‘Providing a vaccine to a healthy person without knowing the statistical probability of protection is unethical’

Dr. Vineeta Bal, immunologist and Faculty, Indian Institute of Science Education and Research (IISER), Pune, and former scientist, National Institute of Immunology, New Delhi, disagrees with the emergency use approval given to Covaxin, the COVID-19 vaccine by Bharat Biotech, on the grounds that there was no evidence yet on if and how it provided protection. Excerpts from an interview with The Hindu’s Jacob Koshy.

Two vaccine candidates have been given emergency use approval in India — Covishield and Covaxin. Both have weaknesses in terms of what is known about them. Two full doses of Covishield in overseas trials showed 62% efficacy, but we don’t know how safe and immunogenic it is in Indians. Covaxin has some safety and immunogenicity data but absolutely no efficacy data. From what’s publicly known, are both these vaccines at least comparably safe? Is one ‘safer’ than the other?

Both have undergone safety testing in experimental animals as well as in Phase-1 human trials. They appear as safe as most of the vaccines currently in use — both childhood vaccines as well as adult vaccines. It is not possible to compare safety between the two vaccine candidates in further minute detail based on data currently available in the public domain.

However, while Covishield efficiency is based on clinical trials in more than one country, and is above the statutory limit put in by the Central Drugs and Standards Control Organisation (CDSCO) for emergency approval, there are no such data on Covaxin.

The Indian Council of Medical Research and several scientists in the government have justified the roll-out of Covaxin in clinical trial mode because of the potential transmissibility of the U.K. strain of the virus. Is that reasonable?

The justification provided is lame. It is not reasonable on a scientific basis. It has also violated norms set up for vaccine/drug approval for emergency use by the same CDSCO which has granted the permission. The sanctity of due process is violated. Since the Covaxin trial has not reached a stage where it can show protection from the existing strains of the virus, there is no reason to believe that it will do so for a mutant [strain].

In the context of COVID-19 in India, is any vaccine that’s at least not harmful but shows promise in animal studies and limited human trials, better than no vaccine at all?

No. There are ethical concerns for the use of drugs, devices, vaccines, etc., and they need to be followed. Otherwise we are losing out on what we have achieved as a civilised society over the years — we go back to a Hitlerian era. Experimenting on Jews, on prisoners, on blacks without consent was practised then and is not acceptable now. Providing a vaccine to a healthy person without knowing the statistical probability of protection is unethical.

 

Besides, COVID-19 is not a highly dangerous disease, unlike some of viral diseases with very high mortality, such as Ebola. That kind of justification also cannot be invoked for such an approval. In fact, in India, the number of cases is steadily falling over the past many weeks. Thus, the so-called emergency-like situation, when infrastructure shortage was a major concern in September 2020, does not exist any longer. In such a scenario, why flout the rules set by authorities keeping safety and efficacy concerns in mind?

From the perspective of immunology, is it true that a whole, inactivated virus could provide better protection against mutated strains, such as the B.1.1.7 ‘U.K.’strain? Have we seen that happen with other viruses in history?

We have come a long way in vaccine development during this pandemic. In the history of vaccines, each [vaccine] took roughly 5-20 years to complete clinical trials and reach the mass vaccination stage. And it was rare that more than one type of vaccine for the same disease was getting developed in parallel, unlike the present situation. What is needed is clinical trial data where native and mutant strains are spreading, and two vaccines are being tested — one with a small portion of the virus, such as the Receptor Binding Domain [RBD, or the part that latches on to the body’s cell to gain entry] as a vaccine, and the other with the whole virus. This is too hypothetical and unethical/impractical.

 

In theory, no generalisation can be made in response to your question. But more specifically, if too many mutations take place in the RBD, it is likely that the virus will stop binding to ACE2 and hence will become non-infectious. Thus virus strains with only ‘permissible’ mutations are likely to stay and the ‘polyclonal’ antibody response triggered by the RBD is likely to be sufficient for quite some time to come. Eventually, the current vaccines may become ineffective because of accumulation of serial mutations. But we don’t need to worry about it in the immediate future because this virus does not mutate very fast.

Whole virus vaccine will trigger antibodies to many more antigens than an RBD-based vaccine. But for viral spread, RBD is the critical domain and antibodies against non-RBD antigens matter minimally.

Could you explain what exactly is a better immune response? Like good and bad cholesterol, are there good antibodies and ‘bad antibodies’?

Ideally, for the prevention of a viral disease, both neutralising antibodies and killer T cell responses are critical and protective, and hence ‘good’. Any vaccine should aim to trigger these responses in adequate quantity and last for a long period. Helper T cell responses [the Th1 and Th2 kind] are necessary to get better quality [as defined by binding to the target with higher strength or ‘avidity’] antibody responses. However, T cell testing is much harder technologically and lab-to-lab variability in the assays is much more than antibody assays. Hence, of the ‘protective immunity’ component, mostly neutralising antibodies get tested, that too in a subset of patients.

In response to your question, neutralising antibodies are certainly good antibodies. Most others (non-neutralising) cannot be called bad antibodies until proved. Their utility may be limited. Some antibodies on binding to their targets lead to ADE [Antibody Dependent Enhancement of viral infection] and they can be labelled as ‘dangerous’ or ‘bad’ in your parlance. But in an immune individual amongst a large number of antibodies, such ADE causing antibodies are pretty much impossible to identify.

Does AstraZeneca-Oxford’s published Phase-1 and Phase-2 trial data show that it produces a ‘better’ immune response than Covaxin?

A major problem is that data of this kind is not comparable at the moment. The trial protocols were different; labs where assays were done were different; and in the same trial, two or more candidates were not used in parallel for any comparison. The WHO’s SOLIDARITY trial [for vaccines] proposed for vaccine candidates did not come through. If that was done, it would have been possible to compare based on lab parameters to some extent.

Are DNA vaccines like that being tested by Zydus Cadilla, and m-RNA vaccines like that of Pfizer and Moderna, inherently better than inactivated-virus vaccines? Is inactivated virus-technology outdated and should all vaccinology be ultimately moving away from it?

So far, no DNA or mRNA based vaccine has been approved for mass use. The two current vaccines approved for emergency use and a few more in the pipeline are the first generation ones for large-scale use. While they appear safe based on all the short-term data that is accumulated so far, it is better to be cautious and report all the side effects of these vaccines for future assessment.

Inactivated vaccines have their utility. Whether technological advances, which made early development of mRNA and DNA vaccines possible for SARS-CoV-2, will make inactivated vaccines redundant in the future remains to be seen. Inactivated vaccines are low-tech. But as you will notice, they can be stored at 2-8 [degrees] C unlike the two mRNA vaccines! Lower and middle-income countries would find inactivated vaccines more practical to store and use as compared to the mRNA vaccines in emergency use today.