An observational study carried out by researchers from the Banaras Hindu University, Varanasi to assess the safety of Covaxin, particularly the long-term adverse events of special interest (AESIs) one year after vaccination, in adolescents and adults has been criticised by ICMR for the poor study design. However, till date, neither ICMR nor Bharat Biotech has published any Covaxin safety data after the drug regulator approved its roll-out in January 2021 in a “clinical trial mode” and wanted the vaccine recipients to be followed up for safety.

Though the researchers acknowledge all the limitations of the study, which is published in the journal Drug Safety, many of the limitations are so critical that they defeat the very purpose of the study. “Ideally, this paper should have been rejected at the peer-review stage. Simply mentioning the limitations, some of them critical to arrive at any useful conclusion, defeats the whole purpose of undertaking the study,” Dr. Vipin M. Vashishtha, director and pediatrician, Mangla Hospital and Research Center, Bijnor, says in an email to The Hindu. Dr. Gautam Menon, Dean (Research) &  Professor, Departments of Physics and Biology, Ashoka University shares the same view. Given the limitations of the study one can “certainly say that the study can’t be used to draw the conclusions it does,” Dr. Menon says in an email.

If the most glaring limitation of the study is the lack of a control group, the absence of data on background rates of adverse events of special interest (AESI) that have been assessed in the vaccinated participants makes it difficult to even find an association between the adverse events and the vaccine. However, Dr. Kishor Patwardhan from BHU and co-author of the paper in a tweet justifies the absence of a control group by saying that “in a longitudinal observational study, a traditional control group might not be feasible or necessary. Instead, researchers use the variability within the cohort over time to draw comparisons and identify associations”.

“The lack of a control arm is a serious limitation of the study and negates any useful inference and interpretation of the study’s findings. Further, they didn’t try to show a real upsurge in the rates of these common ailments in the vaccinated population as the background rates are not mentioned,” says Dr. Vashishtha. “Most of the symptoms the authors describe as adverse effects of special interest are typically seen in a population as a result of COVID, Long COVID or incidental health problems. Refractive error, for instance, is common among adolescents but is listed here as a side effect of vaccination. Thus their conclusion that “nearly one-thirds of participants receiving the BBV152 vaccine reported adverse effects of special interest” is misleading, and most likely erroneous,” says Dr. Rajeev Jayadevan, co-chairman of the National IMA COVID task Force.

Dismissing Dr. Patwardhan’s argument that a control group may not be necessary in a longitudinal observational study, Dr. Menon says: “If the question, as here, is the possibility of adverse effects following vaccination, it is a question about causality. To answer these, it is important to remove as many confounders as possible, such as the possibility that some fraction of participants were infected by the virus prior to or after vaccination. If, in a normal non-COVID year, an equally substantial fraction of people were afflicted by upper respiratory tract infections, that would certainly be relevant to asking if the vaccine was [indeed] responsible for the AESIs picked up by this survey.”

Objecting to Dr. Patwardhan’s claim made in a tweet that the “goal [of the longitudinal study] is often to observe natural progressions and associations rather than to establish direct causal relationships with the use of a control group”, Dr. Menon points out that the paper clearly states that “serious adverse events may occur in 1% of BBV152 [Covaxin] recipients”, which is a statement of specific causality. The only robust way of linking the administration of the vaccine to a specific set of adverse effects is to have an appropriate control group, stresses Dr. Menon. Dr. Vashishtha too says that it is difficult to conclude natural progression without comparing it with the control arm.

The second most critical limitation of the study is the failure to test the participants for SARS-CoV-2 infection/COVID-19 disease and associating all the adverse events solely to vaccination. Since the study lasted from January 2022 to August 2023, the chances that the participants were truly uninfected and all adverse events seen were only due to vaccination are slim. “Serological studies in Uttar Pradesh [where the participants lived] after the Delta wave point to over 80% of the population having been infected. Some of the AESIs in question could have been a consequence of an initial SARS-CoV-2 infection and not the vaccination,” says Dr. Menon.

Worse is when the researchers claim some of deaths to be “possibly” associated with Covaxin even when infection/disease was not ruled out through testing or taking into account pre-existing conditions/diseases such as hypertension and diabetes. The researchers have followed the WHO classification for AEFI categories, and one of WHO’s AEFI categories is coincidental reaction/event. “These deaths possibly belong to this category,” says Dr. Vashishtha. “They failed to provide substantial evidence on the causal association of some of the serious adverse events like Guillain-Barre syndrome (GBS). The only subject with this neurological condition had a history of GBS. Most of the instances mentioned by the authors can merely be termed as coincidental.”

“The same group of investigators had studied the Covishield vaccine using an almost similar methodology. They found that Covishield had led to AESIs in 14%, whereas Covaxin led to AESIs in one-third of the participants of the trial. This defies logic. Globally, inactivated vaccines are considered safer than Adenovirus vector-based vaccines,” adds Dr. Vashishtha.

The third major limitation is that the observational study was conducted over telephone and participants were asked to recall persistent AESIs (lasting for at least one month) at the end of the one year follow-up. The design of the study did not include direct interaction with participants and clinical evaluation of the AESIs though the study was done well past the dangerous phase of the pandemic. “On a pedestal of quality of evidence generated by types of studies, the observational studies lie at the lowest rung, just above the case reports and personal experiences,” says Dr. Vashishtha.

If evidence collected from observational studies per se does not rank high, relying solely on telephone interaction with participants one year after vaccination further dents the study. “Physical follow-up is costly and as a first step, substituting this by a telephone survey can be acceptable. But this said, it’s certainly not a preferred choice in cases such as these. And without a comparator non-vaccinated group being asked the same questions, this exercise cannot be really trusted,” says Dr. Menon. “Furthermore, it relies on recall over a long period, rather than any independent quantitative measure, and this can be inaccurate. Such inaccuracy can go both ways, in terms of both exaggerating an effect or minimising it, since memories, especially over long periods, can be untrustworthy.”

The researchers recruited 1,024 individuals (635 adolescents and 291 adults) to assess the safety of Covaxin at the end of one year following vaccination. On the merit of including a small number of participants for the study, Dr. Menon says: “Whether the number of participants is small or large can only be answered with some prior idea of whether the effect that is being investigated is a large effect or a small one. Worldwide, there is consensus that long-term adverse effects arising solely out of vaccinations are rare. One must therefore go to very large samples in what is called a phase-4 clinical trial. The numbers included in the BHU study are too small for definitive statements to be made.” The paper notes that the “sample size was decided based on the primary outcome of AEFIs and not based on AESIs.

New Delhi:

The Indian Council of Medical Research, or ICMR, has distanced itself from a follow-up study by two Banaras Hindu University professors that said nearly a third of 926 individuals who received the India-made Covaxin COVID-19 vaccine reported serious side-effects.

The study claimed that around one per cent of respondents reported strokes and an autoimmune disorder called Guillain-Barre Syndrome, which causes weakness in nerves in the arms and legs.

Conducted between January 2022 and August 2023, the study also said 50 per cent of the sample size complained of respiratory infections, and over 30 per cent reported assorted physical problems, ranging from skin and nervous system disorders to bone and muscle problems.

READ | Over 30% Covaxin Takers Had Health Issues After Year: Study

Specifically, between adolescents and adults respondents the study claimed 10.5 per cent reported new-onset skin and subcutaneous disorders and 10.2 per cent claimed nervous system concerns.

Among female respondents, 4.6 per cent claimed menstrual disorders.

ICMR Criticises Study Flagging Covaxin AESIs

However, the ICMR faulted the study – ‘Long-Term Safety Analysis of BBVl52 Coronavirus Vaccine in Adolescents and Adults: Findings From a 1-Year Prospective Study in North India’ published by Springer Nature – for poor methodology, and objected to it “acknowledging” the medical body.

ICMR Director-General Rajiv Bahl said the study had no control arm (of unvaccinated individuals) to compare rate of AESIs, or Adverse Events of Special Interest, and, therefore, the reported side-effects could not be linked or attributed to being administered Covaxin as COVID-19 vaccination.

Continuing a long list of critical observations, the ICMR boss also declared the study does not provide background rates of observed events in the population, making it impossible to assess change in such incidences in the post-vaccination period.

FACT CHECK | Can Covaxin Lead To Death After 2 Years Of Vaccination?

The method of data collection – study participants were contacted via telephone a year after vaccination and their responses were recorded without confirming them via medical records or examination by doctors – was also severely criticised.

Dr Bahl stressed that the ICMR is not associated with the study claiming side-effects from the India-developed vaccine, and had not provided any support – technical or financial – to the study authors.

The study authors and publishers have been urged to remove the acknowledgement to the ICMR.

“The authors are urged to rectify acknowledgment to ICMR and publish an erratum. Additionally, they are asked to address methodological concerns raised,” the ICMR chief said.

“Failure to do so may prompt ICMR to consider legal and administrative action.”

What Study Authors Said

Among the points made, the researchers acknowledged that understanding the AESIs-vaccines link required a control arm of unvaccinated individuals to compare rates of reported serious side-effects.

The authors also said that in the absence of data on background rates of observed AESIs, no comments were possible on changes in incidence of observed events in post-vaccination periods.

“Our findings are confined to BBV152 (Covaxin) and should not be extrapolated to viral vector or mRNA vaccines. The study primarily involved adolescents and the sample size of adults was relatively small. Larger adult-based studies are needed to understand long-term safety of BBV152 in adults.”

Bharat Biotech Responds

The study has also been questioned by Covaxin developers and manufacturers Bharat Biotech, which pointed to multiple alternate studies to emphasise its drug’s “excellent safety track record”.

READ | Bharat Biotech Flags Covaxin’s Excellent Safety Record In Risks Row

The ICMR’s strong reaction to the study comes amid concern over potentially fatal side-effects for those who received the vaccine developed by British pharma giant AstraZeneca and Oxford University, and manufactured and sold in India – as Covishield – by the Serum Institute.

Concerns Over Covishield

Given the questions about Covishield and Covaxin’s long-term safety records, a group of doctors last week called for a review all the science behind all Covid vaccines, as well implementation of surveillance and monitoring measures to ensure vaccine AESIs are identified as early as possible.

READ | Covishield Safety Row: Doctors Urge Centre To Review All Vaccines

The spotlight, so far, has been squarely on Covishield after AstraZeneca was hit by multiple lawsuits in the United Kingdom, with at least one patient claiming he suffered a serious brain injury following a blood clot that formed after he was injected in April 2021.

Fact Check | Are Indians Who Got Covishield Vaccine Susceptible To TTS?

AstraZeneca initially contested the claim but later said its vaccine could “in very rare cases” cause Thrombosis with Thrombocytopenia Syndrome, or TTS, which is a medical condition that can cause blood clots and low platelet counts, and has been linked to over 80 deaths in the UK alone.

READ | AstraZeneca Drops Covid Vaccine After Rare Side Effect Report

The company has expressed sympathy for those who have lost loved ones or reported health problems, but has reiterated its commitment to patient safety and adherence to “stringent (safety) standards”

It has also announced a global withdrawal of all vaccine stock, but attributed the withdrawal to commercial reasons, i.e., to a “surplus of available updated vaccines” for COVID-19.

Vaccinations In India

As of this morning, approximately 17 per cent of all vaccines administered were Covaxin, according to data from the government’s CoWIN dashboard.

The overwhelming majority of the population received the Covishield vaccine, while a small section got the Corbevac jab.

Serum Institute On Covishield

The SII told NDTV that all its product packaging had “disclosed all rare to very rare side-effects”, including TTS, and pointed out the vaccine had been “instrumental” in saving lives worldwide.

READ | “We Disclosed All Rare Side-Effects”: Covid Vaccine Maker On Safety Row

The company also said it discontinued Covishield manufacture from 2021 due to “the emergence of new mutant variant strains”, which had led to decreased demand for previous vaccines”.

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