India: How ICMR and Others Spun Covaxin’s Phase 1 Trial Results Out of Context

Even though ICMR chief Balram Bhargava is one of the paper’s authors, he has attempted to hype up its results.

On January 23, the Times of India published a story under the headline, “Amid efficacy row, Covaxin gets a thumbs up from Lancet”.

This ‘efficacy row’ (see here and here) pertained to the Indian drug regulator’s decision to approve Bharat Biotech’s COVID-19 vaccine candidate – BBV152, now known as Covaxin. And the newspaper’s ‘thumbs up’ referred to a paper published in the British medical science journal The Lancet.

The newly published peer-reviewed paper adds technical details to the preprint paper, of the same phase 1 trial of BBV152, that was previously available online.

(A preprint paper is the manuscript that its authors have directly uploaded to the internet, to be widely accessible and which will be subjected to a public post-public peer-review. A peer-reviewed paper is technically a manuscript that has been published by a scientific journal, after peer-review.)

Even the usually staid Indian Council of Medical Research (ICMR) took to Twitter to proclaim – with an all-caps headline – “Lancet Infectious Diseases publishes remarkable results of ICMR and Bharat Biotech’s indigenous COVID-19 vaccine”. Considering that ICMR director-general Balram Bhargava is one of the paper’s authors, someone in the organisation should have pointed out the unnecessary hype and spin in that tweet.

 

While the January 21 paper is indeed a welcome and much-needed scientific advance in the ongoing development of vaccines against COVID-19, we need to calmly and rationally assess it for what it is. By way of a broad summary, to quote directly from the paper: “BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted.”

In the rest of this article, we will see what this paper adds to our knowledge, and why the attempts to spin the results are unwarranted and disingenuous.

The clinical trial process

The objective of a vaccine against a new viral infection is to get enough of the virus safely into the human body to stimulate the natural defence mechanism in sufficient strength. This is complex and complicated science, and we can be justly proud that India is one of few countries with the scientific expertise and technological capacity to develop and manufacture vaccines at scale.

The process starts in the laboratory, with a study of the virus and its chemical, antigenic and genetic make-up. The next step is animal studies, which check that the candidate vaccine is not toxic or lethal and that it stimulates an immune response. Challenge studies – in which an animal is administered the vaccine and exposed to the virus – can also establish that the immune response generated by the vaccine protects the animal. Of course, the ‘challenge’ can happen only in controlled conditions.

Conventionally, the first human experiments are called phase 1 trials: healthy volunteers are injected with one of a range of possible doses, to determine the optimal dose for further research in phases 2 and 3. Given the emergent nature of the COVID-19 pandemic, researchers and officials have together expedited almost all candidate vaccines through these phases.

BBV152 phase 1 trial

The Lancet published online on January 21 a peer-reviewed paper by Raches Ella and 23 colleagues that described the phase 1 clinical trials of Bharat Biotech’s candidate vaccine, Covaxin. On January 3, 2021, the Drug Controller General of India granted it “restricted emergency use” approval.

Covaxin is an inactivated version of the SARS-CoV-2 virus that causes COVID-19. It is combined with one of two adjuvants: Algel (basically alum) and Algel-IMDG. While alum as adjuvant is common, Algel-IMDG is an innovation known to preferentially promote a particular kind of cell-mediated immunity, known as a T-helper cells 1 (Th-1) response. The other kind of T-cell mediated immune response, Th-2, is associated with cytokines. And we all know by now that a cytokine storm could make matters worse.

ICYMI: Explained: What is a Cytokine Storm?

Ella and his colleagues started this phase 1 study in July 2020. They recruited 375 volunteers out of 897 who had been screened for suitability in 11 centres around India. The chosen people were then randomly assigned to four groups to receive two doses of the following formulations:

A: 3 micrograms of inactivated virus + Algel-IMDG

B: 6 micrograms of inactivated virus + Algel-IMDG

D: Algel only, to serve as a control

Indian health minister Harsh Vardhan holds a dose of Bharat Biotech’s COVID-19 vaccine called COVAXIN, during a vaccination campaign at All India Institute of Medical Sciences (AIIMS) hospital in New Delhi, India, January 16, 2021. Photo: Reuters/Adnan Abidi

The results

As anyone would expect in a first research report on a new vaccine candidate, there is a great deal of rich technical detail.

Seroconversion – the body’s production of virus-neutralising antibodies – occurred in 88% of Group A, 92% of Group B and 83% of Group C. It also occurred in six of the control group, possibly due to natural asymptomatic infections. The responses in Groups A to C were similar to those observed in the serum of 41 patients who had recovered from COVID-19.

A minority of subjects reported local adverse reactions and solicited adverse reactions in a few more. (‘Solicited’ here means the research team discovered the reactions during a planned check-up. When participants report reactions voluntarily, they’re called ‘unsolicited’ reactions.)

The broad conclusion from this paper is that BBV152 – either the 3-µg or the 6-µg formulation – is a potentially promising vaccine candidate. Both are probably safe and certainly immunogenic. We don’t know how long Ella et al followed up with the participants, so, by the authors’ own acknowledgement, there is “no data either on persistence of vaccine induced antibody responses or on longer term safety”.

As is standard practice, The Lancet commissioned an independent commentary on this study. Christina Rostad and Evan Anderson, both of the Emory University School of Medicine, Atlanta, noted that there will probably be a shortage of vaccines to meet global demand and so there will always be a need for several vaccines. They discuss at some length the “lingering concerns” about 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”. This risk is due to the Th-2 type immune response.

Also read: How Covaxin Trial Participants in Bhopal Were Misled

(Antibody-dependent enhancement: “Some antibodies can bind to the pathogen the second or third time it infects the body and ‘smuggle’ it into the body’s cells, so to speak” – source)

The Bharat Biotech team dealt with this potential concern by using a particular adjuvant called IMDG (imidazoquinoline chemosorbed to be ‘sucked’ onto a surface by chemical bonds onto aluminium hydroxide gel). Their studies with animals (as reported in preprint papers) found that BBV152 elicited neutralising antibodies in hamsters and macaques, as well as that it protected against illness when challenged with the virus – “without evidence of enhanced respiratory disease”.

Rostad and Anderson also noted differences in the type of antibody response in groups given the Algel-IMDG adjuvanted formulations, suggesting the presence of a Th-1 immune response.

Dr Able Lawrence, a professor of immunology and rheumatology in Lucknow’s Sanjay Gandhi Institute of Post-Graduate Medical Research and Education, agreed.

“One of the potential risks of a vaccine based on an inactivated whole virus particle is an unintended vaccine-associated enhanced respiratory disease upon infection with the coronavirus,” he told this author.

“In their Lancet paper, Ella and colleagues don’t show the Th-2 cytokine data and we cannot assume that the Th1-biased immune response will translate into efficacious clinical protection. The ultimate proof that this is sufficient to avoid a Th2-based enhancement of disease can only come from much larger, pragmatic phase 3 studies.”

Rostad and Anderson would agree: they conclude their commentary with three pending questions:

2. Will IMDG (as part of the adjuvant) prove sufficient to avoid a Th-2 response?

3. Is enhanced disease a risk?

The Bharat Biotech team that conducted this well-reported phase 1 trial would also agree. They state categorically in their paper: “The results reported here do not permit efficacy assessments. The analysis of safety outcomes requires more extensive phase 2 and 3 clinical trials.”

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

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