What exactly do clinical trials for a new vaccine involve?
The first step after a potential vaccine is developed is to try it out on animals to check that it is not toxic and that it leads to an immune response. If this step is successful, the next stage is to move to human trials, where these preliminary trials are called phase 1 trials.
In such trials, healthy volunteers (typically 20-50 in number) are injected with one of a range of possible doses of the vaccine, to determine the optimal and safe dose, starting from very small doses. Whether the vaccine elicits an immune response is also verified. In phase 2 trials, the immune response is examined further, and questions of side effects and safety are also explored in a larger group of volunteers, typically more than 100.
Finally, phase 3 trials involve administering the vaccine to a much larger group, often tens of thousands of people, selected to be representative of the population. These trials are called “randomized control trials”. In these trials, about half the participants enrolled are given a placebo, something that is harmless to the body, while the other half is given the vaccine. No one knows, not even the doctors administering it, whether the injection contains a placebo or the real thing.
In India, emergency use authorization has been granted to two vaccines: Covishield, made by the Serum Institute of India and Covaxin, made by Bharat Biotech.
Since Covaxin didn’t complete its phase 3 trials and publish them, what can we confidently say about its efficacy?
At the moment we can say little since there simply is no data yet. In the much smaller phase-1 and phase-2 trials, the vaccine elicited a robust immune response, making antibodies against the virus. The vaccine was also shown to be safe in appropriate doses. It is based on an inactivated whole-virus vaccine platform which is well-understood. However, it is important to understand that efficacy—whether a vaccine works well at preventing you from getting the disease under ideal conditions—is not a simple and immediate consequence of immunogenicity, the ability of a vaccine to provoke an immune response. That is why we need phase 3 trials in the first place.
Is there a broader misunderstanding of immunogenicity and efficacy? What is the difference and why is it important?
A vaccine should certainly provoke a response from the immune system. That’s central to how vaccines function. But whether it works in preventing people from getting the disease – protective immunity – is a harder question and there are a few things that could go wrong. One extreme case is that getting vaccinated might, paradoxically, increase your chances of severe disease, through what is called ADE or antibody-dependent enhancement. Another possibility is a vaccine-associated enhanced respiratory disease, in which antibodies induced by the vaccine bind with viruses and form immune complexes that clog the lungs. These are possibilities that a phase-3 trial should rule out.
How is Covaxin going to complete phase 3 trials?
What should happen, in principle, is the following: The scientists running the trial will wait till a certain number of people, a number pre-approved in the trial protocol, within the group that received an injection, are diagnosed with COVID-19. They then go back and check whether these people belonged to the group that was administered the placebo or the actual vaccine. If there are many more cases in the placebo group than the vaccine group than can be accounted for by chance, that suggests that the vaccine works in protecting against developing the actual disease.
The problem is that it may take some time to reach this stage of having a predetermined number infected with the disease. Since most people develop no or only mild symptoms of the disease, they may not notice they have been infected.
A second problem is that phase-3 trials are being done in a background where a good number of people have already been infected in the past, so are immune to the disease for at least some time, as far as we know. These people won’t develop the disease even if they encounter an infected person.
Finally, currently in India, all this is happening in the background of a steadily decreasing number of new cases. This makes it harder to have new infections in the trial group.
Why aren’t people given a choice on which vaccine they would prefer?
The government, which is, after all, making these vaccines available for free at this point, may have wanted to ensure that they did not appear to be favouring one over the other when granting emergency-use approval. Perhaps there is also an element of national pride in this, in that Covaxin is a fully indigenous vaccine while Covishield is the result of a collaboration with international groups, at Oxford University and the pharmaceutical giant AstraZeneca.
What, according to you, is the biggest health concern with not having any efficacy data on Covaxin?
Whenever one is administering a vaccine to a healthy person, one would like to know that it has been worth it. Does the vaccine, for example, provide protection against the disease to more than 50% of the population it is administered to? A phase-3 trial, precisely because it is so large and planned as a randomised control trial, is a good way to ask this question as well as to look out for possible rare but serious side-effects of being vaccinated.
Would it have been a better move to rollout Covaxin after phase 3 clinical trial data was published? Why do you think it was encouraged over other alternatives?
It would have been better to rollout Covaxin after the efficacy data became available, in my opinion. Data demonstrating good efficacy and safety, which could have taken another month or so to obtain, would have spoken for itself.
Of course, these decisions have to be made based on available information as well as projections for what might happen in the future, such as new variants that are more transmissible. There are certainly cases where granting emergency use authorisation might have been justified. This is why scientists as well as the lay public need to understand the basis on which these decisions were made.
The committee that approved Covaxin distribution may have had data that was shown to it that suggested that it was efficacious. We don’t know because neither the names of the committee members nor the minutes of their deliberations are available to us.
Transparency should always be a central consideration in such matters, especially since you will be vaccinating people who are healthy and you don’t want to compromise on safety.
Considering how the vaccination drive is going right now, do you think vaccine hesitancy is slowly eroding and that target numbers will be met?
Yes, the numbers of those getting vaccinated each day are steadily increasing. That is a good sign. Unlike in the USA and some other developed countries, there is no strong anti-vaccination movement in this country and people are accustomed to large-scale immunization programs, such as the pulse polio campaign.
Do you think the vaccine rollout should’ve been critiqued more or less than it was by the Indian scientific community? What could have been different?
I think the sections of the scientific community that critiqued the Covaxin rollout did the right thing. Prof. Shahid Jameel of Ashoka University and Prof. Gagandeep Kang of the CMC Vellore, in particular, were sane voices in this, pointing out gently, but firmly, the need to stick to established procedure. One has to ensure that the public does not feel that they would be guinea pigs. Several fellows of the Indian Academy of Science also signed a document expressing their concern.
I was dismayed at the counter signature campaign, supporting the Covaxin rollout, from a group of 49 medical doctors and scientists. Their arguments made little sense to me.
Can anything be said about whether the current vaccine candidates can be effectively used for the new strains of the virus?
There is some encouraging news of the effectiveness of some of the international vaccines against the new strains, although perhaps not at the same level. Bharat Biotech has claimed very recently that its Covaxin was effective against the UK variant of the virus. Our understanding is rapidly evolving.
Do you think that the overall vaccine development process has changed in the course of the global effort in formulating a COVID-19 vaccine?
Absolutely. I thought, as many others did, that a period of 18 months to two years would be the minimum time required for a vaccine to be distributed. That we managed to do this in less than a year is a remarkable achievement. Without our ever-improving knowledge of both basic and applied science, this would simply have been impossible. Indeed, it would have been impossible even a decade ago.
I am, in many ways, proud of what India has achieved. The Serum Institute of India, located in Pune, is the world’s largest vaccine manufacturer. Bharat Biotech, the manufacturers of Covaxin, has a manufacturing plant that is the largest of its kind in the Asia-Pacific region. It is a respected company which exports therapeutics and vaccines across the world. India itself produces 60% of global vaccines. The Director-General of the WHO commented recently that “…the production capacity of India is one of the best assets the world has today”.
As an Indian, this does make me very happy.
Gautam Menon is Professor of Physics and Biology at Ashoka University as well as Professor of Theoretical Physics and Computational Biology at the Institute of Mathematical Sciences in Chennai. He works in biophysics as well as in, more recently, the modelling of infectious disease.
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