The virus that has dominated our lives in 2020 must be chuckling to itself even as 2021 dawns, when it sees the consternation caused by its mutations and the controversies clouding the vaccines directed at it. That should not distract us from the fact that science has led a valiant battle against SARS CoV-2, from speedy characterisation of the virus to the development of vaccines at an unprecedented pace. We should not let the smoke generated by unclear regulatory rulings, crossfire between vaccine manufacturers and fusillade of political tweets obscure the path that science-led public health must follow to achieve protection from the defiant virus.
Each of the two vaccines that have been cleared by the Indian regulator has strengths of well-designed research to justify consideration but also some inadequacies of revealed evidence to warrant questions and cautious interpretation. It is very likely that both vaccines will prove useful against COVID-19 and come handy in India’s fight against it. Yet, questions must be asked and answered, because science demands it and public confidence warrants it.
So, let me raise the concerns with respect to each, not to reject either but to refine our collective understanding.
The Oxford Vaccine: Questions of Efficacy Remain
The Oxford vaccine came with considerable promise of prior research on primate corona viruses and a large multi-country trial. The harmless chimpanzee Adenovirus vector carries the code for the spike protein of SARS CoV-2 into the human body. That code, when delivered by the vector postman, is expected to stimulate the human immune response to the spike protein of the SARS CoV-2 virus and prepare the body for future combat.
The reports of efficacy and safety of the Oxford vaccine are well-publicised. There are, however, some puzzling issues that still need to be clarified. Since two doses are to be given, should they be 28 days apart or three months apart? Are both doses to be full doses or is the regimen one of half dose first and the full dose next? These questions have risen from the spate of confusing reports from the UK.
It was first claimed that the Oxford group achieved an efficacy of 70 percent – a figure extrapolated to the Serum Institute of India’s (SII) vaccine by the Indian regulator. It emerged in the UK that this was a computed estimate from two strands that accidentally emerged in the trial due to “contractor error”. The protocol compliant larger strand had two full doses administered. The aberrant strand, with smaller numbers, was reported to show 90 percent efficacy. Combining both to generate a value of 70 percent is scientifically unacceptable.
Then came an announcement from Prime Minister Boris Johnson that the UK will administer the two doses three months apart, so that the first dose can be provided to many persons for partial protection. Was that a time lag in the trial protocol? It was not initially reported to be so, but there came another twist.
A media report from the UK on December 30 quoted Professor Sir Munir Pirmohamed, Chair of the Expert Group, which reviewed the vaccine data, as saying that only 80 percent efficacy was observed and not 90 percent. That too when the doses were administered three months apart. “We looked at the half dose regimen, which has been publicised quite widely, but we felt that the results were not borne out by the full analysis,” he told a news conference, where the UK regulatory agency presented its decision.
To further create concerns, news reports states that AstraZeneca and Sputnik-V were planning a trial in which they would use their vaccines as single shots in a two-shot combo. This was because of an expressed apprehension that the Adenovirus vectors (the chimpanzee virus in one and human in the other) used in their vaccines may themselves become victims of host immunity in the second shot. This may render them incapable of delivering their booster payload of spike protein code. It was felt that better immunity can be achieved through such a combo which employs two different Adenoviruses. The currently approved vaccine carries the same Adenovirus in both shots.
Bharat Biotech: Phase 3 Trials a Must
The Bharat Biotech vaccine has provided evidence of immunogenicity and safety to the regulator. However, the Phase 3 clinical trials of efficacy was getting delayed. Would inclusion of more trial sites in the beginning have helped faster recruitment of volunteers, as at that time, there was great public concern at rising cases and deaths? Difficult to say; but the enthusiasm for participation in trials may have ebbed with the fading sense of danger.
The inactivated virus vaccine has several potential advantages. Being a known platform supplying a virus that is incapable of causing infection after entering the body, it has a high level of safety. For that reason, it can also be given to immunocompromised or immunosuppressed persons. It can be stored and transported at usual temperatures, without stringent cold chain requirements. Supply to remote rural areas should become easy for that reason. Since it is not targeting only the spike protein but also presents other antigens to evoke a broader band of immunity, the inactivated virus can potentially overcome a mutant which has made its spike protein unrecognisable to the immune response.
However attractive these considerations may seem, there is still the requirement of demonstrated efficacy in a Phase 3 clinical trial. The regulator has not made clear what continuation ‘in a clinical trial mode’ means.
Will the Phase 3 trial continue as a blinded two-arm trial, even as others receive the vaccine with monitoring of efficacy and safety? If so, the latter will not have a comparison group. Will Phase 3 and Phase 4 (post-licensure surveillance) data be gathered simultaneously but analysed separately? Did the regulator conclude, after weighing all data, that provisional approval for this vaccine may be granted in recognition of an urgent need and anticipation of an early review after the trial is completed? If so, what were the overriding public health considerations for an interim approval?
It is likely that this vaccine will prove to be effective, but the proof is not there yet, of a completed clinical trial. Let us hope it comes soon.
Approval for the Oxford vaccine in the UK did not attract media criticism or scientific challenge in the country, because the protocol deviations were openly revealed and discussed by the regulator. The conclusion of efficacy, despite the many glitches in the study, was unchallenged because of that openness.
The moral of the story for India is that regulators must share critical findings, including shortcomings of the vaccine evaluation process, with the wider scientific community and the public. If the regulator can then convincingly present that the reasoning for the decision was based on all evidence available, there would be willingness to accept some infirmities in larger interest.
On the other hand, approvals which are worded as inscrutably as Sir Humphrey Appleby’s Christmas greeting, are likely to create a backlash that hurts potentially useful vaccines. Even now, clear and credible explanations will help to build vaccine confidence.
(The author, a cardiologist and epidemiologist, is President, PHFI. He is the author of ‘Make Health in India: Reaching a Billion Plus’. This is an opinion piece and the views expressed are the author’s own. The Quint neither endorses nor is responsible for them.)