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What makes people tick? What are the stories they carry with them? In a world of shouting heads, veteran journalist, radio commentator and novelist Sandip Roy sits down to have real conversations about the fascinating world around us and the people who shape it. Catch these engaging interviews every other Sunday

Episode 77 May 30, 2021

Dr Gagandeep Kang addresses the concerns around India’s vaccine policy

How efficacious are the COVID-19 vaccines? Do some vaccines work better than the others? How worried should we be about breakthrough infections? How did India, the world’s biggest vaccine supplier, run into a vaccine shortage? And when will enough vaccines be available? In this episode, Sandip talks to Dr Gagandeep Kang who answers these questions, and addresses the concerns around India’s vaccine policy.
Transcript:
As the US contemplates taking off masks, India extends lockdowns, or whatever we are calling them, in different states to combat the second Covid wave, as well as a vaccine shortage. So there are two questions that have us worried – One, are the vaccines that we have working as well as we hope? Because every other day we hear about someone we know who had been vaccinated but still had to be hospitalised. And 2, how did the world’s biggest vaccine manufacturing country suddenly run into a vaccine shortage.

We asked Dr Gagandeep Kang, to help us figure out these issues. She’s a microbiologist and professor at the Christian Medical College in Vellore, and pioneered the Indigenous RotaVirus vaccine.

Sandip Roy
Dr Gagandeep Kang, welcome back to the show.

Dr Gagandeep Kang
Happy to be here again, Sandeep.

Sandip Roy
Let me jump straight into something that’s been on everyone’s mind, which is the efficacy of the vaccines we are using against the strains that are most prevalent now in India. There was a recent study that just came out in the UK. Could you explain that a bit for us, what the findings were?

Dr Gagandeep Kang
So this was an observational study, the Public Health England and a lot of researchers in the UK have been tracking the data on what’s happening with their rollout. When the UK decided to introduce vaccines into their program in December of 2020, they decided to go with a 12 week interval between the two doses of vaccine. And what they found was that there has been a reduction in both morbidity and mortality.

Now, they’ve also done other studies to look at whether these vaccines decrease transmission and they have demonstrated that there is a 50% reduction in household transmission with a single dose of either the AstraZeneca or the Pfizer vaccines. This study focuses on symptomatic infections, and what it shows is that with the AstraZeneca vaccine giving a single dose results in a 33% reduction in symptomatic vaccine efficacy. After you give two doses, this rises to about 60 percent. Pfizer, on the other hand, seems much more efficacious for the first dose and also increases for the second dose.

Now, the question really is, what do these data mean when you have B.1.617.2 circulating? Now in the UK, a decision has been made to reduce the gap between the two AstraZeneca doses to eight weeks, particularly in older individuals. Again, important to place this in context. In the UK, they have pretty much managed to finish immunizing older individuals with a single dose. They followed a very strictly age descending strategy, so right now they are offering bookings for immunization for people who are in their mid 30s.

So I think for them, it’s a very sensible decision to make. Does this apply to India? I think I’d like to know a little more before making a call on that, because in India we have much higher rates of infection in our population, so we don’t know the percentage of people for whom a first dose of vaccine is actually their second encounter with the virus, which could quite significantly influence our ability to translate the UK data directly to India.

The other thing that’s important for your listeners to remember is that the UK deciding to reduce its gap to eight weeks is a decision that is not based on evidence of what happens with an eight week gap. I’m sure as soon as they start implementing the eight week gap, they will be providing us with data very, very quickly on how the 8 week gap compares to the 12 week gap.

Sandip Roy
But in our case, Dr Kang, now that we have actually increased the gap from 6-8 to 12-16 weeks, is there any data out there for 16 weeks?

Dr Gagandeep Kang
So in fact, if you look at interviews that Andy Pollard, who has led the studies of AstraZeneca vaccine in the UK, he actually advises a gap of three to four months because that is the gap that gives the best immune response. There are also data that come from the phase three clinical trials where the best efficacy was seen in those who received the vaccination after 12 weeks. So there are data that support a 12 to 16 weeks interval, but I think the most important thing to remember is that when it comes to generating real world evidence, you really have to do it in the context where you are using the vaccines. And unfortunately, we have very very limited data that has come from the over 190 million doses of vaccine that have been given in India.

Sandip Roy
When we see that AstraZeneca has 60% efficacy, what’s that against infection, serious infection or death?

Dr Gagandeep Kang
So I think it’s important again to understand that when you do phase three efficacy studies, everything related to that magic number of 60 or 90% relates to what you have defined as your primary outcome. So if you say that we are measuring efficacy against severe disease, then you have to have a definition of severe disease. Is this a requirement for oxygen? Is it a requirement for hospitalization? Is it a requirement for a ventilator? So depending on how you define where severe disease starts, your assessment of how the vaccine is performing will change. In the case of the AstraZeneca vaccine, we’ve got so many numbers because there were so many arms to these trials. They had, I think, 12 groups in the UK that they were studying. And there is a simpler, larger study that was done in the US. Somehow people seem to ignore the US study, but the US study was done with a four week gap and showed an efficacy of over 75%. So it’s very important to remember that it is design and measurement that influence the number that you finally wind up with for efficacy.

Sandip Roy
Well, the logic of a larger population getting at least one dose as opposed to a smaller, more vulnerable population getting both, only holds if one shot offers a signal of a significant protections and knowing that if the efficacy of one shot at AstraZeneca is about 30 percent, would it not have made more sense to get more of the 45+ people covered with both doses..

Dr Gagandeep Kang
It depends on what you’re trying to prevent, because the data are 33% against any symptomatic infection, not against severe disease or death. We don’t currently have the data on how one dose is protecting against severe disease and death, except for what we have seen reported before, for B117 predominant circulation of virus which was 80%. So is it that for B.1.617.2? So when people talk about immunizing people with two doses, I’d really like to see the data before we make yet another switch.

Sandip Roy
Speaking of data, though, has it surprised you that the number of breakthrough infections that have been happening?

Dr Gagandeep Kang
I think it’s important to remember that, one, health care workers are a special population. They have much higher rates of exposure than others and are also likely to be tested at higher rates. Now, if you follow the numbers again and do a deeper dive into how many people develop symptomatic infections and how many people died after receiving both doses of vaccines, those are the numbers that we should not see as just, I know five people who died. It’s five out of how many vaccinated individuals. And as I said, in India we’ve given 190 million plus doses of vaccine, of which 90%, I believe, is Covishield and 10% is Covaxin. For both vaccines, there are enough people vaccinated for us to have information on how these vaccines are performing if we had set out to measure that.

Unfortunately, it doesn’t seem that we did, or if the government has the data, we have certainly seen it. Remember, with the Pfizer vaccine being used in Israel, we had data on half a million vaccinated individuals and half a million unvaccinated individuals that were published in February. With a vaccination program that started towards the end of December. So I think this is very very doable if we have the right data systems and we are committed to being able to analyze and interpret our own data.

Sandip Roy
Isn’t this weird that we don’t seem to have this..

Dr Gagandeep Kang
So this is my problem with evidence. Everybody expects you to be certain, right? How many doses do you need? What should the dose be? What’s the dosing interval? How well will the vaccine work? And it has to be exact. But for science to become more and more exact requires more and more experimentation. So given that we were giving out these vaccines, why did we not say, ‘OK, four weeks is how the vaccines were evaluated in the clinical trial that was done in India. Why can’t we just ask people or randomised people to receive vaccines at 4, 6, 8, 10, 12, 14, 16, whatever we want, weeks. And then we will make sure that we follow them up to figure out what the optimum dosing interval is for us in order to achieve efficacy against this defined outcome that really matters. We could have done it. We can still do it. The only way to reduce uncertainty is to make sure that you generate the evidence.

Sandip Roy
So have we come to a point where one can say that one vaccine is better than others, at least against certain kinds of mutations? Because reading the articles out there, it seems that M-RNA vaccines seem to be working the best against the variants.

Dr Gagandeep Kang
So at least in terms of this latest study from the UK with the AstraZeneca and the Pfizer vaccines, it does look like there might be a difference. But once again, this is symptomatic infection and I’d really like to see the outcomes stratified by severity and by which variant we are looking at severity with. It’s very rare actually to have this kind of data where you have a head to head comparison between two vaccines that have been used in the program. So I think the world kind of owes a huge debt of gratitude to countries that are releasing data so quickly. I wish we could contribute in a similar way. We certainly have a large enough population and enough vaccines to do that.

Sandip Roy
The French Nobel laureate Luc Montagnier has attracted a lot of attention lately by saying that stronger infection by variants in vaccinated individuals might result due to antibody dependent enhancement. What does that mean? Is he basically saying that vaccines create variants?

Dr Gagandeep Kang
So he seems to have said a number of different things. One of which is that variance will arise more easily in a vaccinated population and that’s unlikely because the whole point in vaccination is to be able to shut down virus replication. Even if you get infected with the vaccine, you tend to have much lower viral loads, which means that the virus is replicating at a lower level and a virus that multiplies less, replicates less, is less likely to mutate. So you are less likely to have variants arising in the vaccinated population than in a population where the virus can spread and multiply unchecked.

There is a very special situation and that applies to not vaccination, but to infection where some people who are immunocompromised for a variety of reasons, may have prolonged replication of the virus and in them, with RNA viruses, variants can develop. We know this from infections like HIV. But people who are immunocompromised are a very special population. Sadly, most people who are immunocompromised because of primary immuno-deficiencies can, if not looked after, appropriately die quickly. And secondary immune-compromise happens because of steroid treatments, transplants, chemotherapy. So a special population that would guard against infection in any case would be less likely to transmit to others. So I don’t think that first part about variance arising more in vaccinated individuals holds.

The second and very fancy sounding film of antibody dependent enhancement essentially is something that is borrowed from other viral infections. And a good example of that is Dengue. Where your first dengue infection in the canonical understanding of dengue tends to be quite mild, but then if you get a second degree infection and it’s of a different type of dengue virus, then your second infection might be much worse and might result in dengue hemorrhagic shock. So that is believed to happen because when you’re infected with dengue, you don’t make enough antibodies to be able to protect you against the second infection, and the antibody molecule that is made actually acts something like a Trojan horse and allows the virus to get inside cells of the immune system where it would not normally go.

Now the question is, will something like that happen with SARS-COV-2? Well SARS-COV-2 is a single type of virus. So then you have to think about are the variants different enough to act like a second type of virus? And will you see antibody dependent enhancement because of that? Well, so far all that we’ve seen is that vaccination for SARS-COV-2 builds up a reasonably high level of neutralising antibodies. And once you have a high level of neutralising antibodies, the other non-neutralising antibodies that would carry the virus into immune cells have no room to function. So, so far absolutely no evidence that antibody dependent enhancement occurs in people who have been vaccinated. Strictly speaking if this was variant dependent then in people who were getting reinfected with SARS-COV-2, we should expect to see the same phenomenon. And so far, there have been no immunological studies that have demonstrated that. Certainly something to keep an eye on but the longer we keep watching for it the less likely it seems.

Sandip Roy
So Dr Kang, viruses will continually mutate, I assume that means there’s probably a second or third generation variant of the B.1.617.2 already out there. How do we handle the fact that variants will be continuously outpacing vaccination?

Dr Gagandeep Kang
I think we need to get ahead of the variants and the only way you can do that is by vaccinating a larger and larger proportion of the population. Viruses mutate when they are multiplying. And essentially, if you can protect people and reduce multiplication in humans, then you’re reducing the population of viruses that are around and you will have less variants. We already have a test case in countries that have generated variants in the past, like the UK and the US, where they’ve had distinct variants arise in different parts of the countries that have then spread to other parts. Now that both of those countries have widespread vaccination and reasonable sized populations, reasonable mixtures from people traveling, it’ll be interesting to see – one, will new variants arise in a better vaccinated population? And two, if new variants are introduced from outside into the country, will they be able to establish a foothold and spread in a vaccinated population? So watch this space.

Sandip Roy
Isn’t our vaccination rate currently falling faster than the infection rate?

Dr Gagandeep Kang
Currently, we are vaccinating at a relatively low rate and this is a concern, but I think what is going to happen is that we will have more vaccine available in the latter part of this year and then we’ll be able to ramp up vaccination even more. What we should be doing and absolutely must do in India is to make sure that no doses of vaccine go to waste. An outstanding example is Kerala, where they use the extra amount of vaccine that is available in every multi dose vial to give out more doses. So Kerala has vaccinated more people than the doses of vaccine it has received. That’s a fantastic example of how a health care system has paid attention to detail and made the best of what it’s got.

Sandip Roy
So according to what you’re seeing out there, what is the vaccination timeline that you foresee? We’re obviously well behind what had been promised.

Dr Gagandeep Kang
Yes, I think projections based on what some of the vaccines companies had told us was a little optimistic, and we continue to be optimistic in the projections that are currently being made, but I think from a sort of clearer sighted view of where we are with vaccines, there is no question that vaccine production capacity will increase marginally in July and then will begin to ramp up. I’m anticipating that from September onwards we should be seeing more vaccine, particularly if Zydus Cadila trials are successful and Bio E is able to deliver its phase three data by August. Then we will have a substantial increase in the number of doses. But if those two trials don’t go well, then we will continue to have very restricted supply.

From the global markets, we know that there are very very few doses available relative to the size of India’s population, and I’m a little concerned that if we have too many products coming into the country, then the public health system would find it a little difficult to manage that many kinds of vaccines to be delivered to different populations.

Sandip Roy
So given the vaccines that are currently out there, which are Covishield and Covaxin, and speaking of data what will it take for Covaxin to get WHO approval? I mean, what has been the stumbling block? Because from what I can tell, if Covaxin doesn’t get on the vaccine passport, then people who’ve taken Covaxin here are going to be at a singular disadvantage when it comes to travel, etc.

Dr Gagandeep Kang
Based on the data that we have from the two interim analyses for Covaxin I have no doubt that Covaxin will be able to generate the documentation package that is required for WHO prequalification. But I think it’s a matter of time, not a matter of the quality or the performance of the product.

Sandip Roy
And what is the data that we do have on the other vaccine that is coming, which is Sputnik?

Dr Gagandeep Kang
So Sputnik has been questioned for the limited amount of data that it has put out in the public domain, and I think it’s in a sense unfair to single Sputnik out for the lack of clinical trial data because we don’t have that from a lot of manufacturers. But questions have been raised about Sputnik’s chemistry manufacturing and controls, and questions about the clinical data that they have published. What Sputnik needs to do is to ensure that that concern is addressed, to demonstrate across multiple batches that there is no replicating virus in the vaccine doses.

Sandip Roy
But given that they haven’t done that yet, or they are yet to do that, is it advisable for us to be rolling it out?

Dr Gagandeep Kang
Well, our regulator has evaluated the batches that have come into India and has certified that they are OK. Sputnik is manufactured at multiple sites in Russia, so this may be a manufacturing site issue. I really have no information on the details of that.

Sandip Roy
So that brings us to the larger question which we’ve been tussling with over the last month or more, which is why does the vaccine factory of the world not have enough doses for its own population? I mean, we knew our population. So the demand supply shouldn’t be rocket science, so to speak.

Dr Gagandeep Kang
Well, look at it from the announcements that were made last year. The government initially made it clear that it intended to vaccinate only 300 million people, and that meant that they would need 600 million doses. And 600 million doses by the end of December 2021 continues to be very feasible.

Now the question is, was the 300 million an accurate projection of what would be required? Well, the rest of the world was convinced at the time that it needed to vaccinate a much larger proportion of the world, and it seems the Indian government came around to that point of view, but did that much later. So while we know the size of our population, it’s also a question of commitment from the national program on what percentage of the population it intended to cover. Where I’m concerned, I think we need to vaccinate everybody. I think we will ultimately need to vaccinate children as well. So I think our projections should be for what it will take to vaccinate our population.

Sandip Roy
Yeah because in the UK, the National Health Service took advantage of their lockdown to aggressively vaccinate the population. We currently have lockdowns in many parts of the country, but there’s not enough vaccines for us to take advantage of that, to vaccinate aggressively.

Dr Gagandeep Kang
That is true. And I think in the UK they kind of vaccinated themselves out of the wave that they were having, so much so that they are thinking about opening up more freely in June and have opened up quite a lot already. For us, the size of our population is both a strength and a limitation. There is no way that we will be able to open up confidently without having a large proportion of our population vaccinated.

But I also am beginning to switch my thinking from the WHO prioritisation framework to consider what kinds of experiments in vaccination are possible while we have a limited supply. Should we go with what we could call a spray and pray approach, where you get a tiny dose of vaccines in any demographic and that’s an equitable way to do it? Or should we be thinking about concentrating vaccination in specific areas? Or specific populations to be able to really answer questions on the impact of vaccination? And in a situation of limited supply these are choices that we have to make.

Sandip Roy
So what do you think about the CDC in the US saying that actually masks will not be necessary soon? What will it take us to get to that point? Or can we think about getting to that point in the foreseeable future?

Dr Gagandeep Kang
Well the foreseeable future depends on how long you’ve got to live. So I think for the CDC to make that decision, one, the US is in a situation where their cases are plummeting. Not absent, but have come down quite significantly. Their immunisation rates have gone up. And one way to think about the ‘remove the mask’ mandate is that for the people who are not currently vaccinated (it) would be an incentive to be mask free, be something that encourages you to get vaccinated. There are many US academics, and I tend to agree with them, that I think the masks are coming off a bit too early.

Infections have declined hugely, a large proportion of the US is vaccinated, but I think taking off masks should depend very much on the level of control locally and not at the national level. And we should have guidance that tells us that if infections or test positivity rates will go above a certain level, then the masks should come back on. There have been umpteen studies done around the world that show that masks reduce infection by at least 40%

Sandip Roy
So at the time of great shortage, we heard a lot of talk about relaxing or waiving of the US patent laws. Could you just explain whether that happened and what’s going to be the significance of that if it happens?

Dr Gagandeep Kang
So there are three things that you need for this framing. The first is intellectual property. The second is technology transfer. And the third is resources for manufacturing. Now, waiving intellectual property during the course of the pandemic is a necessary first step. The move is a good one. It is one that sets a precedent for what will happen in future pandemics as well. So I think it’s something that we should applaud, but we also should not place unreasonable expectations on what will happen just because of an IP waiver, because without the other two components, it’s not going to make a significant change in the amount of vaccine that is available to developing countries.

You need technology transfer and finding the right people to do those transfers is very, very difficult. Doing transfers for drugs is much simpler than doing it for vaccines. And I’m told by Indian vaccine manufacturers as well as people globally, that there is a huge shortage of people who have experience in tech transfers.

And the third is resources. If you don’t have the right chemicals, substrates, filters, fillers, bags, vials, stoppers, rubber bungs to be able to make vaccines at the scale that you want to make them, then you’re not going to be able to make vaccines. And currently, practically every component of a vaccine is in short supply. If we look at what happens with routine immunisation programs or pre pandemic, the world used about 4 billion doses of vaccine every year. And we are now in a situation where we are talking about needing 16 billion doses of vaccine to be able to vaccinate the world with two doses. Even if you say let’s leave children out of it, at the moment, you’re talking 10 to 12 billion doses. So that is 3 times the capacity of the world to produce vaccines in the pandemic period. So just IP? Not enough.

Sandip Roy
Got it. And what about the controversy around vaccine pricing, is that going to impact the rollout?

Dr Gagandeep Kang
There are many things about government policy that I don’t understand, and this is one of them. How can the centre and state pay different prices for the same product? I’m not sure that I know of any example where this has happened before, where the central government can negotiate a price and then the state price is set by the companies, and there is yet a third price for the private sector.

It seems now from communications that are publicly available that the Centre is keeping the 50% that it had allocated to itself, but is also deciding on the allocations that go to the state. So even though the state is buying it, the number of doses is decided not by the company, but by the Centre. So that seems even more confusing to me and nobody is sure what number of doses are going to the private sector.

Yet it does look like you can get appointments for a private sector vaccination much easier than you can get a free vaccine in a state. And that private sector vaccination seems to be available to some of the larger hospital chains, but maybe not elsewhere. So I really don’t know what’s going on.

Sandip Roy
That could set up a very much a vaccine have and have not situation. Do you have any sense of the situation in rural India right now? From which all the data seems to be very spotty.

Dr Gagandeep Kang
Yes, rural India is a bit of a black box. Mainly because we just don’t have systems of surveillance and testing in rural parts of the country. I’ll give you an example of some work that we did. We were trying to map typhoid across the country and we found that there were lots of studies that were set in cities and there were practically no studies from rural India. So we went out hunting across the length and breadth of the country to find small places that could set up to do blood cultures. Took an incredible amount of training, investment, to build a picture of how bad typhoid is in the country and it’s there in rural areas that just had not been measured. Urban areas are worse affected, but there was no place in the country where we didn’t find it. Now, in the absence of surveillance systems, it’s easy to say that there isn’t disease in rural areas.

But at least in terms of vaccination, given that we have the routine immunisation program that runs in rural areas, we should be able to vaccinate people there and get data on them. But all the data that are coming out for SARS-COV-2 vaccination right now seem to indicate that coverage in rural India is very, very low. People don’t necessarily know about the vaccine. Also the requirement for registering on this CoWin app has created a situation of digital haves and have nots. And the solution is not find a friend.

Sandip Roy
So what will be the effect of this on the rest of India, because at one level we are saying India’s current Covid second wave crisis is of importance to the world because what happens in India is not going to just stay in India. So what happens in rural India is also not going to necessarily stay in rural India.

Dr Gagandeep Kang
Absolutely not. And that’s why ramping up vaccine coverage is important. The problem, of course, is that we’ve had a routine immunisation program that has improved over decades. But this adult immunisation is the first time. There are some states that have done adult immunisation for Japanese encephalitis, but pretty much nothing else. I mean, even for things like Cholera where using vaccines to control an outbreak, makes sense, we just don’t do it. So building out an adult immunisation program in rural areas is a significant challenge, and the sooner we have ways of addressing it, the better.

Sandip Roy
What is going to be the effect of this on the larger Covax program for low income countries?

Dr Gagandeep Kang
Serum Institute has made commitments to sell a large number of doses to Covax, and it had a delivery schedule that it’s fallen far behind. This, of course, means that countries that were expecting to get vaccines through the Covax facility will have to wait until India solves its problems and allows for a vaccine to be exported. I think as a global community, no one has a doubt that India needs the vaccines that it is producing at the moment and will continue to need them for a while. But I think the world is now beginning to think that it made a miscalculation in relying so heavily on India. So for future pandemics, I think we’ll see a much more distributed manufacturing of vaccines in parts of the world that are likely to need vaccines in a pandemic.

Sandip Roy
And what would you say to a layperson now who says in the middle of this second wave that if I still need to wear masks, observe social distancing and still see way too many people I know who are vaccinated end up in hospital? What’s the point? How is my quality of life improving as a result of vaccination?

Dr Gagandeep Kang
I think it’s very important to understand that vaccination masks and distancing and ventilation are the tools that we have. We need to use a combination of all of these tools until we can suppress virus replication that allows us in a phased manner to dispense with some of them. The first to go, I guess, would be the requirements for lack of crowding and distancing. And after that, we could think about removing masks and trying to get back to normal, as long as we have a vaccinated population that functions in environments where air handling is an additional safeguard for reducing the risk of infection.

Sandip Roy
Dr Gagandeep Kang, thank you so much for joining us today.

Dr Gagandeep Kang
Thank you


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Dr Gagandeep Kang addresses the concerns around India’s vaccine policyHow efficacious are the COVID-19 vaccines? Do some vaccines work better than the others? How worried should we be about breakthrough infections? How did India, the world’s biggest vaccine supplier, run into a vaccine shortage? And when will enough vaccines be available? In this episode, Sandip talks to Dr Gagandeep Kang who answers these questions, and addresses the concerns around India’s vaccine policy. Transcript: As the US contemplates taking off masks, India extends lockdowns, or whatever we are calling them, in different states to combat the second Covid wave, as well as a vaccine shortage. So there are two questions that have us worried – One, are the vaccines that we have working as well as we hope? Because every other day we hear about someone we know who had been vaccinated but still had to be hospitalised. And 2, how did the world's biggest vaccine manufacturing country suddenly run into a vaccine shortage. We asked Dr Gagandeep Kang, to help us figure out these issues. She's a microbiologist and professor at the Christian Medical College in Vellore, and pioneered the Indigenous RotaVirus vaccine. Sandip Roy Dr Gagandeep Kang, welcome back to the show. Dr Gagandeep Kang Happy to be here again, Sandeep. Sandip Roy Let me jump straight into something that's been on everyone's mind, which is the efficacy of the vaccines we are using against the strains that are most prevalent now in India. There was a recent study that just came out in the UK. Could you explain that a bit for us, what the findings were? Dr Gagandeep Kang So this was an observational study, the Public Health England and a lot of researchers in the UK have been tracking the data on what's happening with their rollout. When the UK decided to introduce vaccines into their program in December of 2020, they decided to go with a 12 week interval between the two doses of vaccine. And what they found was that there has been a reduction in both morbidity and mortality. Now, they've also done other studies to look at whether these vaccines decrease transmission and they have demonstrated that there is a 50% reduction in household transmission with a single dose of either the AstraZeneca or the Pfizer vaccines. This study focuses on symptomatic infections, and what it shows is that with the AstraZeneca vaccine giving a single dose results in a 33% reduction in symptomatic vaccine efficacy. After you give two doses, this rises to about 60 percent. Pfizer, on the other hand, seems much more efficacious for the first dose and also increases for the second dose. Now, the question really is, what do these data mean when you have B.1.617.2 circulating? Now in the UK, a decision has been made to reduce the gap between the two AstraZeneca doses to eight weeks, particularly in older individuals. Again, important to place this in context. In the UK, they have pretty much managed to finish immunizing older individuals with a single dose. They followed a very strictly age descending strategy, so right now they are offering bookings for immunization for people who are in their mid 30s. So I think for them, it's a very sensible decision to make. Does this apply to India? I think I'd like to know a little more before making a call on that, because in India we have much higher rates of infection in our population, so we don't know the percentage of people for whom a first dose of vaccine is actually their second encounter with the virus, which could quite significantly influence our ability to translate the UK data directly to India. The other thing that's important for your listeners to remember is that the UK deciding to reduce its gap to eight weeks is a decision that is not based on evidence of what happens with an eight week gap. I'm sure as soon as they start implementing the eight week gap, they will be providing us with data very, very quickly on how the 8 week gap compares to the 12 week gap. Sandip Roy But in our case, Dr Kang, now that we have actually increased the gap from 6-8 to 12-16 weeks, is there any data out there for 16 weeks? Dr Gagandeep Kang So in fact, if you look at interviews that Andy Pollard, who has led the studies of AstraZeneca vaccine in the UK, he actually advises a gap of three to four months because that is the gap that gives the best immune response. There are also data that come from the phase three clinical trials where the best efficacy was seen in those who received the vaccination after 12 weeks. So there are data that support a 12 to 16 weeks interval, but I think the most important thing to remember is that when it comes to generating real world evidence, you really have to do it in the context where you are using the vaccines. And unfortunately, we have very very limited data that has come from the over 190 million doses of vaccine that have been given in India. Sandip Roy When we see that AstraZeneca has 60% efficacy, what's that against infection, serious infection or death? Dr Gagandeep Kang So I think it's important again to understand that when you do phase three efficacy studies, everything related to that magic number of 60 or 90% relates to what you have defined as your primary outcome. So if you say that we are measuring efficacy against severe disease, then you have to have a definition of severe disease. Is this a requirement for oxygen? Is it a requirement for hospitalization? Is it a requirement for a ventilator? So depending on how you define where severe disease starts, your assessment of how the vaccine is performing will change. In the case of the AstraZeneca vaccine, we've got so many numbers because there were so many arms to these trials. They had, I think, 12 groups in the UK that they were studying. And there is a simpler, larger study that was done in the US. Somehow people seem to ignore the US study, but the US study was done with a four week gap and showed an efficacy of over 75%. So it's very important to remember that it is design and measurement that influence the number that you finally wind up with for efficacy. Sandip Roy Well, the logic of a larger population getting at least one dose as opposed to a smaller, more vulnerable population getting both, only holds if one shot offers a signal of a significant protections and knowing that if the efficacy of one shot at AstraZeneca is about 30 percent, would it not have made more sense to get more of the 45+ people covered with both doses.. Dr Gagandeep Kang It depends on what you're trying to prevent, because the data are 33% against any symptomatic infection, not against severe disease or death. We don't currently have the data on how one dose is protecting against severe disease and death, except for what we have seen reported before, for B117 predominant circulation of virus which was 80%. So is it that for B.1.617.2? So when people talk about immunizing people with two doses, I'd really like to see the data before we make yet another switch. Sandip Roy Speaking of data, though, has it surprised you that the number of breakthrough infections that have been happening? Dr Gagandeep Kang I think it's important to remember that, one, health care workers are a special population. They have much higher rates of exposure than others and are also likely to be tested at higher rates. Now, if you follow the numbers again and do a deeper dive into how many people develop symptomatic infections and how many people died after receiving both doses of vaccines, those are the numbers that we should not see as just, I know five people who died. It's five out of how many vaccinated individuals. And as I said, in India we've given 190 million plus doses of vaccine, of which 90%, I believe, is Covishield and 10% is Covaxin. For both vaccines, there are enough people vaccinated for us to have information on how these vaccines are performing if we had set out to measure that. Unfortunately, it doesn't seem that we did, or if the government has the data, we have certainly seen it. Remember, with the Pfizer vaccine being used in Israel, we had data on half a million vaccinated individuals and half a million unvaccinated individuals that were published in February. With a vaccination program that started towards the end of December. So I think this is very very doable if we have the right data systems and we are committed to being able to analyze and interpret our own data. Sandip Roy Isn't this weird that we don't seem to have this.. Dr Gagandeep Kang So this is my problem with evidence. Everybody expects you to be certain, right? How many doses do you need? What should the dose be? What's the dosing interval? How well will the vaccine work? And it has to be exact. But for science to become more and more exact requires more and more experimentation. So given that we were giving out these vaccines, why did we not say, 'OK, four weeks is how the vaccines were evaluated in the clinical trial that was done in India. Why can't we just ask people or randomised people to receive vaccines at 4, 6, 8, 10, 12, 14, 16, whatever we want, weeks. And then we will make sure that we follow them up to figure out what the optimum dosing interval is for us in order to achieve efficacy against this defined outcome that really matters. We could have done it. We can still do it. The only way to reduce uncertainty is to make sure that you generate the evidence. Sandip Roy So have we come to a point where one can say that one vaccine is better than others, at least against certain kinds of mutations? Because reading the articles out there, it seems that M-RNA vaccines seem to be working the best against the variants. Dr Gagandeep Kang So at least in terms of this latest study from the UK with the AstraZeneca and the Pfizer vaccines, it does look like there might be a difference. But once again, this is symptomatic infection and I'd really like to see the outcomes stratified by severity and by which variant we are looking at severity with. It's very rare actually to have this kind of data where you have a head to head comparison between two vaccines that have been used in the program. So I think the world kind of owes a huge debt of gratitude to countries that are releasing data so quickly. I wish we could contribute in a similar way. We certainly have a large enough population and enough vaccines to do that. Sandip Roy The French Nobel laureate Luc Montagnier has attracted a lot of attention lately by saying that stronger infection by variants in vaccinated individuals might result due to antibody dependent enhancement. What does that mean? Is he basically saying that vaccines create variants? Dr Gagandeep Kang So he seems to have said a number of different things. One of which is that variance will arise more easily in a vaccinated population and that's unlikely because the whole point in vaccination is to be able to shut down virus replication. Even if you get infected with the vaccine, you tend to have much lower viral loads, which means that the virus is replicating at a lower level and a virus that multiplies less, replicates less, is less likely to mutate. So you are less likely to have variants arising in the vaccinated population than in a population where the virus can spread and multiply unchecked. There is a very special situation and that applies to not vaccination, but to infection where some people who are immunocompromised for a variety of reasons, may have prolonged replication of the virus and in them, with RNA viruses, variants can develop. We know this from infections like HIV. But people who are immunocompromised are a very special population. Sadly, most people who are immunocompromised because of primary immuno-deficiencies can, if not looked after, appropriately die quickly. And secondary immune-compromise happens because of steroid treatments, transplants, chemotherapy. So a special population that would guard against infection in any case would be less likely to transmit to others. So I don't think that first part about variance arising more in vaccinated individuals holds. The second and very fancy sounding film of antibody dependent enhancement essentially is something that is borrowed from other viral infections. And a good example of that is Dengue. Where your first dengue infection in the canonical understanding of dengue tends to be quite mild, but then if you get a second degree infection and it's of a different type of dengue virus, then your second infection might be much worse and might result in dengue hemorrhagic shock. So that is believed to happen because when you're infected with dengue, you don't make enough antibodies to be able to protect you against the second infection, and the antibody molecule that is made actually acts something like a Trojan horse and allows the virus to get inside cells of the immune system where it would not normally go. Now the question is, will something like that happen with SARS-COV-2? Well SARS-COV-2 is a single type of virus. So then you have to think about are the variants different enough to act like a second type of virus? And will you see antibody dependent enhancement because of that? Well, so far all that we've seen is that vaccination for SARS-COV-2 builds up a reasonably high level of neutralising antibodies. And once you have a high level of neutralising antibodies, the other non-neutralising antibodies that would carry the virus into immune cells have no room to function. So, so far absolutely no evidence that antibody dependent enhancement occurs in people who have been vaccinated. Strictly speaking if this was variant dependent then in people who were getting reinfected with SARS-COV-2, we should expect to see the same phenomenon. And so far, there have been no immunological studies that have demonstrated that. Certainly something to keep an eye on but the longer we keep watching for it the less likely it seems. Sandip Roy So Dr Kang, viruses will continually mutate, I assume that means there's probably a second or third generation variant of the B.1.617.2 already out there. How do we handle the fact that variants will be continuously outpacing vaccination? Dr Gagandeep Kang I think we need to get ahead of the variants and the only way you can do that is by vaccinating a larger and larger proportion of the population. Viruses mutate when they are multiplying. And essentially, if you can protect people and reduce multiplication in humans, then you're reducing the population of viruses that are around and you will have less variants. We already have a test case in countries that have generated variants in the past, like the UK and the US, where they've had distinct variants arise in different parts of the countries that have then spread to other parts. Now that both of those countries have widespread vaccination and reasonable sized populations, reasonable mixtures from people traveling, it'll be interesting to see – one, will new variants arise in a better vaccinated population? And two, if new variants are introduced from outside into the country, will they be able to establish a foothold and spread in a vaccinated population? So watch this space. Sandip Roy Isn't our vaccination rate currently falling faster than the infection rate? Dr Gagandeep Kang Currently, we are vaccinating at a relatively low rate and this is a concern, but I think what is going to happen is that we will have more vaccine available in the latter part of this year and then we'll be able to ramp up vaccination even more. What we should be doing and absolutely must do in India is to make sure that no doses of vaccine go to waste. An outstanding example is Kerala, where they use the extra amount of vaccine that is available in every multi dose vial to give out more doses. So Kerala has vaccinated more people than the doses of vaccine it has received. That's a fantastic example of how a health care system has paid attention to detail and made the best of what it's got. Sandip Roy So according to what you're seeing out there, what is the vaccination timeline that you foresee? We're obviously well behind what had been promised. Dr Gagandeep Kang Yes, I think projections based on what some of the vaccines companies had told us was a little optimistic, and we continue to be optimistic in the projections that are currently being made, but I think from a sort of clearer sighted view of where we are with vaccines, there is no question that vaccine production capacity will increase marginally in July and then will begin to ramp up. I'm anticipating that from September onwards we should be seeing more vaccine, particularly if Zydus Cadila trials are successful and Bio E is able to deliver its phase three data by August. Then we will have a substantial increase in the number of doses. But if those two trials don't go well, then we will continue to have very restricted supply. From the global markets, we know that there are very very few doses available relative to the size of India's population, and I'm a little concerned that if we have too many products coming into the country, then the public health system would find it a little difficult to manage that many kinds of vaccines to be delivered to different populations. Sandip Roy So given the vaccines that are currently out there, which are Covishield and Covaxin, and speaking of data what will it take for Covaxin to get WHO approval? I mean, what has been the stumbling block? Because from what I can tell, if Covaxin doesn't get on the vaccine passport, then people who've taken Covaxin here are going to be at a singular disadvantage when it comes to travel, etc. Dr Gagandeep Kang Based on the data that we have from the two interim analyses for Covaxin I have no doubt that Covaxin will be able to generate the documentation package that is required for WHO prequalification. But I think it's a matter of time, not a matter of the quality or the performance of the product. Sandip Roy And what is the data that we do have on the other vaccine that is coming, which is Sputnik? Dr Gagandeep Kang So Sputnik has been questioned for the limited amount of data that it has put out in the public domain, and I think it's in a sense unfair to single Sputnik out for the lack of clinical trial data because we don't have that from a lot of manufacturers. But questions have been raised about Sputnik's chemistry manufacturing and controls, and questions about the clinical data that they have published. What Sputnik needs to do is to ensure that that concern is addressed, to demonstrate across multiple batches that there is no replicating virus in the vaccine doses. Sandip Roy But given that they haven't done that yet, or they are yet to do that, is it advisable for us to be rolling it out? Dr Gagandeep Kang Well, our regulator has evaluated the batches that have come into India and has certified that they are OK. Sputnik is manufactured at multiple sites in Russia, so this may be a manufacturing site issue. I really have no information on the details of that. Sandip Roy So that brings us to the larger question which we've been tussling with over the last month or more, which is why does the vaccine factory of the world not have enough doses for its own population? I mean, we knew our population. So the demand supply shouldn't be rocket science, so to speak. Dr Gagandeep Kang Well, look at it from the announcements that were made last year. The government initially made it clear that it intended to vaccinate only 300 million people, and that meant that they would need 600 million doses. And 600 million doses by the end of December 2021 continues to be very feasible. Now the question is, was the 300 million an accurate projection of what would be required? Well, the rest of the world was convinced at the time that it needed to vaccinate a much larger proportion of the world, and it seems the Indian government came around to that point of view, but did that much later. So while we know the size of our population, it's also a question of commitment from the national program on what percentage of the population it intended to cover. Where I'm concerned, I think we need to vaccinate everybody. I think we will ultimately need to vaccinate children as well. So I think our projections should be for what it will take to vaccinate our population. Sandip Roy Yeah because in the UK, the National Health Service took advantage of their lockdown to aggressively vaccinate the population. We currently have lockdowns in many parts of the country, but there's not enough vaccines for us to take advantage of that, to vaccinate aggressively. Dr Gagandeep Kang That is true. And I think in the UK they kind of vaccinated themselves out of the wave that they were having, so much so that they are thinking about opening up more freely in June and have opened up quite a lot already. For us, the size of our population is both a strength and a limitation. There is no way that we will be able to open up confidently without having a large proportion of our population vaccinated. But I also am beginning to switch my thinking from the WHO prioritisation framework to consider what kinds of experiments in vaccination are possible while we have a limited supply. Should we go with what we could call a spray and pray approach, where you get a tiny dose of vaccines in any demographic and that's an equitable way to do it? Or should we be thinking about concentrating vaccination in specific areas? Or specific populations to be able to really answer questions on the impact of vaccination? And in a situation of limited supply these are choices that we have to make. Sandip Roy So what do you think about the CDC in the US saying that actually masks will not be necessary soon? What will it take us to get to that point? Or can we think about getting to that point in the foreseeable future? Dr Gagandeep Kang Well the foreseeable future depends on how long you've got to live. So I think for the CDC to make that decision, one, the US is in a situation where their cases are plummeting. Not absent, but have come down quite significantly. Their immunisation rates have gone up. And one way to think about the 'remove the mask' mandate is that for the people who are not currently vaccinated (it) would be an incentive to be mask free, be something that encourages you to get vaccinated. There are many US academics, and I tend to agree with them, that I think the masks are coming off a bit too early. Infections have declined hugely, a large proportion of the US is vaccinated, but I think taking off masks should depend very much on the level of control locally and not at the national level. And we should have guidance that tells us that if infections or test positivity rates will go above a certain level, then the masks should come back on. There have been umpteen studies done around the world that show that masks reduce infection by at least 40% Sandip Roy So at the time of great shortage, we heard a lot of talk about relaxing or waiving of the US patent laws. Could you just explain whether that happened and what's going to be the significance of that if it happens? Dr Gagandeep Kang So there are three things that you need for this framing. The first is intellectual property. The second is technology transfer. And the third is resources for manufacturing. Now, waiving intellectual property during the course of the pandemic is a necessary first step. The move is a good one. It is one that sets a precedent for what will happen in future pandemics as well. So I think it's something that we should applaud, but we also should not place unreasonable expectations on what will happen just because of an IP waiver, because without the other two components, it's not going to make a significant change in the amount of vaccine that is available to developing countries. You need technology transfer and finding the right people to do those transfers is very, very difficult. Doing transfers for drugs is much simpler than doing it for vaccines. And I'm told by Indian vaccine manufacturers as well as people globally, that there is a huge shortage of people who have experience in tech transfers. And the third is resources. If you don't have the right chemicals, substrates, filters, fillers, bags, vials, stoppers, rubber bungs to be able to make vaccines at the scale that you want to make them, then you're not going to be able to make vaccines. And currently, practically every component of a vaccine is in short supply. If we look at what happens with routine immunisation programs or pre pandemic, the world used about 4 billion doses of vaccine every year. And we are now in a situation where we are talking about needing 16 billion doses of vaccine to be able to vaccinate the world with two doses. Even if you say let's leave children out of it, at the moment, you're talking 10 to 12 billion doses. So that is 3 times the capacity of the world to produce vaccines in the pandemic period. So just IP? Not enough. Sandip Roy Got it. And what about the controversy around vaccine pricing, is that going to impact the rollout? Dr Gagandeep Kang There are many things about government policy that I don't understand, and this is one of them. How can the centre and state pay different prices for the same product? I'm not sure that I know of any example where this has happened before, where the central government can negotiate a price and then the state price is set by the companies, and there is yet a third price for the private sector. It seems now from communications that are publicly available that the Centre is keeping the 50% that it had allocated to itself, but is also deciding on the allocations that go to the state. So even though the state is buying it, the number of doses is decided not by the company, but by the Centre. So that seems even more confusing to me and nobody is sure what number of doses are going to the private sector. Yet it does look like you can get appointments for a private sector vaccination much easier than you can get a free vaccine in a state. And that private sector vaccination seems to be available to some of the larger hospital chains, but maybe not elsewhere. So I really don't know what's going on. Sandip Roy That could set up a very much a vaccine have and have not situation. Do you have any sense of the situation in rural India right now? From which all the data seems to be very spotty. Dr Gagandeep Kang Yes, rural India is a bit of a black box. Mainly because we just don't have systems of surveillance and testing in rural parts of the country. I'll give you an example of some work that we did. We were trying to map typhoid across the country and we found that there were lots of studies that were set in cities and there were practically no studies from rural India. So we went out hunting across the length and breadth of the country to find small places that could set up to do blood cultures. Took an incredible amount of training, investment, to build a picture of how bad typhoid is in the country and it's there in rural areas that just had not been measured. Urban areas are worse affected, but there was no place in the country where we didn't find it. Now, in the absence of surveillance systems, it's easy to say that there isn't disease in rural areas. But at least in terms of vaccination, given that we have the routine immunisation program that runs in rural areas, we should be able to vaccinate people there and get data on them. But all the data that are coming out for SARS-COV-2 vaccination right now seem to indicate that coverage in rural India is very, very low. People don't necessarily know about the vaccine. Also the requirement for registering on this CoWin app has created a situation of digital haves and have nots. And the solution is not find a friend. Sandip Roy So what will be the effect of this on the rest of India, because at one level we are saying India's current Covid second wave crisis is of importance to the world because what happens in India is not going to just stay in India. So what happens in rural India is also not going to necessarily stay in rural India. Dr Gagandeep Kang Absolutely not. And that's why ramping up vaccine coverage is important. The problem, of course, is that we've had a routine immunisation program that has improved over decades. But this adult immunisation is the first time. There are some states that have done adult immunisation for Japanese encephalitis, but pretty much nothing else. I mean, even for things like Cholera where using vaccines to control an outbreak, makes sense, we just don't do it. So building out an adult immunisation program in rural areas is a significant challenge, and the sooner we have ways of addressing it, the better. Sandip Roy What is going to be the effect of this on the larger Covax program for low income countries? Dr Gagandeep Kang Serum Institute has made commitments to sell a large number of doses to Covax, and it had a delivery schedule that it's fallen far behind. This, of course, means that countries that were expecting to get vaccines through the Covax facility will have to wait until India solves its problems and allows for a vaccine to be exported. I think as a global community, no one has a doubt that India needs the vaccines that it is producing at the moment and will continue to need them for a while. But I think the world is now beginning to think that it made a miscalculation in relying so heavily on India. So for future pandemics, I think we'll see a much more distributed manufacturing of vaccines in parts of the world that are likely to need vaccines in a pandemic. Sandip Roy And what would you say to a layperson now who says in the middle of this second wave that if I still need to wear masks, observe social distancing and still see way too many people I know who are vaccinated end up in hospital? What's the point? How is my quality of life improving as a result of vaccination? Dr Gagandeep Kang I think it's very important to understand that vaccination masks and distancing and ventilation are the tools that we have. We need to use a combination of all of these tools until we can suppress virus replication that allows us in a phased manner to dispense with some of them. The first to go, I guess, would be the requirements for lack of crowding and distancing. And after that, we could think about removing masks and trying to get back to normal, as long as we have a vaccinated population that functions in environments where air handling is an additional safeguard for reducing the risk of infection. Sandip Roy Dr Gagandeep Kang, thank you so much for joining us today. Dr Gagandeep Kang Thank you You can follow us and leave us feedback on Facebook and Twitter @expresspodcasts, or send us an email at podcasts@indianexpress.com. If you like this show, please subscribe and leave us a review wherever you get your podcasts, so other people can find us. You can also find us on https://www.indianexpress.com/audio.
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