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BHU's Covaxin Safety Study: Cautious Interpretation of Results Needed

The fact that the study pointed out that 33% of participants developed adverse reactions has been overstated in various media reports without going into the study's limitations, which the authors themselves admit as a part of standard scientific practice.
Representative image. Credit: Pan America Health Organisation/Flickr CC BY-ND 2.0

New Delhi: A study conducted by a group of researchers at the Banaras Hindu University (BHU) on safety of Covaxin said that close to one-third of their study’s participants developed adverse events of special interest (AESIs).

This study was published on May 13 and it made it to various newspapers and other publications on May 16 as it was shared by one of its authors on social media.

These newspaper reports on Covaxin came out after a controversy around Covishield erupted earlier this month based on some misinterpretations after AstraZeneca admitted to a rare side effect in a UK court.

The headline that most publications tend to pick up from this Covaxin study is one sentence from the paper: Close to one-third of individuals developed AESIs.

Some of these reports even go on to say that the vaccine, like Covishield, was not safe, referring to many misinterpreted conclusions about the controversy.

A screenshot of the collage of news items on the Covaxin study; taken at 8:05 pm on May 17.

At the outset, AESIs are adverse events, or the side effects, as the name suggests, of ‘special interest’. These are not necessarily all AEFIs (adverse effects following immunisation). In fact AESIs may be referred to as a subset of AEFIs.

AEFIs are a bigger basket that would record all adverse effects, including minor ones, and not just those of special interest.

While the Covaxin paper did say that one-third (33%) of the study’s participants developed AESIs. Only 1% of all participants developed serious AESIs.

A total of 926 Covaxin recipients took part in the study – 635 adolescents and 291 adults. They were interviewed by researchers between January 2022 and August 2023 via telephone. The researchers tried to understand any health issues post-vaccination in this period.

As for the study, one of the major adverse effects it highlighted was ‘respiratory infections’, or what are called ‘viral upper respiratory tract infections’ in scientific jargon.

It said about half of the enrolled participants developed these respiratory infections.

Dr Aviral Vatsa, who is a general practitioner and scientist working with the National Health Service-Scotland and who was not involved in the study, sounded a note of caution against making interpretations from the study.

“[The] participants who reported viral upper respiratory tract infections were not routinely tested for COVID-19. This means some cases of COVID-19 might have been missed, potentially skewing the results,” he told The Wire.

In fact, this is something the paper also mentions.

The paper says many of those who were reported to have a respiratory infection after vaccination might have got COVID-19 itself and not any other infection.

Reporting a COVID-19 infection could have been missed because testing rates went down by the end of the third wave, when this study was being conducted.

Had a COVID-19 test been done on individuals following a respiratory infection, it would have become clear whether what they had post-vaccination was a COVID-19 infection or any other respiratory infection, as Vatsa says.

This is significant because the occurrence of a COVID-19 infection was commonplace at the time when the study was being done. Even a COVID-19 infection after vaccination was not uncommon.

For context, none of the COVID-19 vaccines were designed to prevent an infection per se, but to prevent the severe form of the disease and hospitalisation.

Getting a COVID-19 infection was common; with or without vaccination.

So the interpretation – that a COVID-19 vaccine led to different types of respiratory infections, as it was reported in several newspaper reports – might not be entirely true.

Some of those respiratory infections could have been a COVID-19 infection.

A screenshot of the collage of news items on the Covaxin study; taken at 8.05 pm on May 17.

Typhoid and other serious AESIs

Another important AESI highlighted was the development of typhoid after the COVID-19 vaccination.

“[But] there are concerns about the accuracy of diagnosing post-vaccination typhoid due to possible false positives, which could affect the attribution of adverse events,” Vatsa said.

Adding to Vatsa’s concerns, the paper also said there were possibilities that a patient reporting positive for a typhoid infection might actually be a COVID-19 case, because of what is known as ‘cross-reactivity’ of typhoid and COVID-19 antibodies for the same test.

Therefore, the association of typhoid fever with Covaxin needed to be interpreted cautiously, the paper warns.

Among the most serious side effects observed was Guillain-Barre Syndrome (GBS), a disorder in which the immune system starts attacking the body’s nerves and can lead to paralysis.

Of all the 1% of participants who reported serious side effects, only one participant – or 0.1% of the total – developed GBS.

But even one is important here due to the impact it can have on one’s life.

Nonetheless, the paper itself clarifies that there was only ‘probable’ association between the vaccine and GBS.

More importantly, it adds that the concerned person had a history of GBS 15 years before the study.

“Hence [s/he] might have been more vulnerable to develop the syndrome [after a COVID-19 infection or vaccination],” it added.

Writing an opinion piece on Covishield in the light of the recent controversy in the Indian Express, virologist Shahid Jameel referred to a multi-country observational study on the Pfizer, Moderna and AstraZeneca COVID-19 vaccines causing GBS. It was published in April this year, Jameel wrote.

“It showed that these vaccines increase the incidence of [GBS] within 42 days of receiving the vaccine. About 200 cases were found among 99 million people who were studied – a risk of one in 5,00,000.”

It must be noted here that the vaccines that Jameel referred to were different from Covaxin, but the GBS data in their case was brought out after studying as many as 99 million people receiving those vaccines.

In fact, this paper on Covaxin also says that the observed rates of serious AESIs such as stroke and GBS will need confirmation from vaccine-specific, larger multi-centre studies.

Also read: Report on Rare Adverse Side Effects of Covishield Causes Panic. But Should It?

Other disorders

The paper reported many general and skin disorders post Covaxin vaccination.

More than 10% of adolescents (out of 635 studied) complained of skin conditions, mainly in the form of alopecia (hair loss), and a similar percentage had general disorders such as weakness. 

While the majority of those with general disorders had recovered, skin disorders were present in the majority of those who had them during the final follow-up and persisted with a median time of 8.5 months, the paper said.

Close to 5% of adolescents and adults complained of nervous system disorders such as headaches, which persisted in the majority of those who had them for around nine months at the final follow-up.

Eye disorders were reported in 3.6% of adolescents. As many as 5% of adolescent female individuals complained of new-onset menstrual abnormalities.

Hypothyroidism was reported by around 0.6% of adolescents and adults each.

Deaths after vaccination

This BHU study also reported four deaths after vaccination. Three of them had prior history of diabetes and/or hypertension. Out of these, two died due to stroke post-vaccination and the cause of the third person’s death was not known.

The fourth had developed mucormycosis – a serious bacterial infection – after having a COVID-19 infection.

The paper concludes about these deaths: “Three of these fatalities shared a ‘possible’ association with the vaccine while the [cause] the fourth was ‘unclassifiable’.”

Other observations

As a generic observation, Vatsa said many of the impacts that have been recorded in this paper as post-COVID-19 vaccination outcomes are incidentally also part of the umbrella called ‘Long COVID’.

It represents a set of diseases that one may develop after one has got rid of the COVID-19 virus due to the long term impact of its infection.

“How do we know that what we are seeing [in this paper] is not due to [the] long term impacts of a COVID-19 infection?”, he asked.

Vatsa also said that since the interviews of the participants – which stretched over the period of one year – were done telephonically, there was a risk of ‘recall bias’ – that is, one can’t say if the participants were accurately able to share the side effects with the researchers.

The study accepts this as one of its limitations. But it says that to reduce this bias, only those issues that were present in participants for at least one month during the course of the study were considered ‘persistent’ AESIs.

Vatsa’s other generic observations about the study included the fact that it had a small sample size – a majority of which were adolescents – raising questions about the replicability of the study’s results over a larger adult population; and its limited geographical scope – it was conducted in northern India – leading to concerns whether the results could be generalised for the rest of the country.

Vatsa also raised concerns about absence of a control group – that is, a comparison of the incidence of these post-vaccination disorders among people who were not vaccinated.

But such a comparison might not have been possible because a large majority of the Indian population had been vaccinated by the time the study was launched, and it would hence have been difficult to have a control group in the study.

The researchers who had conducted the Covaxin study also conducted a similar study on Covishield, the other vaccine administered in India.

That study had a predominantly adult-based population. It found nearly 14% of participants developed AESIs after taking Covishield, as against 33% in the Covaxin study. The incidence of the general disorders was also low in Covishield’s case.

Bharat Biotech’s response

In response to the study, Covaxin maker Bharat Biotech issued a statement raising a few points – the subjects’ AESI safety profile prior to their participation in the study; the comparison of the safety profiles of non-vaccinated subjects during the course of the study; the comparison of the safety profiles of subjects who received other vaccines during the course of the study and the following up of all study participants during the course of the study instead of only a subset.

It also claimed that “several studies have been executed on the safety of Covaxin, and published in peer reviewed journals, demonstrating an excellent safety track record.”

When The Wire mailed these points to Upinder Kaur, the BHU study’s corresponding author, she refused to react.

“I would not like to respond to the same. As we are scientists, our work is to bring information to the public domain after due peer-review. People can interpret all data as per their own expertise,” she replied.

The researchers said that since a majority of AESIs persisted for about a year, long-term surveillance of vaccinated individuals was warranted.

It must also be mentioned here that Covaxin was rolled out by the government in what it termed ‘clinical trial mode’ even without waiting for the interim results of its phase-3 trial.

This attracted sharp criticism from vaccinologists.

Eleven months after the vaccine’s rollout, the phase-3 results were published, which concluded that the vaccine was safe.

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