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Covaxin Trial’s Info Sheet Skips Mention of Two Rare but Known Risks

Covaxin Trial’s Info Sheet Skips Mention of Two Rare but Known Risks

A man applies finishing touches to graffiti showing a vaccine, in Kolkata, January 2, 2021. Photo: Reuters/Rupak De Chowdhuri.

Bengaluru: Last week, Union home secretary Ajay Bhalla wrote to state chief secretaries asking them to prosecute people who make “misleading claims” about the “safety and immunogenicity” of the two vaccine candidates in India’s ongoing COVID-19 vaccination drive. These are Covaxin, made by Bharat Biotech in Hyderabad, and Covishield, by Serum Institute of India, Pune.

Covaxin in particular has been in rough weather because the Drug Controller General of India (DCGI) approved its use sans any data of its safety and efficacy (taken together) from phase 3 clinical trials. And observers noted that Bhalla’s request could only deepen mistrust instead of alleviate it.

As it happens, the third and fourth versions of the information sheet Bharat Biotech has shared with recipients of Covaxin – based on which they are required to make an informed decision about receiving a dose – do not mention two risks associated with vaccines of its kind. These risks pertain to antibody-dependent enhancement (ADE) and vaccine-associated enhanced respiratory disease (VAERD).

ADE happens when some antibodies bind to a virus as it is infecting the body after the first time – but instead of fighting it, the antibodies might sneak it into the body’s cells and help found an infection.

Alternatively, the antibodies could bind with the viral particles brought by the vaccine to form large molecules, called immune complexes, that go on to block the lungs. This is VAERD.

Gaps in knowledge

“I feel misled,” a volunteer in Covaxin’s phase 3 clinical trials, who received their second dose on January 5, 2021, along with the fourth version of the information sheet, told The Wire Science. “If I had been told that there is the possibility of me experiencing exacerbated disease, I would have not participated in the trial. I live with folks who have a high risk of COVID-19; this puts them at risk too.”

The volunteer also said it “feels stupid” to discover the possibility of ADE and VAERD, no matter how unlikely, from an article in the press instead of from Bharat Biotech. “How is it informed consent if the information given to me is incomplete?”

The article in question, by UK-based public health physician Dr Jammi Nagaraj Rao and published by The Wire Science on January 24, discussed a paper The Lancet had published three days earlier. It was written by Bharat Biotech researchers and described Covaxin’s phase 1 clinical trial that they had conducted in July 2020. The article also addressed an independent commentary that The Lancet had commissioned to discuss the paper’s implications for the medical research community. This commentary, penned by two scientists from the Emory University School of Medicine, Atlanta, stated:

Despite [the] favourable phase 1 results, concerns linger regarding the potential for an inactivated whole-virus vaccine to elicit antibody-dependent enhancement of infection or vaccine-associated enhanced respiratory disease upon SARS-CoV-2 infection.

The commentary’s authors, Christina Rostad and Evan Anderson, go on to discuss the reasons to believe Covaxin may reduce the risk of ADE and VAERD.

One is that pre-clinical trials with hamsters and rhesus macaques indicated Covaxin may not provoke the more dangerous immune response that leads to ADE or VAERD. Bharat Biotech researchers have uploaded preprint papers with these results.

The other is centred on the adjuvant Covaxin uses. An adjuvant is a substance that accentuates the immune response. Covaxin uses imidazoquinoline chemically adsorbed onto an aluminium hydroxide gel, forming a compound dubbed Algel-IMDG. The vaccine candidate can provoke one of two broad kinds of immune responses, and IMDG can reportedly bias against the less desirable one – something Bharat Biotech MD Krishna Ella has said as well. However, IMDG hasn’t yet been tested in humans.

In light of this gap, as well as the need for a larger trial, Rostad and Anderson added that they don’t yet have enough information about the vaccine candidate to say with meaningful certainty that it won’t cause ADE or VAERD in human recipients. “These questions might only be answered in a more diverse multinational phase 3 trial, which must comprehensively assess efficacy and long-term safety,” they finish.

Bharat Biotech’s information sheet only states the following:

A screenshot from the Bharat Biotech information sheet for Covaxin, dated January 5, 2021.

Unlikely but known

Anant Bhan, a bioethics and health policy expert at Yenepoya University, Mangalore, was more cautious. “It is not possible to include all potential side-effects of a vaccine. Otherwise the information sheet could be 60 pages long,” he said.

Then again, he continued, “it is better to err on the side of caution if an outcome is known, even if unlikely, especially of a certain vaccine platform” (or type). For example, and to compare, consider the following portion from the information sheet accompanying phase 2/3 clinical trials of AstraZeneca’s vaccine candidate in the UK (emphasis in the original):

In the past, experimental vaccines were developed by different research groups against the SARS virus, which is in the same family as the COVID-19 virus and also infects the lungs. In some cases, animals that received certain types of experimental SARS vaccines appeared to develop more severe lung inflammation when they were later infected with SARS compared with unvaccinated animals. There has also been one report of this increased disease associated inflammation being seen in a mouse study for a vaccine against MERS-CoV (another related virus) but this has not been observed in any other reported animal studies. These problems were not seen in animal studies with ChAdOx1-MersCoV vaccine, which is very similar to the vaccine being used in this study, when the animals were exposed to the wild virus. Studies of the ChAdOx1 nCoV-19 vaccine in animals are currently ongoing but: we do not yet know whether this could also be a side effect of exposure to the pandemic COVID19 virus in this COVID-19 vaccine study, whether this effect could occur in humans or whether this might lead to more severe COVID-19 disease in some cases.

The information sheet that Serum Institute of India has been distributing among recipients of Covishield doesn’t contain this level of detail either, and doesn’t mention ADE or VAERD – by these or other names. The Covishield vaccine candidate is AstraZeneca’s candidate rebranded for the Indian market.

“Whether or not a vaccine causes ADE and/or VAERD depends on the virus and the vaccine in question, including whole-virion inactivated vaccines,” a virologist The Wire Science spoke to said. Covaxin is one such. ADE and VAERD “are not common at all but that is why we have large trials to check” if they could be in play.

Indeed, phase 3 trials for vaccines aimed at new viruses typically involve many thousands of participants, often across multiple regions. One reason is to create the chance for the vaccine to produce a rare effect – and see if it does. Another is that unlike other drugs, vaccines are administered to healthy people, so they need to be safer as well as to a higher degree of certainty.

But the volunteer in Covaxin’s phase 3 clinical trial told The Wire Science that the third and fourth iterations of Bharat Biotech’s information sheet for trial participants do not mention the risk of ADE or VAERD – even though the data the company has submitted to the DCGI thus far and the medical literature together imply that this risk has yet to be completely eliminated.

The Wire Science has seen copies of these two documents (version #3 is available to view here). The volunteer received their second dose of Covaxin on January 5, 2021, and the fourth version of the factsheet corresponds to this date. Prime Minister Narendra Modi kicked off India’s vaccination drive on January 16.

The volunteer also said they had written to the Indian Council of Medical Research, which helped Bharat Biotech develop Covaxin and is the trial’s co-sponsor, and to the trial’s principal investigator Dr Krishna Mohan, with their concerns. The volunteer did not receive a reply.

Sandhya Srinivasan, a researcher and consulting editor at the Indian Journal of Medical Ethics, described the events surrounding Covaxin’s approval as “worrying” and “ridiculous”. But “just the fact that this invisible, theoretical risk exists and has not been mentioned is outrageous,” she added.

‘Clinical trial mode’

On January 3, 2021, the DCGI, Dr V.G. Somani, had approved Covaxin and Covishield for “restricted” use and added that Covaxin could be used in “clinical trial mode”. Dr Samiran Panda of the Indian Council of Medical Research subsequently explained that Covaxin’s use in the first stage of the vaccination drive will be treated as an open-label, single-arm clinical trial.

‘Open label’ means the vaccine administrators will know the identity of the people who are vaccinated; ‘single arm’ means there won’t be a comparator group. This is a group of randomly assigned volunteers who will receive a placebo – a substance that ought not to have any effects – or a form of treatment deemed to be the currently accepted standard. When the trial ends, researchers will compare outcomes in the vaccine group to those in the comparator group to quantify the relative significance of the vaccine’s effects.

The information sheet is a document that Bharat Biotech personnel hand out to Covaxin’s recipients – both in the phase 3 clinical trial, which has enrolled around 26,000 volunteers, and the open-label trial – so that they may read it and based on its contents make an informed decision about receiving Covaxin. Similarly, Serum Institute will hand the sheet for Covishield out to potential recipients, although they won’t be enrolled in a clinical trial.

A screenshot from Serum Institute’s information sheet for Covishield, dated January 1, 2021.

Bhan added that it was also possible the Covaxin trial’s investigators had informed the ethics committee that they are excluding the mention of ADE or VAERD from the information sheet “but are going to actively look out for these outcomes during the trial itself”.

The Wire Science emailed Bharat Biotech, Dr Mohan, Krishna Ella and ICMR chief Balram Bhargava with requests for comment. We will update this article as and when we receive a response.

Note: This article was originally published on January 28 and was republished at 8:30 am on January 29. It was updated at 2:10 pm on January 28, 2021, to note that Bharat Biotech researchers had uploaded preprint papers of preclinical trials with hamsters and rhesus macaques.

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