trial, Sputnik V had 91.6% efficacy against Covid-19.

That percentage is slightly higher than the 91.4% announced by the Gamaleya research centre and the RDIF on December 14, 2020.

Both calculations were based on an analysis of 78 confirmed cases of Covid-19 (62 cases in the placebo group and 16 in the vaccinated group).

The data reported upon on February 2 relates to 19,866 volunteers who received two doses of the Sputnik V vaccine or a placebo.

“Efficacy in the elderly group of 2,144 volunteers over 60 years old was 91.8% and did not differ statistically from the 18-60 group,” the researchers reported.

From 21 days after the first dose of vaccine (the day of dose 2), 16 of 14,964 participants in the vaccine group and 62 of 4,902 in the placebo group were confirmed to have Covid-19, Logunov et al. report, so vaccine efficacy was shown to be 91·6%.

Ninety-four percent of the reported adverse events were mild and included flu-like syndromes, injection site reactions, headache and asthenia, Logunov et al. reported.

Forty-five of 16,427 participants in the vaccine group and 23 of 5,435 participants in the placebo group had serious adverse events, but none were considered associated with vaccination, and this was confirmed by the independent data monitoring committee, they said. There were no reported cases of anaphylactic shock.

The twenty confirmed severe cases of Covid-19 were all recorded in the placebo group.

Four deaths were reported during the study (three of 16 427 participants in the vaccinated group and one of 5,435 participants in the placebo group). None of the deaths were considered to be related to the vaccine, Logunov et al. said.

The researchers said that more than 98% of the trial participants developed humoral immune response and 100% – cellular immune response.

“The level of virus neutralising antibodies of volunteers vaccinated with Sputnik V is 1.3–1.5 times higher than the level of antibodies of patients who recovered from Covid-19, they added.

In a linked comment published in The Lancet, Ian Jones and Polly Roy said that the vaccine efficacy, based on the numbers of confirmed Covid-19 cases from 21 days after the first dose, and the suggested lessening of disease severity after one dose was “particularly encouraging for current dose-sparing strategies.”

More than 200,000 people had already been vaccinated against Covid-19 as part of Russia’s mass vaccination programme, which began in September alongside the Moscow-based trial.

The two vectors being used in Sputnik V, which is also known as Gam-COVID-Vac, are a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for the SARS-CoV-2 spike glycoprotein.

Logunov says that, if there is booster vaccination that uses the same adenovirus vector, the immune system may recognise and attack the vector. The Russians used two vectors to try and avoid this.

The RDIF said that the cost of the Sputnik V vaccine for international markets would be less than $10 per dose.

Russia 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.

A whole-virion inactivated vaccine has also been developed at the Chumakov Federal Scientific Centre for the Research and Development of Immune and Biological Products.

The US, British, and Canadian governments accused Russia of using hackers to steal vaccine research from Western labs. Russia denied the allegation.

Phase 1 and 2 non-randomised clinical trials of the two formulations (frozen and freeze-dried) of the two-part Sputnik V vaccine were completed on August 1. Results from the two 42-day trials were published on September 4, 2020, in The Lancet.

The frozen formulation of Sputnik V was envisaged for large-scale use using the existing global supply chains for vaccines while the freeze-dried formulation was developed for hard-to-reach regions as it is more stable and can be stored at 2–8 degrees Celsius.

In January 2021 the Russian Ministry of Health authorised the storage and transportation of a new liquid formulation of the vaccine at 2–8 degrees Celsius.

In February, Alexander Gintsburg said storage of the liquid vaccine at 2–8 degrees Celsius was allowed for just two months, but developers hoped to extend this to six months.

Naor Bar-Zeev and the director of the Center for Health Security at the Johns Hopkins Bloomberg School of Public Health, Tom Inglesby, wrote a linked comment about the September 4 report. Neither commentator was involved in the study.

They said that the studies carried out by Logunov and his colleagues were encouraging, but small.

“The immunogenicity bodes well, although nothing can be inferred on immunogenicity in older age groups, and clinical efficacy for any Covid-19 vaccine has not yet been shown.”

They added: “Unlike clinical trials of therapeutics, in which safety is balanced against benefit in patients, vaccine trials have to balance safety against infection risk, not against disease outcome. Since vaccines are given to healthy people and, during the Covid-19 pandemic, potentially to everyone after approval following Phase 3 trials, safety is paramount.”

Bar-Zeev and Inglesby said that licensure in most settings should depend on proven short-term and long-term efficacy against disease, not just immunogenicity, and more complete safety data.

Surveillance would be vital for showing transmission reduction, the two scientists said, adding that, with Covid-19, the general public could expect striking reductions in disease transmission after widespread vaccine introduction.

“Such effects would be very welcome if they occur, but they are far from certain,” the scientists said. “A vaccine that reduces disease but does not prevent infection might paradoxically make things worse. It could falsely reassure recipients of personal invulnerability, thus reducing transmission mitigating behaviours.

“In turn, this could lead to increased exposure among older adults in whom efficacy is likely to be lower, or among other higher-risk groups who might have lower vaccine acceptance and uptake.”

On October 17, 2020, the Russian Direct Investment Fund and the Indian multinational pharmaceutical company Dr Reddy’s Laboratories announced that they had received approval from the Drugs Controller General of India to conduct an adaptive Phase 2/3 clinical trial for the Sputnik V vaccine in India.

Under the partnership agreement signed by Dr Reddy’s and the RDIF in September 2020, the RDIF was to supply 100 million doses of the vaccine to Dr Reddy’s upon regulatory approval in India.

The RDIF and one of the leading pharmaceutical groups in Egypt, Pharco (acting through its key operational subsidiary, Biogeneric Pharma), agreed that 25 million doses of the Sputnik V vaccine would be supplied to Egypt.

On April 5, 2021, the RDIF and Panacea Biotec in India announced that they would cooperate to produce 100 million doses per year of Sputnik V.

The RDIF also agreed to supply up to 35 million doses of the Sputnik V vaccine to Uzbekistan.

Also subject to approval by the country’s regulators, the RDIF agreed to supply 32 million doses of Sputnik V to Mexico.

India

Twelve Covid vaccines have been approved by the Drugs Controller General of India.

Covaxin, which is manufactured by Bharat Biotech, and Covishield, which is manufactured by the Serum Institute of India (SII), were the first vaccines to be approved by the Drugs Controller General of India.

The other approved vaccines are Covovax (Nuvaxovid), manufactured by the SII; Corbevax, manufactured by Biological E.; the Sputnik V vaccine, Sputnik Light; Moderna’s Spikevax; ZyCoV-D, manufactured by Zydus Cadila; GEMCOVAC-19, manufactured by Gennova Biopharmaceuticals; iNCOVACC, manufactured by Bharat Biotech; Jcovden, manufactured by Janssen; and the AstraZeneca-Oxford vaccine that is branded as Vaxzevria.

ZyCoV-D is a three-dose plasmid DNA vaccine that is administered using a needle-free system in which an injector delivers the vaccine using a narrow stream of fluid to penetrate the skin. The authorisation was issued for use for children and adults aged 12 years and above.

Zydus Cadila, which is headquartered in Ahmedabad, conducted clinical trials of ZyCoV-D in more than 50 centres. This included testing the vaccine in about 1,000 trial participants aged 12–18 years. Zydus Cadila said on July 1 that “the tolerability profile was similar to that seen in the adult population”.

Zydus Cadila said that, in an interim analysis of results of a Phase 3 trial involving more than 28,000 participants, ZyCoV-D had been shown to have 66.6% efficacy against symptomatic Covid-19.

The company said no moderate cases of Covid-19 were observed in the vaccine arm of the trial after the third dose, suggesting 100% efficacy against moderate Covid-19.

“No severe cases or deaths due to Covid-19 occurred in the vaccine arm after administration of the second dose of the vaccine,” the company said.

Zydus Cadila has also evaluated a two-dose regimen for ZyCoV-D, using three-milligram doses, and says the immunogenicity results were equivalent to those of the three-dose regimen.

The DCGI has authorised Bharat Biotech to test Covaxin on children and teenagers aged two to 18 years.

Bharat Biotech is also reported to have been authorised to give some trial participants a third dose of its Covid vaccine as a booster six months after the second dose.

The SEC recommended that the booster should only be given to participants in the Phase 2 trial who received six-microgram doses of the antigen, local media reported.

On November 1, 2021, Novavax and the SII announced that Indonesia’s National Agency of Drug and Food Control had granted emergency use authorisation for Nuvaxovid, which the SII is manufacturing in India and markets in Indonesia under the brand name Covovax.

The Philippine Food and Drug Administration has also granted emergency use authorisation for Covovax.

Pfizer withdrew an application for emergency use authorisation of its Covid vaccine in India, Reuters reported on February 5.

Based on the deliberations at a meeting with India’s drugs regulator, and Pfizer’s understanding that the regulator may need additional information, the company had decided to withdraw its application for now, Pfizer told Reuters.

Pfizer added that it would continue to engage with the regulator and resubmit its approval request with additional information as it becomes available in the near future.

The Central Drugs Standard Control Organisation (CDSCO) had declined to accept Pfizer’s request for approval without a small local bridging trial to test the vaccine’s safety and immunogenicity for Indians, Reuters reported.

India has sent Covishield to several other countries, including Bhutan, the Maldives, Bangladesh, Sri Lanka, Brazil, and Nepal.

Covaxin

Releasing the results of its phase 3 trial of Covaxin, Bharat Biotech said the vaccine had 93.4% general efficacy against severe infection and provided 65.2% protection against the Delta variant. The results were published as a preprint on medRxiv on July 2, 2021.

The study was funded by Bharat Biotech and the ICMR. One of the co-authors is the chairman and managing director of Bharat Biotech, Krishna Ella, and another is his son, Raches Ella, who is the company’s head of business development and advocacy.

Between November 16, 2020, and January 7, 2021, 12,221 trial participants received two doses of Covaxin (BBV152) and 12,198 received a placebo. The trial was conducted over 25 sites in India and involved participants aged between 18 and 98 years.

A total 130 cases of symptomatic Covid-19 were reported in 16,973 participants (0.77%) with follow-up at least two weeks after the second vaccination. Twenty-four cases occurred in the vaccine group and 106 in placebo recipients. This gives an overall vaccine efficacy of 77.8% (95% CI: 65.2, 86.4), Raches Ella et al. report.

Sixteen cases of severe symptomatic Covid-19 were reported (one in the vaccine group and 15 among the placebo recipients). This gave a vaccine efficacy of 93.4% (57.1, 99.8), Ella et al. said.

Efficacy against asymptomatic Covid-19 was 63.6% (29.0, 82.4), the researchers added.

“BBV152 conferred 65.2% (95% CI: 33.1, 83.0) protection against the SARS-CoV-2 Variant of Concern, B.1.617.2 (Delta),” they wrote.

There were 15 deaths during the trial, none of which were considered by the investigators to be related to the vaccine or the placebo. Six deaths were reported to be related to Covid-19.

“In BBV152 recipients there were five deaths all due to causes unrelated to vaccination: cerebellar haemorrhage, haemorrhagic stroke, ovarian cancer with metasases, sudden cardiac death, and Covid-19,” Ella et al. report.

“Ten placebo recipients died, also from unrelated conditions: alcohol overdose, myocardial infarction, cardiac arrest with underlying hypertension, five from Covid-19 and two which remain to be determined. No anaphylactic events were reported.”

Ella et al. say a total of 79 variants were reported from 16,973 samples (18 in the vaccine group and 61 in the placebo group).

“Among 50 Delta (B.1.617.2) positive-confirmed cases, 13 and 37 participants were in the vaccine and placebo arms, resulting in vaccine efficacy of 65.2% (95% CI: 33.1–83.0),” the researchers wrote.

“In breakthrough symptomatic Delta variant infections, based on Ct values, the viral load in the vaccine arm was significantly lower than the placebo arm.”

Efficacy against the Kappa (B.1.617.1) variant was 90.1% (95% CI: 30.4–99.8), the researchers say.

No cases of severe variant-related cases of Covid-19 were reported in the vaccinees but four severe cases were reported in the placebo recipients, who were infected with Alpha, Kappa, Delta, or unclassified variants.

“As previously reported, BBV152-induced antibodies show no significant decrease in neutralisation activity against the Alpha (B.1.1.7) variant, but demonstrate marginal reductions in neutralisation activity, by 2-, 2-, 3-, and 2.7-fold, respectively, of the B.1.1.28, B.1.617.1, B.1.351 (Gamma), and B.1.617.2 (Delta) variants,” Ella et al. reported.

Ella et al. say that vaccination with BBV152 was well tolerated “with an overall incidence of adverse events observed over a median of 146 days that was lower than that observed with other Covid-19 vaccines”.

Serious adverse events occurred in 99 participants, the researchers wrote. Thirty-nine of these participants were in the vaccine group and sixty received the placebo.

“Two related serious adverse events were reported among BBV152 recipients,” the researchers added. “Long-term safety monitoring will continue for one year after administration of the first dose of BBV152.”

Overall, incidence rates were lower after the second dose than the first, and tended to be slightly higher in the BBV152 group than in the placebo group. However, all incidence rates were low, with only 12·4% reporting any solicited adverse events after receiving the vaccine or the placebo, Ella et al. wrote.

The most frequent solicited systemic adverse event overall was headache, followed by pyrexia, fatigue, and myalgia, but at incidences below 1% in both groups, the researchers said.

Rates of local and systemic adverse events reported in the BBV152 group as mild (11.2%), moderate (0.8%), or severe (0.3%) were comparable to those in the placebo group: mild (10.8%), moderate (1.1%), and severe (0.4%), they added.

The researchers said their study had several limitations. Due to the low number of Covid-19 cases reported between doses one and two, they could not calculate vaccine efficacy after a single dose, they said.

“This report contains a median safety follow-up of 146 days for all participants, so long-term safety follow-up of BBV152 is required and is currently underway,” they added.

“The data presented on efficacy against variants other than Delta must be considered preliminary as the numbers reported are small. Additional efforts to assess the clinical efficacy of BBV152 against VoC are being planned.”

In the Phase 2 trial of Covaxin, two formulations of BBV152 were used. Ella et al. reported in a preprint published on medRxiv on December 22 that the Phase 1/2 data showed that levels of neutralising antibodies in those who received one of the two formulations were similar to those in people who had recovered from Covid-19.

Half of the 380 volunteers (healthy children and adults aged 12 to 65 who had tested negative for SARS-CoV-2) received three micrograms of the antigen and half received six micrograms. Two five-millilitre doses were administered four weeks apart. Covaxin incorporates the adjuvant Algel-IMDG, which is an imidazoquinoline molecule chemisorbed on alum (Algel) that is designed to traffic vaccine antigen directly to draining lymph nodes without diffusing into the systemic circulation.

The imidazoquinoline molecule, which is a toll-like receptor (TLR) 7/8 agonist, is used to stimulate cell-mediated responses. Alum does not itself have the ability to induce cell-mediated responses.

Ella et al. reported that, among the trial participants who received the three-microgram formulation, 92.9% developed neutralising antibodies on day 56 and, among those given the six-microgram formulation, the percentage was 98.3%.

The responses of those who received the six-microgram formulation with Algel-IMDG were comparable to those observed in convalescent serum collected from patients who had recovered from Covid-19, Ella et al. said.

The six microgram with Algel-IMDG vaccine formulation was selected for the Phase 3 efficacy trial.

Ella et al. reported that, after two vaccine doses, 9.7% of those in the group who received the three-microgram vaccine formulation experienced “solicited local and systemic adverse reactions”. Among those who received the six-microgram formulation the percentage was 10.3%. Most adverse reactions resolved within 24 hours of onset, the researchers said, and no serious adverse events were reported.

Adverse events included pain and swelling at the injection site, fever, fatigue, malaise, muscle pain, body aches, headache, nausea, vomiting, anorexia, chills, a generalised rash, and diarrhoea.

On January 21, Ella et al. published a paper in The Lancet about the Phase 1 trial of BBV152. The paper is a peer-reviewed, and more detailed, version of a pre-print that was published on medRxiv on December 15.

The Indian Council of Medical Research and others were accused of putting a spin on the Phase 1 trial results.

In an article in The Wire, public health physician, independent researcher, and epidemiologist Jammi Nagaraj Rao, who is based in the UK, said that much of the report’s contents were known already, but added “as disinformation campaigns go, this one takes the biscuit”.

On January 23, The Times of India published a story under the headline ‘Amid efficacy row, Covaxin gets thumbs-up from Lancet’, Rao noted.

The ICMR took to Twitter to exclaim that the Phase 1 trial results were “remarkable”.

.@TheLancetInfDis publishes findings from trial of inactivated SARS-CoV-2 vaccine, BBV152 developed by @BharatBiotech & ICMR. @TheLancet @MoHFW_INDIA @DeptHealthRes Read more: https://t.co/KKZJOf6Ew1 pic.twitter.com/ZCfu2pfOwb

— ICMR (@ICMRDELHI) January 22, 2021

The ICMR’s director-general, Balram Bhargava, is one of the report’s authors.

The Phase 1 trial involved 375 volunteers in 11 centres around India. Groups of 100 participants received one of three vaccine formulations and 75 were randomly assigned to the control group, who received only the Algel adjuvant.

In the Phase 1 trial, more than 80% of patients in each vaccine group seroconverted, with at least a four-fold increase in binding antibody titres, Ella et al. reported.

In a linked commentary, Christina Rostad and Evan Anderson from the Emory University School of Medicine in Atlanta in the US said that, despite favourable Phase 1 results, concerns lingered about the potential for an inactivated whole-virus vaccine to elicit antibody-dependent enhancement of infection or vaccine-associated enhanced respiratory disease if the vaccinee was later infected with SARS-CoV-2.

“Both of these effects are thought to be attributable to the development of binding, poorly neutralising antibodies that can promote either enhanced infection of Fc bearing immune cells or immune complex deposition with T-helper-2 cell-biased allergic inflammation,” Rostad and Anderson said.

Questions remained, they wrote. “Will BBV152 be efficacious? Is IMDG sufficient to subvert a Th2 response? Will enhanced disease occur?

“These questions might only be answered in a more diverse multinational Phase 3 trial, which must comprehensively assess efficacy and long-term safety.”

In vitro studies and some animal studies with other coronaviruses had raised concern about antibody-dependent enhancement of infection and vaccine-associated enhanced respiratory disease, but, to date, neither had been observed in SARS-CoV-2 vaccine clinical trials, Rostad and Anderson wrote

“The inactivated platform raises concern because inactivation might alter antigenic structures and thereby elicit binding, non-neutralising antibodies. Thus, achieving high titres of neutralising antibodies and T-helper-1 (Th1)-biased cellular responses are considered important safety metrics in the assessment of candidate vaccines,” they added.

“Although not yet published in peer-reviewed journals, preclinical studies of BBV152 in hamsters and rhesus macaques showed that the vaccine elicited high titres of neutralising antibodies and protected against SARS-CoV-2 challenge without evidence of enhanced respiratory disease.”

Ella et al. followed up their preprint published on medRxiv on December 22 with another paper about the Phase 2 trial that was published in The Lancet on March 8. The paper in The Lancet also included a report on the three-month follow-up of the Phase 1 trial.

The researchers said: “With several reports questioning the efficacy of SARS-CoV-2 vaccines against antigenically divergent strains, we previously reported neutralising antibody responses in homologous and heterologous strain assessments.

“Day 56 serum samples from 38 participants in the 6 µg with Algel-IMDG group of the Phase 2 trial effectively neutralised a SARS-CoV-2 variant of concern (lineage B.1.1.7 or 20B/501Y. V1).”

When vaccines are made from an inactivated virus, they don’t lead to as strong an immune response as those made using a live virus. Several doses, including boosters at regular intervals, are usually necessary, and the virus has to be grown in large quantities.

The Research Institute for Biological Safety Problems in Kazakhstan; the Wuhan Institute of Biological Products, which is a manufacturing entity of the state-run China National Pharmaceutical Group Corporation (Sinopharm) and is working in collaboration with the Wuhan Institute of Virology; the Institute of Medical Biology under the Chinese Academy of Medical Sciences; Sinovac Biotech; and the Beijing Institute of Biological Products are also developing vaccines made from an inactivated virus.

In a discussion in the New York Times in June, the director of the Center for Virology and Vaccine Research at the Beth Israel Deaconess Medical Center in Boston, Dan Barouch, said there were safety concerns about inactivated virus vaccines.

“If the virus is not fully inactivated, the danger is that it might actually cause the disease,” said Barouch, who is also a professor of medicine at Harvard Medical School.

In the same discussion, associate professor of medicine at Columbia University and cancer physician and researcher Siddhartha Mukherjee said that great care needed to be taken with RNA and DNA vaccines.

“The data discussed by Moderna in May would suggest that their vaccine can elicit antibodies in humans. It did so in eight patients. But whether that is protective against SARS-CoV-2, and how long the protection lasts, is an open question,” Mukherjee said.

Mukherjee emphasised that elderly people needed particular protection, so it needed to be understood how much the Moderna vaccine, or others like it, were eliciting long-term immunity in the elderly, whose immune systems might be already somewhat attenuated in their response.

Bharat Biotech and the American biopharmaceutical company Ocugen announced on December 22 that they had signed a binding letter of intent to co-develop Covaxin for the US market.

Adverse reactions

The Indian government has confirmed that a 68-year-old man died as a result of anaphylaxis after receiving a Covishield vaccination on March 8.

The cause of death was confirmed by the national committee responsible for studying reports of serious Adverse Events Following Immunisation (AEFI), which described the death as a “vaccine product related reaction”.

The Press Trust of India (PTI) quoted the chairperson of the AEFI committee, Dr N. K. Arora, as saying: “It is the first death linked to Covid-19 vaccination due to anaphylaxis. It re-emphasises the need to wait for thirty minutes at the inoculation centre after receiving the jab. Most of the anaphylactic reactions occur during this period and prompt treatment prevents deaths.”

The committee assessed 31 reported AEFIs, 28 of which were deaths. As per data collated in the first week of April, the reporting rate was 2.7 deaths per million vaccine doses administered and 4.8 hospitalisations per million vaccine doses administered, the committee said.

“Mere reporting of deaths and hospitalisations as serious adverse events does not automatically imply that the events were caused due to vaccines,” the immunisation division of the Ministry of Health and Family Welfare said in a report published on June 4. “Only properly conducted investigations and causality assessments can help in understanding if any causal relationship exists between the event and the vaccine.”

Eighteen of the reported deaths were classified as having an “inconsistent causal association to vaccination (coincidental – not linked to vaccination)”, seven were classified as indeterminate, and two were found to be unclassifiable. Of the three patients who were hospitalised and recovered, two of the adverse reactions, which were cases of anaphylaxis (one after administration of Covishield and one after administration of Covaxin), were found to be vaccine-product related and one, which was a case of fainting after the administration of Covaxin, was described as anxiety related.

In the case of anaphylaxis after administration of Covishield the patient was female and aged 21, and in the case of anaphylaxis after administration of Covaxin, the patient was male and aged 22.

In the case of many of the fatalities, there were cardiac or thrombotic disorders, including one case in which the patient had thrombocytopenia.

During a presentation to the AEFI committee on March 31, an analysis was presented of 492 of the adverse reaction reports received. (There were reported to be at least 617 serious adverse events as of March 29, including 180 deaths.)

it was stated that, of the 492 reports for which a detailed analysis was provided, more than 90% of hospitalisations of people suffering adverse reactions (276 of 305 people), more than 87% of cases of severe adverse reactions (55 of 63 cases), and 93 out of 124 deaths of people who had suffered adverse reactions happened within three days of Covid vaccination.

The Ministry of Health and Family Welfare reported on May 17 that, since the Covid vaccination drive started, more than 23,000 adverse events were reported through the CoWIN platform, from 684 of the 753 districts in the country.

Of these, 700 cases (about 9.3 cases per million doses administered) were reported to be serious and severe, the ministry said.

The national AEFI committee noted that, as of April 3, 75,435,381 vaccine doses had been administered (68,650,819 doses of Covishield and 6,784,562 doses of Covaxin). Of these, 65,944,106 were first doses and 9,491,275 were second doses.

The ministry said that the AEFI committee had completed an in-depth case review of 498 serious and severe events, of which 26 cases had been reported to be potential thromboembolic events following administration of the Covishield vaccine. This was a reporting rate of 0.61 cases per million doses, the ministry said.

There were no potential thromboembolic events reported following administration of the Covaxin vaccine, the ministry added.

“AEFI data in India showed that there is a very miniscule but definitive risk of thromboembolic events,” the ministry said.

“The reporting rate of these events in India is around 0.61/million doses, which is much lower than the 4 cases/million reported by UK’s regulator … Germany has reported 10 events per million doses.”

In a report on July 12, the ministry reported on the results of a causality assessment for 88 cases that was completed on June 28.

The ministry said that 61 of the 88 cases were found to have “consistent causal association to vaccination”.

“Of these 61 cases, 37 were vaccine product related reactions, 22 cases were immunisation anxiety related reactions, and two cases were immunisation error related reactions,” the ministry said.

“Eighteen cases have inconsistent causal association to vaccination (coincidental – not linked to vaccination).”

This included three deaths, the ministry said, adding that nine cases, including two deaths, were in an “indeterminate category”.

According to Indian government data accessed by CNN-News18, there had been 26,200 reports of adverse reactions after Covid vaccination, including 488 deaths, as of June 7. A total 2,318 of those reporting adverse reactions were hospitalised.

Of the 488 people who died, 457 received the Covishield vaccine and twenty received Covaxin, CNN-News18 reported. Details for 11 people were missing from the government data.

CNN-News18 reported that at least 27 of those who died were aged under 39 years and at least ten of them were aged under 29 years. The youngest person reported to have died was a 21-year-old man from Jammu and Kashmir and the oldest was reported to be a 97-year-old man from Karnataka.

A total 235 million Covid vaccine doses had been administered as of June 7 (26,200 is 0.01 percent of that total).

A total 24,703 cases (94.2% of the adverse reaction cases) were linked to Covishield and 1,497 were linked to Covaxin. As of June 7, 210 million doses of Covishield and 25 million doses of Covaxin had been administered.

A total 1.57% of the adverse reactions (412 cases) were described as severe and about 3.39% (887) cases were categorised as serious.

About 16.15% of those who reported adverse reactions (4,230) had underlying health conditions, according to the government data.

The most common adverse reaction was fever, which was reported in more than 45 percent (11,859) of the cases.

A total of 23,022 (87.87%) adverse reactions were reported after the first vaccine dose and 3,718 (14.19%) after the second dose, CNN-News18 reported. Just over 25% (6,560) of the adverse reactions were reported to have occurred within 30 minutes after vaccination.

In just over 28% of the cases, those affected were aged 51 years and above; in just over 26% of cases they were aged between 18 and 30 years, in just over 24% of cases they were aged between 31 and 40 years, and in nearly 21% of cases, they were aged between 41 and 50 years.

There were 5,622 more adverse reactions reported by women than by men, although 16.1 million more men were vaccinated during the time period, CNN-News18 reported.

A man in Chennai, India, who was a volunteer in the trial of Covishield launched a legal action against the SII for 50 million rupees (about US$680,000) in compensation. He says he suffered serious adverse effects after vaccination, including a severe neurological illness and impairment of his cognitive functions.

According to local media, the SII said the allegations made by the trial participant were “malicious and misconceived” and the SII would seek more than 1 billion rupees in damages.

The SII stated: “The incident with the Chennai volunteer, though highly unfortunate, was in no way induced by the vaccine.”

The legal notice issued by the volunteer’s lawyer states that the man received the Covishield vaccine on October 1, 2020, and, on October 11, he started suffering severe headaches and vomiting, and was not able to respond to questions.

His wife was quoted as saying there was a total “behavioural change” in her husband and he seemed unaware of his surroundings. “He showed irritation towards light and sound, and was resisting any effort to make him get up from bed,” she is quoted as saying.

The trial participant alleges that he became unable to speak or recognise anyone, and was completely disoriented. He was admitted to an intensive care unit.

The volunteer says he suffered acute encephalopathy. He says that he was discharged from the hospital on October 26, but his health is still not stable, he has severe mood swings and problems with comprehension, and still finds it difficult to do simple, routine things.

He says he was led to believe that Covishield had already been shown to be safe and that there was no risk of any side effects, let alone severe adverse effects.

He has called for the testing, manufacture, and distribution of Covishield to be stopped immediately in India.

The SII said Covishield was “safe and immunogenic”. It said it was sympathetic with the volunteer’s medical condition, but that all the requisite regulatory and ethical processes and guidelines were followed diligently and strictly.

The institute says the volunteer is falsely laying the blame for his medical problems on the vaccine trial. . “There is absolutely no correlation with the vaccine trial and the medical condition of the volunteer,” the SII said.

The SII said the concerned authorities were informed and the principal investigator, the Data and Safety Monitoring Board (DSMB), and the ethics committee, independently concluded that the volunteer’s health problems were not related to the vaccine trial.

“We would want to assure everyone that the vaccine won’t be released for mass use unless it is proven immunogenic, and safe,” the SII said. “Taking into consideration the complexities and existing misnomers about vaccination and immunisation; the legal notice was sent therefore to safeguard the reputation of the company which is being unfairly maligned.”

According to The Economic Times, a participant in the Phase 1 clinical trial of Covaxin, which was developed by Bharat Biotech in collaboration with the ICMR, fell ill and had to be hospitalised after being vaccinated in July 2020, but the trial was not halted and no public disclosure was made about the incident.

The Times of India reported that the adverse event occurred in a 35-year old participant with no co-morbidities during the trial at a site in western India. The participant was hospitalised with viral pneumonitis a couple of days after being vaccinated and was discharged after a week’s stay in hospital, the Times of India reported.

Bharat Biotech said the adverse event was investigated thoroughly and was determined not to be vaccine related.

In an article published in The Lancet on January 23, 2021, Anoo Bhuyan says participants in a Covaxin trial in Bhopal recounted that they could not read consent forms and were unable to report adverse events.

Many Bhopal residents told how a vehicle with a loudspeaker had come around their neighbourhood in December, 2020, Bhuyan, who covers health policy for The Wire, reported.

Bhuyan says the residents alleged that they were told that, if they went to the People’s University private hospital, they could get a Covid-19 vaccine and 750 rupees (about US$10).

“This hospital was one of the sites conducting the Covxin trial,” Bhuyan wrote. “Many locals have been unemployed over the past year and children have been out of school because of the pandemic, so the small sum of money was attractive enough for them to take part in the trial.”

Bhuyan tells the story of 57-year-old Ramesh, who said he got his first Covaxin vaccination on December 7, 2020.

“I was told it is the Covid-19 vaccine,” Bhuyan quotes Ramesh as saying. ‘’I did not know it was a trial. The people at the hospital did not give me any time to see what I was told to sign. I did not know that I could refuse the injections.”

Bhuyan also writes about carpenter Jai Ram, who said he had difficulty reporting adverse events. She quotes Ram as saying: “I felt quite weak after taking the injection for many days. I did not know what to do but someone advised me to drink juice made from ginger and so I did that.”

Ram said he didn’t have a phone so had not spoken to anyone from the hospital. “Thus his complaint of feeling weakness would not be recorded as an adverse event,” Bhuyan wrote.

Bhuyan quotes the dean of People’s University, A.K. Dixit, as saying there was a videographer in the room who took audio-video recordings of the informed consent. “However, both Ramesh and Ram said that they did not see anyone recording their consent,” she wrote.

“The Covaxin trial was not paused despite the alleged death of a participant. In an official statement, Bharat Biotech has said that the participant had died nine days after taking part in the trial.

“The post-mortem report says that the person had died from a ‘suspected poisoning’. The company’s statement says that their own investigation has concluded that the death was ‘not related to vaccine or placebo’.

Bharat Biotech and the ICMR did not respond to Bhuyan’s requests for comment.

Both Bharat Biotech and the ICMR have brushed aside allegations that there were protocol violations in the Covaxin phase 3 trials at a hospital in Bhopal.

There is a constantly updated account under the #VAERS_India hashtag on Twitter of adverse reactions, deaths, and Covid-19 cases occurring after Covid vaccination.

A Mumbai-based company, Gem Tours and Travels, caused controversy when it said it would offer ‘vaccine tourism’ packages for customers, and would facilitate vaccination in the US.

The company said in a WhatsApp message that it would facilitate tours to the US for ‘VVIP’ clients as soon as Pfizer’s vaccine gets final approval.

Pfizer said it was not working with any other partner at this time and had not authorised any agency to conduct or facilitate vaccination against SARS-CoV-2.

The company said it would supply its vaccine only to governments across the world on the basis of agreements with respective government authorities and following regulatory authorisation or approval.

Business Today in India reported that Gem Tours and Travels had issued a clarification in which the company stated: “We are not taking any money as of now. This opportunity is for people who are co-morbid and in need of the vaccination. This advertisement was misunderstood.”

 

China

 

This section has not yet been updated.

China has approved 12 Covid-19 vaccines in total. One is the ‘Recombinant COVID-19 Vaccine (Adenovirus Type 5 Vector) for Inhalation’, manufactured by CanSino Biologics and administered as a booster dose through the mouth. Five are inactivated vaccines, four are recombinant protein vaccines, and two are viral vector vaccines.

This December (2022) China has experienced a massive surge in Covid-19 infections.

The Chinese authorities authorised three vaccines – CoronaVac, Ad5-nCoV, and BBIBP-CorV – for limited or emergency use without Phase 3 trials having being conducted. Only BBIBP-CorV has been given conditional approval for general public use. The authorisation was given by China’s top drug regulator, the National Medical Products Administration (NMPA). It was the first NMPA approval for a Covid-19 vaccine.

The Ad5-nCoV viral vector vaccine was approved for use for one year by the military in advance of Phase 3 trials. The same vaccine is being tested in Canada.

The manufacturer, CanSino Biologics, said that clinical trials had shown the vaccine to be safe and indicated some efficacy. The company is reported to be in talks with several countries to get emergency approval for its use.

Reuters reported that eight SARS-CoV-2 vaccines have been approved in China for human trials at home and abroad.

On December 9, 2020, the United Arab Emirates’ Ministry of Health and Prevention (MOHAP) announced the official registration of BBIBP-CorV.

The MOHAP said that, in collaboration with the Abu Dhabi Department of Health, it had reviewed Sinopharm’s interim analysis of the Phase 3 vaccine trials. The trials showed the vaccine to have 86 percent efficacy, the ministry said.

On 30 December, 2020, Sinopharm had announced 79.34% efficacy.

Results of the Phase 1/2 trial of BBIBP-CorV, which was jointly developed by the Beijing Institute of Biological Products and the China Centres for Disease Control and Prevention, were published in The Lancet online on October 15, 2020.

Researchers found that humoral responses against SARS-CoV-2 were induced in all vaccine recipients on day 42.

“Two-dose immunisation with 4 μg vaccine on days 0 and 21 or days 0 and 28 achieved higher neutralising antibody titres than the single 8 μg dose or 4 μg dose on days 0 and 14, Xiaoming Yang et al. said.

Humoral immune responses are mediated by antibodies produced by B cells whereas cell-mediated immune responses do not involve antibodies.

Xiaoming Yang et al. said their research indicated that BBIBP-CorV was “safe and well tolerated” at all tested doses in two age groups and induced neutralising antibodies.

The vaccine was tested in 640 healthy volunteers. In Phase 1, 192 volunteers aged between 18 and 80 years were enrolled and were separated into two age groups, those aged 18–59 and those aged 60 or older. The trial participants were randomly assigned to receive the vaccine or a placebo in a two-dose schedule.

In Phase 2, the 448 participants were aged 18–59 years. They were randomly assigned to receive the vaccine or a placebo in a single-dose or two-dose schedule.

In Phase 1, at least one adverse reaction was reported within the first seven days of vaccination in 42 of 144 vaccine recipients.

“The most common systematic adverse reaction was fever (18–59 years, one [4%] in the 2 μg group, one [4%] in the 4 μg group, and two [8%] in the 8 μg group; ≥60 years, one [4%] in the 8 μg group),” Yang et al. reported. “All adverse reactions were mild or moderate in severity. No serious adverse event was reported within 28 days post vaccination.”

In phase 2, at least one adverse reaction within the first seven days was reported in 76 of 336 vaccine recipients. Again, the most common systematic adverse reaction was fever.

In a comment published in The Lancet, Irina Isakova-Sivak and Larisa Rudenko from the Institute of Experimental Medicine in Saint Petersburg, Russia, noted that the older age group in the Phase 1/2 trials had lower rates of “solicited adverse events” than the younger adults.

“The overall rates of adverse events within 28 days after vaccination were 34 (47%) of 72 participants in the group aged 18–59 years, compared with 14 (19%) of 72 participants in the group aged 60 years and older,” Isakova-Sivak and Rudenko wrote. “At the same time, in both age groups the vaccine was similarly immunogenic.”

Isakova-Sivak and Rudenko noted that the trials included an assessment of the effect on the vaccine’s immunogenicity of shortening the interval between two doses from 28 days to 21 or 14 days.

“The 4 μg dose of the vaccine was the most immunogenic when given at the 21-day interval (neutralising antibody titre 283), but its immunogenicity significantly decreased when the interval was reduced to 14 days (neutralising antibody titre 170), suggesting that the interval cannot be shorter than 3 weeks,” Isakova-Sivak and Rudenko wrote.

The two researchers say that encouraging results have been obtained when testing BBIBP-CorV in various animal models, where no disease enhancement on SARS-CoV-2 challenge was found.

“However, we need to acknowledge that for this new infection, all possible animal models have not yet been worked out for simulating antibody-dependent disease enhancement in humans,” they wrote.

“Therefore, long-term careful monitoring of quantitative and qualitative characteristics of the induced SARS-CoV-2 antibodies after vaccination with inactivated SARS-CoV-2 vaccines is critically important.”

Isakova-Sivak and Rudenko also said that more studies were needed to establish whether the inactivated SARS-CoV-2 vaccines were capable of inducing and maintaining virus-specific T-cell responses, “because CD4-positive T-cell help is important for optimal antibody responses, as well as for cytotoxic CD8-positive T-cell activation, which, in turn, are crucial for viral clearance if neutralising antibody-mediated protection is incomplete”.

On December 13, 2020, the National Health Regulatory Authority (NHRA) in Bahrain announced that it had approved the registration of BBIBP-CorV.

The MOHAP in the UAE said in its announcement on December 9 that no serious safety concerns were reported in the trials of BBIBP-CorV. The ministry granted the vaccine emergency use authorisation in September.

The UAE is conducting post-authorisation safety and efficacy studies. The MOHAP says the safety and efficacy results are similar to those reported in Sinopharm’s interim analysis.

Phase 3 vaccine trials were carried out in several countries, including in the UAE, where 31,000 volunteers participated.

The NHRA in Bahrain said its decision to approve and use BBIBP-CorV was based on clinical trial data conducted in several countries.

Results from Phase 3 clinical trials showed an 86% efficacy rate, a 99% seroconversion rate of neutralising antibodies, and 100% effectiveness in preventing moderate and severe cases of Covid-19, following testing on 42,299 volunteers, the regulator said.

In a report in Nature on January 15, 2021, Smriti Mallapaty said that results of trials in Brazil of CoronaVac “were tinged with disappointment and confusion”.

Researchers in Brazil reported that the vaccine was 50.4% effective at preventing severe and mild Covid-19 in late-stage trials.

The efficacy statistics were much lower than those from early trials of CoronaVac in Turkey and Indonesia and those first reported by the researchers from the Butantan Institute in São Paulo, who had announced on January 7 that the vaccine’s efficacy was 78%, Mallapaty reported.

The researchers now point out that the earlier statistic was based on the criteria of people needing medical attention.

In the trial in Brazil, 252 cases of Covid-19 were recorded (85 in the vaccinated group and 167 among those who received the placebo). None of the participants who received the vaccine had to be hospitalised with severe Covid-19.

In late December, researchers said that, in the trial in Turkey, CoronaVac had been shown to be 91.25% effective at preventing symptomatic disease. The result was based on just 29 Covid-19 cases among 1,322 trial participants.

Indonesia has authorised CoronaVac for emergency use and started its national vaccination programme on January 13.

In a trial involving about 1,600 people, researchers found the vaccine to be 65.3% effective at preventing symptomatic disease, Mallapaty reported. This calculation was made based on the confirmation of just 25 Covid-19 cases, he wrote, quoting a vaccinologist at Gadjah Mada University in Yogyakarta, Jarir At Thobari.

Researchers involved with the Brazil trial say the lower efficacy compared with other vaccines could be because the two shots were administered only two weeks apart, which did not leave sufficient time for participants to reach peak immunity, Mallapaty wrote.

“They also say that the trial, which recruited only health professionals, who are more likely to be exposed to the virus, report symptoms and get tested, probably identified more mild infections than did trials in Indonesia and Turkey, which included the public,” he added.

The results of the Phase 1 and 2 trials of CoronaVac, which took place in Jiangsu province, China. were published in The Lancet on November 17, 2020.

Just 144 participants were involved in Phase 1 and 600 in Phase 2. Volunteers were aged 18 to 59 years.

Anvisa authorised the emergency use of CoronaVac and the AstraZeneca-Oxford vaccines on January 17, 2021.

Anvisa said on November 9, 2020, 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 conducted Phase 3 trials abroad because the number of active cases of SARS-CoV-2 infections in China is too low to provide trial cohorts.

The company said that Phase 2 trials involving 600 people in China indicated that CoronaVac appeared to be safe and induced detectable antibody-based immune responses in the participants.

China’s foreign ministry spokesman Wang Wenbin announced on February 3, 2021, that China had, at the request of the WHO, decided to provide ten million Covid-19 vaccine doses to COVAX.

History of vaccine authorisations in the EU

On January 29, 2021, the EC granted a conditional marketing authorisation for the AstraZeneca-Oxford vaccine. This followed a recommendation from the EMA.

The EMA said: “Combined results from four clinical trials in the United Kingdom, Brazil and South Africa showed that Covid-19 Vaccine AstraZeneca was safe and effective at preventing Covid-19 in people from 18 years of age.”

The agency said it based its calculation of how well the vaccine worked on the results from studies conducted in the UK and Brazil.

“The other two studies had fewer than six Covid-19 cases in each, which was not enough to measure the preventive effect of the vaccine,” the EMA said.

“In addition, as the vaccine is to be given as two standard doses, and the second dose should be given between four and 12 weeks after the first, the agency concentrated on results involving people who received this standard regimen.”

The EMA said the results showed a 59.5% reduction in the number of symptomatic Covid-19 cases in people given the vaccine (64 of 5,258 people got Covid-19 with symptoms) compared with those given control injections (154 of 5,210 got Covid-19 with symptoms).

“This means that the vaccine demonstrated around a 60% efficacy in the clinical trials,” the EMA said.

AstraZeneca points out that its vaccine can be stored, transported and handled at normal refrigerated conditions (two-eight degrees Celsius/36-46 degrees Fahrenheit) for at least six months.

The vaccine has been granted a conditional marketing authorisation or emergency use in nearly fifty countries on four continents.

On December 21, 2020, the EC granted a CMA for use of the Pfizer-BioNTech Covid vaccine for individuals aged 16 years and above.

The FDA’s EUA for BNT162b2a was issued on December 11, 2020, and allowed the vaccine to be distributed in the US and to be given to individuals aged 16 years and older.

The EC’s decision followed a recommendation by the EMA earlier in the day that the CMA should be granted.

The CMA was the first marketing authorisation of a Covid-19 vaccine in the European Union (EU) by the EC. The EC’s decision applied to all 27 EU member states. The vaccine is marketed in the EU under the brand name Comirnaty.

On January 6, 2021, the commission granted a CMA for use of the Moderna Covid vaccine for people aged 18 years and above.

On March 11, the EC granted a CMA for use, for people aged 18 years and above, of the Covid-19 vaccine developed by Janssen Biotech.

The EMA had recommended the authorisation, saying that its Committee for Medicinal Products for Human Use concluded by consensus that the data about the vaccine were robust and met the criteria for efficacy, safety, and quality.

On March 4, 2021, the CHMP announced that it had started a rolling review of the Sputnik V vaccine. The EU applicant for the review was R-Pharm Germany GmbH.

The CHMP said its decision to start the review was based on results from laboratory studies and clinical studies in adults.

“The EMA will evaluate data as they become available to decide if the benefits outweigh the risks,” the committee said. The rolling review would continue until enough evidence was available for a formal marketing authorisation application, it added.

“The EMA will assess Sputnik V’s compliance with the usual EU standards for effectiveness, safety and quality. While the EMA cannot predict the overall timelines, it should take less time than normal to evaluate an eventual application because of the work done during the rolling review.”

In November 2020, Pfizer and BioNTech reached an agreement with the EC to supply 200 million doses of their Covid vaccine in 2020 and 2021, with an option for the EC to request an additional 100 million doses.

The EMA said that Pfizer would continue to provide results from the main vaccine trial, which would continue for two years. “This trial and additional studies will provide information on how long protection lasts, how well the vaccine prevents severe Covid-19, how well it protects immunocompromised people, children and pregnant women, and whether it prevents asymptomatic cases.”

Pfizer would also carry out studies “to provide additional assurance on the pharmaceutical quality of the vaccine as the manufacturing continues to be scaled up”, the EMA said.

Pfizer and BioNTech previously said that their vaccine needed to be stored in an ultra-cold freezer at temperatures between -80ºC and -60ºC (-112ºF to ‑76ºF) and could remain stored at these temperatures for up to six months. This temperature condition was cited in the emergency use authorisation granted in the US.

The FDA announced on February 25, 2021, however, that it would allow undiluted frozen vials of the vaccine to be transported and stored at conventional temperatures found in pharmaceutical freezers for a period of up to two weeks.

“This reflects an alternative to the preferred storage of the undiluted vials in an ultra-low temperature freezer … ,” the FDA said.

“This alternative temperature for transportation and storage of the undiluted vials is significant and allows the vials to be transported and stored under more flexible conditions.”

The FDA’s announcement was in response to the companies’ submission of new data that they say demonstrate the stability of the vaccine when it is stored at -25°C to -15°C (-13°F to 5°F), temperatures more commonly found in pharmaceutical freezers and refrigerators.

The data were submitted to the FDA to support a proposed update to the EUA prescribing Information, which would allow for vaccine vials to be stored at these lower temperatures for a total of two weeks as an alternative or complement to storage in an ultra-cold freezer.

The alternative temperature for storage of frozen vials is not applicable to the storage of thawed vials before dilution, which can be held in a refrigerator for up to five days, or the storage of thawed vials after dilution, which can be held at refrigerator or room temperature for use within six hours.

The storage data were also being submitted to other regulatory agencies, Pfizer and BioNTech said.

The original labelling said the Pfizer-BioNTech vaccine needed to be shipped in a specially designed thermal container that could be used as temporary storage for a total of up to thirty days by refilling with dry ice every five days.

The labelling said that, before it was mixed with a saline diluent, the vaccine could also be refrigerated for up to five days at a standard refrigerator temperature, between 2⁰C and 8⁰C (36⁰F and 46⁰F).

Pfizer and BioNTech said that, as additional stability data were obtained, they anticipated that the shelf life and/or expiration date of the vaccine could be extended.

Development of CSL vaccine stops because of false HIV positives

The Australian government announced on September 7, 2020, that it had struck Covid vaccine supply and production agreements with AstraZeneca and the Australian biotechnology company CSL. Under the agreements, and on the condition that clinical trials were successful, CSL would manufacture the AstraZeneca vaccine. Australia has also ordered vaccine doses from Novavax and Pfizer-BioNTech.

CSL was developing a vaccine against SARS-CoV-2 in collaboration with the University of Queensland (UQ), but the Australian government terminated its agreement with the CSL subsidiary Seqirus to supply 51 million doses of its vaccine after trial participants returned false positive test results for HIV. The participants subsequently tested negative for HIV.

CSL said in a statement on December 11, 2020, 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.”

Virologist Nikolai Petrovsky from Flinders University in Adelaide 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.