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New Covaxin Study Makes Absence of Phase 3 Data More Conspicuous

New Covaxin Study Makes Absence of Phase 3 Data More Conspicuous

A healthcare worker receives a dose of Bharat Biotech’s COVID-19 vaccine, Covaxin, at AIIMS Delhi, January 16, 2021. Photo: Reuters/Adnan Abidi

India had a torrid two months in April and May, when the country’s second COVID-19 outbreak resulted in 16 million officially reported new infections. That beats all the cases recorded until the end of March 2021 by 6:5.

Now, though the second wave may be receding, it might be leaving another problem in its wake – in the form of a new, more infectious variant that confronts us with some new unknowns.

The bulk of the cases recently recorded in different parts of India are believed to be of the highly transmissible B.1.617.2 variant, called ‘delta’ in the WHO’s new naming system.

Meanwhile, India has administered 240 million doses of the vaccines in its drive. The big question facing policymakers and public health experts at this point is whether these protect against the delta variant.

Based on a case-control design, a study from Public Health England concluded in May 2021 that, among other things, the Covishield vaccine is 33% efficacious against symptomatic COVID-19 caused by the delta variant after one dose, and 60% after two doses.

Also read: For Strong Protection Against B.1.617.2 COVID, Need Two Covishield Doses: Study

What protection does Covaxin offer against the delta variant? Researchers from Bharat Biotech and the Indian Council of Medical Research (ICMR), which developed Covaxin together, attempted to answer this question in a study published as a preprint paper on June 7.

Let’s consider its findings and understand them in the context of emerging research.

The study

The authors of this paper are from ICMR’s National Institute of Virology, Pune, and Bharat Biotech Ltd., Hyderabad.

They took sera from two groups of subjects:

1. 20 people who had recovered from COVID-19, with the sera obtained 5-20 weeks after recovery. Of these 20, 17 had been infected with the B.1 variant and three with the B.1.617.1 variant.

2. 17 people who had received their second of two doses of Covaxin, at least 28 days before the study began.

The researchers tested these serum samples for their ability to neutralise novel coronavirus particles cultured in the lab, of three strains: B.1 (the ‘original’), B 1.351 (beta variant) and B.1.617.2 (delta variant).

In simple terms, the researchers serially diluted the serum samples with the virus specimens. Then, they measured the levels – or titre – of neutralising antibodies that reduced the number of viral plaques by 50% (hence the name of the test, ‘50% plaque reduction neutralisation’). The higher the titre, the greater the level of potentially protective antibodies.

What did they find?

Broadly, the key finding was that the sera from the vaccinated people was 2.7x more neutralising against the B.1 variant than against the delta variant, on average. The sera from people who had recovered from COVID-19 was 3x more neutralising against the B.1 variant than the beta variant, also on average.

That is, the sera had a lower neutralising effect against the beta and delta variants than against the B.1 strain.

Despite this reduction in the immunological protection against the delta variant after both doses of Covaxin, the authors suggest that “its neutralisation potential is well established.”

Also read: Are Bharat Biotech’s Prices for Covaxin Justified?

Problems with the study

First, the study’s authors seem to not have understood what it means to declare any conflicts of interest in a scientific paper. They write that the “authors do not have a conflict of interest among themselves.”

One would hope that the authors are part of a team that worked together on the study and that they didn’t have any internal falling out among themselves. If their statement was not a serious error, one could be forgiven for thinking the authors were pulling our legs with it.

The obvious conflict of interest that the authors should have declared is that ICMR and Bharat Biotech together developed Covaxin, and that eight of the 13 authors were also authors of a paper in the The Lancet that described Covaxin’s phase 2 trial results.

Second: there is no detailed description of how the authors selected the recovered and vaccinated subjects for their study. This may not matter a great deal but it’s always helpful to know if, for example, the vaccinated people had been vaccinated when the delta variant was circulating or if they received their shots in the early days of the vaccination drive.

In addition, did the authors collect the participants’ blood samples before vaccination to establish if the participants were SARS-CoV-2 naïve (i.e. hadn’t been infected so far)? Or could they have had asymptomatic infections? Likewise, it would have been helpful to know when those who recovered from COVID-19 first acquired their infections.

Implications of the study

Clearly, the neutralising effect of the antibodies following Covaxin was lower against the delta variant than against the B.1 variant. Does this necessarily mean Covaxin is less efficacious against the delta variant? More than a few outlets reported that this is the case. However, so far, we have little understanding of the relationship between circulating antibody levels and protection against infection.

And it’s precisely because we don’t fully understand this relationship that we have to depend on well-conducted clinical trials (with a placebo group) to establish efficacy.

It’s also important to realise that this study, and some others, only examined humoral immunity – immunity conferred by circulating antibodies that seek to prevent the virus from entering the cells, and thus prevent symptomatic illness. This is separate from T-cell immunity, which is harder to study in the laboratory and which kicks in after the cells have been infiltrated, and attempts to prevent severe illness and death.

Again, phase 3 clinical trials are more suitable to look for and study T-cell immunity. The next best option is to conduct case-control studies, such as the one Public Health England conducted to assess the Pfizer-BioNTech and Oxford-AstraZeneca vaccines’ real-world effectiveness.

Also read: COVID Vaccines: Without WHO Approval, Covaxin Remains Second Among Equals

Taken together, the paper has no evidence to support the authors’ claim that the neutralisation potential of sera obtained from the vaccinated participants against the beta and delta variants is “well-established”.

Instead, the result of the study is that Covaxin’s neutralisation effectiveness is much lower against the beta and delta variants than against the B.1 strain.

As it happens, most of this same research team is involved in Covaxin’s phase 3 clinical trial. The trial recruited participants from November 16, 2020, to January 7, 2021, and the trial administrators followed up on the cohort of 25,800 participants through the worst of India’s second wave.

If the follow-ups were as lossless as possible and if the company and/or ICMR have sequenced the genomes of the viral samples that infected members in the cohort, then this research group is sitting on a goldmine of data. This data could answer vital questions about vaccine effectiveness against different severities of illness after infection with the delta variant.

So the best thing ICMR and Bharat Biotech could do would be to expedite the analysis of the phase 3 trial data and publish the results. Nothing will reward the altruism of the thousands who volunteered for the trial more – and nothing less will satisfy the many millions of Indians who have taken Covaxin on faith.

Note: This article originally said the Covaxin phase 3 trial finished recruitment in November 2020 when in fact it began recruiting that month. The mistake was corrected at 6:19 am on June 10, 2021.

Dr Jammi Nagaraj Rao is a public health physician, independent researcher and epidemiologist in the UK.

This work by The Wire Science is licensed under CC BY-ND 4.0

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