Mumbai: A study on vaccine effectiveness by Sir Gangaram Hospital, New Delhi published on August 16, 2021 has shown that a double dose of the Covishield vaccine is about 67% effective against moderate to severe illness with the Delta variant of SARS-CoV-2 which causes Covid-19, while a single dose is only 37% effective. Many studies have been done to test vaccine effectiveness against Delta, but not as many in India. A study by Public Health Scotland, for instance, says that vaccine efficacy against the Delta variant is only between 25% and 60%. The Sir Gangaram Hospital study also says that a double dose of Covishield has been shown to be about 97% effective in preventing deaths and 28% against symptomatic infections.

How do we, as laypersons and potential patients, interpret this study? To what extent should we rely on or be sceptical about its findings? Does it mean that we need more vaccine doses and booster shots? To understand, we spoke with the lead author of the study, Ruma Satwik from the Centre of IVF and Human Reproduction at Sir Gangaram Hospital, and with Chandrakant Lahariya, epidemiologist, vaccinologist, author and columnist.

Edited excerpts:

Dr Satwik, this study looked at 4,296 hospital staff mostly in May, when India's second wave of Covid-19 was at its peak. Could you tell us more about how the study was conducted?

RS: The idea for this study was generated by what we were experiencing. There were several anecdotal reports, and reports based on what we were seeing, that fully vaccinated individuals were contracting Covid-19 infection as well. What we needed to know was how much the vaccines are protecting [against] symptomatic infections and serious outcomes, which is what initiated the study.

Healthcare models or hospitals are the best places to perhaps conduct such studies. It has a cohort study design. This is perhaps one of the strongest study designs to assess real-world vaccine effectiveness. It divides people into three groups: one which has received two vaccine doses, another that has received a single dose, and a third [unvaccinated group] which has not received any doses at all. It compares outcomes after a very robust follow-up with participants in the [first] two [groups] versus the unvaccinated. So the study will try and tell you how much the vaccine is protecting from those baseline rates [of unvaccinated people].

What we have also done is not just make it a hospital record-based study, which means that we are not relying on hospital-based RT-PCR [test results] alone, or on hospitalised patients or hospitalised healthcare workers alone. The reason for this is that, in our own experience, we saw that many people who required a hospital bed in a city like Delhi did not find it. Even though the hospital provides equitable access to free healthcare to all its employees, irrespective of their designation, there were these two-three weeks where people could not find beds. So if we had based our study only on hospitalised [staff], it would have missed out a significant chunk of people who would have still been at home. This study thus relies on follow-up with all participants, which is why we feel that it has a very robust study design.

The third thing is the statistical analysis. It's what we call a confounder-adjusted analysis, [accounting] for influences from factors like previous Covid-19 infections, which our study shows has an independent protective effect in preventing serious outcomes. In a confounder-adjusted analysis, the protection our study is showing is the effect of vaccines alone. So, based on this, when we say that two vaccine doses are offering reduced protection against the Delta [variant], they don't seem to be protecting against symptomatic infections. That rate is significantly reduced. I don't want to take away from the protective effect of vaccines per se, so vaccines are protecting against serious outcomes. But the second thing we are saying is that single doses in the context of a Delta [variant] surge are not doing much in terms of protection.

Dr Lahariya, using this study as a starting point, how do you see where we are now in the overall battle against Covid-19 in terms of seroprevalence and the vaccination that we've achieved, and the distance that we still have to travel?

CL: First, we need more such studies to understand how vaccines are working in real-life settings. Having said that, we also need to be mindful of the study's settings when interpreting it. For example, the Sir Gangaram Hospital study which Dr Ruma has led is mostly focused upon healthcare workers in a setup which is very controlled, and where there is a high level of exposure [to Covid-19]. So this is an important study for that particular population. But we should be a little careful in comparing it with other setups, such as the Public Health England study which has been done in the general population, because the exposure [to Covid-19 infection] in general populations is very different from the exposure in hospital setups. That's the first caveat we need to remember.

Second, we should not worry too much about all symptomatic infections. We know that vaccines prevent moderate to severe illness, and that's where we need to see [vaccine] effectiveness, rather than [against] any symptomatic infection. We know vaccines do not prevent mild infection. When we compare all symptomatic infections, the efficacy or effectiveness in real life comes down. That is not a concern for me.

Coming to single-dose effectiveness, I would again add caution because that depends upon various parameters. We know that vaccines work and they take around three weeks before developing antibodies. The approach to measure effectiveness against a single dose is very different. For example, what Public Health England did was a sample size of hundreds of thousands of people, and that's how we know it was very different from a hospital setup. So we need to remember all those caveats. What this study shows, and what we already know, is that the vaccines are working against moderate to severe illness and mortality. That's what the purpose [of vaccines] is.

Finally, I would like to flag that the Delta variant is, of course, highly transmissible. And we know that when this study was conducted, when vaccination was happening, Delta was the most commonly circulating variant. So the mere fact that the vaccine effectiveness against a circulating variant is very similar to the previous [strain], which was found during the study, is very reassuring to me. We don't have to worry. All people need to do is get the first and second shot of the vaccine and then keep following Covid-appropriate behaviour.

So whether it's from the Sir Gangaram Hospital study or from the Public Health England or Public Health Scotland studies, overall, you're more than happy with the protection the vaccines are seemingly offering right now?

CL: That's correct. We are not worried about mild symptomatic infections or asymptomatic infections. The purpose of vaccination is to prevent moderate to severe illness, which essentially means hospitalisation and mortality. And this study has found that this vaccine [Covishield] is working against moderate to severe illness and mortality, and reducing hospitalisation. That's what we have found in the United Kingdom and also in the United States. Wherever people were vaccinated, even with the increase in the Delta variant, the number of hospitalisations has come down drastically, though infections are high. This is very reassuring, in my opinion.

Dr Satwik, give us the 'inside-the-hospital' view. If you were to look at any disease prevention, any vaccine, how does Covid-19 vaccination stack up?

RS: The study does not take away from the importance or need for vaccines. Like Dr Lahariya correctly identified, this study is saying that two doses are working. The other difference between our study and other studies, I think, is that other studies have shown some protective effect of a single dose. And perhaps, the previous studies and trials on single doses have led to a change in vaccine policy and a prolongation of the interval between first and second doses. Our submission here through our data analysis is only that if you are anticipating a surge, especially in areas where seroprevalence is low, you are better protected with two doses than with a single dose. It will not be prudent to allow unprotected susceptible populations to rely on the effect of a single dose alone.

When you say vaccination is 97% effective in preventing deaths and 28% against symptomatic infection, how should a layperson interpret this? Is this very good? Is it the best that medicine can do to keep you protected against a pandemic? Or is this a halfway point?

RS: In terms of deaths and moderate to severe disease, I think vaccination is achieving its mark. It could have been better with respect to moderate to severe illness. We have shown an effectiveness of 75% [of full immunisation with Covishield against the need for oxygen therapy]. But, you have the world's data to consider. It is not just this vaccine, but with mRNA vaccines as well. Studies have repeatedly shown that efficacy or effectiveness against symptomatic infections, against hospitalisation is lower [against the Delta variant] with respect to most vaccines. So it is the virus that is evolving, we have to understand this, and vaccines should evolve with the virus.

Dr Lahariya, give us the 'outside-the-hospital', epidemiological, public health point of view. There is now talk about booster doses in some countries, though not in India as yet. Is vaccine effectiveness not for as long as we thought it would be?

CL: Before I come to the booster dose, let me talk briefly about the findings of the Sir Gangaram Hospital study once again. One point we need to remember is that the findings of any study are applicable for the population in which the study was done. So, for example, this is for a hospital set up so we cannot generalise this for the general public. Thus there is limited value for making policy decisions on how our general population should be vaccinated.

Second, the 75% effectiveness against moderate to severe disease is really very good, which essentially for the general public means that among vaccinated people, the rate of infection was 75% less than in unvaccinated individuals. A 75% effectiveness against hospitalisation is a really big number. We need to remember that WHO [World Health Organization] had set a cutoff of 50% for this.

About booster doses, I personally believe that there is emerging evidence that people who develop natural infection are likely to have antibody protection for really, really long. There was one study in Nature magazine on May 24, 2021, which identified that even after 11 months of recovery from illness, people had Covid-19 antibodies and they were properly protected. We know that there is antibody-based protection and that antibody level goes down with time, especially after four months of vaccination. But whether that translates into reduced protection or not, we do not really know because we do not know the correlates of protection. Similarly, there is a T-cell-based response, which assures us that the person is likely to be protected.

In my opinion, some countries [are recommending booster doses] a little too early, based upon very small studies. Pfizer-BioNTech and other companies are saying, based on studies on just 20-100 people, that subsequent shots increase the level of antibodies, which is likely to provide protection against the Delta variant. But that is not enough scientific evidence to argue for booster shots.

Second, the vaccination programme is a combination of scientific evidence and operational feasibility. We know that we don't have enough scientific evidence to argue for a booster shot. Then there is the operational feasibility part, which is that there is a large part of the world population that has not received even a single dose. So the world should be thinking globally [about] supply of the vaccine as a single unit, and people should be receiving their first and second shot before booster shots can be considered.

Finally, I would like to flag that we need to separate people into two groups. One is the specific population which immunologically requires a third shot, as part of the primary immunisation schedule for some immunocompromised people (not more than 2% of the population in any setup). That should not be considered a booster shot--that's a different story. But for people who need only two shots, the world is not ready--and there is not enough evidence--to give them a booster shot. India should defer that.

Dr Satwik, many people in India were vaccinated in January 2021, when the first vaccines started being administered. Doctors, healthcare and other frontline workers were being vaccinated. What's your sense from within the hospital on whether those who were vaccinated much earlier need another shot now?

RS: We will only notice in the context of the third Covid-19 surge, as and when that happens. But I can tell you that studies are underway from the microbiologists within our hospital that look at antibody decay with time, and very soon we should be out with that data. That's a different set of authors.

Looking at whether booster shots would be needed, I would say if natural infections are giving you the highest protection as of now, and there can be reinfections after six months--which is the minimum duration that we saw for protection from a secondary infection--it is entirely possible that the effect of vaccines may wane after a certain time.

Dr Lahariya, how long do vaccine effects last? I took a yellow fever vaccine that was supposed to last for 10 years. Many vaccines we take as children are supposed to last forever.

CL: That is something that is continuously evolving based on scientific knowledge. You gave yellow fever as an example. Once initial protection was given, it was recommended that people take the yellow fever vaccine again after another 10 years. But current evidence says that once you have taken the yellow fever vaccine, it provides protection for life and you don't have to take a second shot ever. Similarly for hepatitis B, earlier people needed to take Hepatitis B booster shots after 10 years or so, but the current recommendation is that once you have received three shots of the Hepatitis B vaccine, it will provide lifelong protection. With flu vaccines, regular annual shots are required. So this varies for different vaccines.

However, in the case of Covid-19, I personally think that we are still developing a better understanding of the virus, the disease and protection. What we do know is that whenever we are in the high transmission period of the pandemic, the people who are getting naturally infected might be protected [from severe disease] for long--possibly lifelong. As long as we are in the pandemic, except for high-risk populations or some identified groups, a healthy individual may not require a booster shot in the subsequent period. So, based on current knowledge, primary immunisation should reach each individual first; then a booster shot may or may not be needed. It possibly would be required for high-risk populations after two years or something. Current evidence is that it's not required within one year. We don't know what happens after one year, because not that much time has gone by since vaccination started.

Dr Satwik, the second Covid-19 wave has ebbed in India, we're at around 40,000 cases a day, lower than some other countries. What are you seeing today which could be early signs of another wave, or possible changes in the way the virus is behaving?

RS: I think Dr Lahariya is best placed to answer that, but what I can say is that the hospital admissions of Covid-19 are at the lowest; they have been there for the past one-and-a-half to two months. A lot depends upon how we behave in future, and upon how much the vaccines are able to protect us beyond six months of use. Most people, at least most healthcare workers, at this point would be at six months from their first dose. So a third surge, if that happens, my sense is that it should not be as much as what we saw in April, because the susceptible populations would be much lower. However, one needs to wait and see what it is like, whenever this third surge starts.

Dr Lahariya, as you look at data and at anecdotal evidence, as you talk to people, what is the sense that you're getting right now about future Covid-19 waves?

CL: What we need to remember is that before the start of the second wave, around 75% of the population in India was susceptible to Covid-19, because we know through the third serosurvey that around 25% of the population had developed antibodies. With the fourth nationwide serosurvey, we know that 67.6% of the population has antibodies. That was at the [serosurvey] mid point of June 25, 2021, and since then an additional population has been vaccinated. So, we can confidently assume that 75% to 80% of the population would have some form of protection, either from natural infection or after vaccination.

Since the susceptible population has come down, with current knowledge, we can say that if and when the third wave or subsequent waves would happen, it will be far smaller. The worst-case scenario, according to some of the groups like IIT's Sutra consortium, is around 150,000 daily Covid-19 cases. The realistic scenario is 70,000 to 80,000 daily cases. [For context, India had about 98,000 daily cases at the peak of the first wave and 414,000 daily cases at the peak of the second.] So we can be really hopeful that [the third wave] would not be really that bad. But that does not mean that we can be carefree. We need to follow proper precautions as we are still evolving our understanding.

Finally, this will also depend upon whether a new variant emerges. We know scientifically that the same Delta variant which caused the second wave is unlikely to cause another wave in such short succession. But if a new variant emerges, the situation and scenario could be different. And as long as the virus is circulating, there is the possibility of new variants. That's why we need to be careful. But we can be assured that [the third wave] will be definitely far smaller than the previous one.

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