Bharat Harne and Sarthak Wadhwa

Prof. (Dr.) Gagandeep Kang is currently a Professor at the Christian Medical College, Vellore. Her research, among other things, focuses on viral infections. In 2019, she became the first Indian woman to be elected as a Fellow of the prestigious Royal Society. She is also co-author of the best-seller book ‘Till We Win: India’s Fight Against the Covid-19 Pandemic.’ In this interview, Bharat Harne (Editor, LSPR) and Sarthak Wadhwa (Managing Editor, LSPR) seek her insights on the ongoing Covid-19 pandemic, both in terms of what we have seen so far and what we foresee for the SARS-CoV-2 virus.

Q1. Some studies seem to suggest that there will be a third wave of the Covid-19 pandemic sometime later this year and that it will not be as severe as the second. But these studies neither saw the second wave coming nor the severe toll it took. In light of this, what are your thoughts on a ‘third wave’ and its severity?

What is frequently not recognised by policymakers and the public is that infectious disease modelling is a very specialised field. Modelers need to analyse very detailed data on the virus and the people and places affected by it to provide a quantitative framework for understanding the dynamics of the epidemic and the potential impact of mitigation strategies. Many so-called models in use in India are actually real-time statistical analyses relying on limited available data rather than the sophisticated simulation models that are needed for this. These models require much more granular data than is currently available or accessible outside of a limited group within the government and its selected partners. Therefore, though we have learnt a great deal about SARS-CoV2, there are too many unknowns to make categorical statements about the likelihood, timing, and size of a surge in cases.

While we can broadly ascertain the severity of a wave as being determined by the characteristics of the virus or variant, the people that are infected, immune or susceptible, and the environment that permits survival, there are complexities that challenge our ability to make predictions. We have had SARS-CoV2 circulating in the human population for less than two years. We do know that the more the virus replicates, the greater the chance of new variants. If a variant escapes the immune-response or encounters an uninfected or unvaccinated population, it can cause a surge in cases.  If the variant does not escape the immune-response, then I think that any third wave will be less severe than the second because the bulk of India’s population is likely to be infected or vaccinated towards the latter part of 2021. The most recent serosurvey from the Indian Council for Medical Research has announced that two-thirds of all people tested had antibodies, indicating that, as expected, most of India has been infected or vaccinated, and is likely to be protected against SARS-CoV2 unless a new variant, better at escaping immunity than we have had so far, emerges.

Q2. We have seen dangerous mutations of the SARS-Cov-2 such as the Alpha and Delta variants which have been shown to be both – more transmissible and more severe in nature. However, with previous viruses such as the very first SARS virus which appeared in 2002, it was observed that viruses mutated to such an extent become weak and ineffectual. Why does the SARS-CoV-2 appear to be getting stronger with new variants?

Firstly, SARS-CoV-1 did not mutate to become weak and ineffectual. It was a virus that was capable of spreading only after the infected person became sick and had visible symptoms. This allowed healthcare authorities to identify and isolate infected people before they could spread the infection to others. The virus was wiped out by effective infection control. Unlike SARS-CoV1, SARS-CoV2 can spread without the infected person being sick and that makes it a virus that can move around any interacting human population quite easily.

Secondly, strictly speaking, we don’t actually know that the Alpha and Delta variants have become more transmissible and more severe, although there is a clear increase in geographic spread and the number of people infected. I say this because transmissibility as a characteristic of the virus requires us to measure to how many completely susceptible people one infected person can spread the virus—the Reproductive Number or R_o. Both Alpha and Delta variants have shown increased spread after a significant part of the population was already exposed. So, the question for virologists is– immune escape or increased transmissibility? Since all people are no longer equally susceptible, we cannot measure this and we cannot extrapolate from animal studies. Nonetheless, the viruses can spread more easily and produce more viral particles, when they multiply in infected people, than the previous variants. The severity of disease with these variants is also an open question. Larger numbers of people in hospitals do not mean more severe disease if we do not know how many are infected. Think of a pyramid where you have infected people at the base, followed by tiers of mild, moderate, and severe infections and deaths—the larger the base, the larger the number in each tier of the pyramid, and hospitals will only see the top tiers of the pyramid and not the infections or mild disease which will be handled at home.

We have no evidence that SARS-CoV2 is getting better at causing disease with time, it is spreading more easily, and this may be due to increased transmissibility or immune escape.

Q3. Do you think we are doing enough to track and analyze data related to Adverse Events Following Immunization (AEFIs)? [Currently, AEFIs are tracked through the CoWin portal] What steps would you suggest to improve our monitoring system so that accurate AEFI data is available to scientists for analysis?

Our AEFI system is definitely better than it was 10 years ago when we were immunizing in the hundreds of millions of doses of vaccines and reporting a few hundred AEFIs. But are we doing enough to be able to pick up AEFIs in SARS-CoV2 vaccinated individuals? We have built a three-tier structure at district, state, and national levels. This looks good in principle but our fundamental issue is that the people who administer vaccines are asked to also report on the side effects from the vaccines their programmes have given. This creates a situation where there is a likelihood of wanting to suppress the information on side effects because it reflects badly on the immunization activities.

One way of getting away from having those who administer vaccines being the ones who need to report side effects is to put information on what and how to report in the hands of those who receive the vaccines. To some extent, this is what CoWin is supposed to do, but the digital divide means that only a proportion of the population can actually report. Further, we know that many people who have tried to report side-effects have been unable to do so, or have received no feedback.

If we compare our systems with systems elsewhere, taking Sri Lanka as an example, we have a long way to go in ensuring the quality and completeness of data, the level of investigation, and the analysis of relatedness. We need stronger, easier data systems that ensure feedback to the people reporting and this should be without fear of consequences.

Q4. Presently, India is looking into approving the world’s first DNA vaccine, i.e., ZyCov-D. This vaccine is based on a completely new technology platform that has not been tried out before. Given that it is a completely new technology, what is the likelihood of unexpected severe adverse events? Do you think that, in India, we have the institutional capabilities to accurately identify rare adverse events and treat them?

The ZyCoV-D vaccine is not yet approved, but it is likely to be. DNA vaccines are not new. There are licensed vaccines for horses and fish, but this would be the first vaccine for humans. Monitoring safety is critical for any new technology. In early-phase clinical testing, safety is paramount but it is important to understand that rare side effects are not going to be identified in pre-licensure studies. This is why building strong surveillance is essential. Given our weaknesses, we should have active surveillance planned and implemented, in addition, to strengthening the reporting systems that already exist.

Take, for example, the finding of thrombosis with thrombocytopenia syndrome (TTS), which has been identified with the adenovirus vectored vaccines. This idiosyncratic response to vaccination results in clotting with a low platelet count. We know it occurs in about 1 in 40,000 vaccinated individuals, affects younger people more, happens mostly with the first dose, and presents itself in about 4 to 20 days after vaccination. We know all this because of studies from the UK, Europe, and Australia. Sri Lanka was able to identify five patients with TTS before they gave a million doses of the Astra Zeneca vaccine. In India, we have used over 300 million doses of the Covishield/Astra Zeneca vaccine and we can barely get the clinical data to make a diagnosis of thrombosis/clotting, and in most of those cases, there is insufficient data to say that there was thrombocytopenia or a low platelet count. This essentially means that our AEFI system cannot identify rare safety signals. With new technologies, it is critical that we ensure that we have stronger safety monitoring in place. How did Sri Lanka do it? They have stronger vaccination programmes where data is closely monitored and can be easily accessed. They also ensure that reporting of a safety signal is considered a success and not a failure of the vaccination programme, and they have feedback loops that encourage reporting. We have a long way to go.

Q5- Although quite a few companies have come up with vaccines for Covid-19 – why is it that, so far, no pharmaceutical company has achieved any breakthrough in coming up with a highly effective anti-viral drug dedicated to Covid-19?

When pandemics hit, in the race for drugs, it makes sense to use what already exists and see whether it works even as we start de novo searches for new antiviral therapies. At the moment, we have a number of anti-inflammatory therapies, including dexamethasone and tocilizumab, which reduce the risk of death or progression to severe disease by dampening the runaway inflammatory response.

Among treatments that target the virus itself, monoclonal antibodies have been reasonably successful with some reducing hospitalisation and deaths in people who had not previously been exposed to the virus, but others becoming ineffective with new variants. Among antivirals that interrupt viral replication, remdesivir developed originally for Ebola (against which it was ineffective), is the only approved drug. Some studies show that it shortens illnesses, while others do not. It is not recommended by the World Health Organisation.

Antiviral therapies have many scientific hurdles. To stop the virus from multiplying, the drug has to bind to some essential viral protein or enzyme and block its activity without harming the host cell. Since viruses multiply inside cells using cellular machinery, the range of targets that can be safely addressed by small amounts of any drug molecule is limited. Further, the effectiveness of a drug might also be limited, because viruses are constantly evolving and may find a different cellular pathway to escape the effect of the drug. Efforts are ongoing, but it will take time because drugs must be both safe and effective. This requires a range of pre-clinical and clinical studies after a potential drug molecule has been chemically engineered to make it functional and easy to produce at scale.

Q6- How would you assess the performance of drug regulators of India (Central Drug Standards Control Organization and Drug Controller General of India) in the pandemic so far?

Certain regulatory authorities are recognized as stringent regulatory authorities. These include the national regulatory authorities of the US, the UK, Japan, Australia, etc., but not India. Nonetheless, India is among the national regulatory authorities that are recognized by the World Health Organisation (WHO) for the recognition of products, such as vaccines, that can be WHO pre-qualified or approved for use globally. For any regulatory authority, there is always room for improvement.

I was very pleased that India developed a draft guidance for the approval of vaccines in September 2020, which was similar to the guidance produced by the US Food and Drugs Administration (FDA). While the US FDA was able to wait until the vaccine efficacy data from phase 3 data was available before approving their vaccines, the CDSCO was unable to wait. Fortunately, although two vaccines were rolled out before efficacy data were available for one vaccine, later data showed that it was effective. We have also had some issues with the clinical trials that led to the approval of repurposed drugs for SARS-CoV2 without convincing data on efficacy, which resulted in an immense use of unproven drugs. This is unfortunate because we have had so many cases which would have been a huge opportunity for the evaluation of drugs and vaccines in well-designed studies and this has not really happened, except for a few exceptions. This is not just a problem with CDSCO but with the overall clinical ecosystem. We need to build out academic clinical research as well as a stronger regulatory authority, which requires independence and investment in regulatory science and implementation.

Bharat Harne and Sarthak Wadhwa are current undergraduate students at the National Law School of India University (NLSIU), Bengaluru.