Dr Gagandeep Kang, one of India’s leading medical scientists and former Chair of an ICMR panel on Covid drugs and vaccines, explains the challenges of vaccine development before a nationwide audience on Zoom. Edited excerpts:
On optimism about a vaccine emerging by early 2021
I think it is highly likely, but it is not guaranteed. Until you actually have efficacy data on a vaccine, it is impossible to say whether a vaccine will work in humans or not. We have very encouraging data on immunogenicity, we have encouraging data from some studies in primate models, that seem to indicate that some of the vaccines that have been evaluated in those systems do prevent severe disease. So that’s all very good, but we have been led astray by animals studies before, so until we have data from humans, I would not be taking bets on it.
On a vaccine (including the Russian vaccine) reaching people
I don’t think I would call the Russian vaccine a vaccine that is ready for prime time. It’s a vaccine that first went into humans on the June 17. It’s been through accelerated phase-1 and phase-2 testing, which means it’s in a very small number of people. We know that the vaccine is not causing severe reactions and it is immunogenic. So just the fact that the vaccine has been licensed by one regulator does not tell us that this vaccine will work to prevent disease. We need phase-3 efficacy trials in order to do that. That’s true for the vaccine licensed in China as well; without efficacy data I wouldn’t think about having that vaccine.
In terms of how quickly will we get the vaccines, if we find that the Oxford vaccine works — and that is in phase-3 trials— given that Serum Institute of India has already started to make the vaccine, I think that would be the first one where we would see that we have data that would allow us to confidently think about using it.
In terms of pricing… when vaccines first start out, and if they are made by multinational manufacturers, the cost is in several hundreds of dollars, and for India we know that if a vaccine is more than $3 a dose, we are going to be unable to take it. So the price that has been quoted for the Serum vaccine, in the order of Rs 900-1000 a dose, might be something that we could think about. That of course is a starting price; all vaccines start out expensive and then once you start to make lots and lots of the vaccine, you can bring prices down quite a lot.
On the logistics of supply and accessibility
This is the really complicated piece of the puzzle. I think people think that if we find that we have a successful vaccine, it will be at your friendly neighbourhood doctor tomorrow. It will not. It takes time to make a vaccine and the reason why vaccine manufacturers are now trying to buy facilities, book time at the manufacturing facilities, is because they want to be able to make the vaccine even before it is proven safe and effective. So this is called at-risk manufacturing, and this is what Serum Institute has done, and this is what a lot of companies around the world are doing. They are making doses of vaccines sufficient to get it out the door as soon as the vaccine is licensed after efficacy data are obtained. That is the fastest way to get to the market but the whole process of regulation takes time. It will take time to review the dossiers, it will take time to get the vaccine licensed, and once the vaccine is licensed we have to think about the logistics of distribution… You need something that fits in with your cold chain infrastructure, you need to be able to buy the vaccine, you need to land the vaccine, you need to distribute the vaccine, you need to train staff in how to give the vaccine.
On whether the sense of security around vaccines still in the pipeline is misplaced
The first thing is, is the vaccine going to work? And in what proportion of people, and for how long, will that protection last? Now, the USFDA and the WHO have said a point estimate of 50% — which means that in the clinical trial you should have at least 50% of the disease prevented through the vaccine. That actually means from the size of the US trials that the lower bound of efficacy may be as low as 30% and that is still acceptable to the regulator. So we are looking at a vaccine that prevents a reasonable proportion of disease and that reasonable proportion is about half.
Now, how long will this vaccine give us protection? We have other examples of vaccines where the protection does not last very long. Will it be months? Will it be years? We don’t know yet; we’ll have to wait for the results of the trials. The current follow-up that is planned in many of the trials is only one year, and within one year it’s unlikely that you are going to have a large number of re-infections. But it is certainly something that we will need to track.
On false assurance… you will feel like you will have an armour and are protected if you have been vaccinated, and that is a problem. I think if we had a correlate of protection — among the people who are vaccinated, if you had a signal that you could describe, antibodies for example, and you knew those antibodies correlated with protection — then you’d be a lot more confident in saying how well the vaccines are working. Until we have that kind of information, I think even after vaccination, we’ll have to proceed with caution and warn people that even though they have been vaccinated, protection may be incomplete.
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On whether 40-50% efficacy is better than no vaccine
That’s right. Remember these are first-generation vaccines. If you understand how they work, then we can look at improving their performance. We can add things like adjuvants to them, see if that increases the proportion of people who are protected, or the duration of protection. Given that in this situation we are going to have lots of vaccine candidates, we could very interestingly also think about the possibility of mixing vaccines…
On the importance of phase-3 trials
You want people to be able to trust the healthcare system, you want people to believe that doctors and scientists and researchers are doing their best to make sure that we get high quality, safe and effective preventive strategies. Any time you get people that short-cut the system, that don’t follow the process, that plays undue risk, it becomes a problem. So we have the Chinese and the Russian vaccines as examples of where the system has been short-circuited in a way. And what that leads to is people being unsure whether these are really quality effective products or not. I would not advise that, one way or the other, you need to prove that a product works before you use it. Now there are regulatory mechanisms that allow you to do these emergency use authorisations, but then the requirement becomes a very high bar of following up everybody who receives the vaccine, to ensure that at least after licensure — if it is an accelerated licensure — you actually treat the vaccinated people like they are in a phase 3 efficacy trial. You still have to follow them up, you have to make sure that they are safe, that nothing goes wrong. If we do things that way, then I think addressing one problem quickly and damaging the entire system is not a good way to go.
On countries signing advance deals that may make vaccines inaccessible to others
The world has seen this before. We saw it with H1N1 when WHO tried very hard to establish a global allocation mechanism, but it got so few doses of vaccines from the manufacturers that it almost wasn’t worth their while to invest a lot of time and effort in distributing those…
The implementation partner for delivering vaccines is the GAVI Alliance. Now will multinationals, will the successful makers of vaccines provide vaccines to the global allocation mechanism? These are the negotiations that are happening now and the idea is from the global pool there will be distribution of vaccines around the world. Now the counter to that is we are all looking after ourselves first and not thinking about global good is something that we are seeing. Governments have a responsibility to their citizens and in the US they have gone to the extent of saying we want to buy your company, that might potentially have a product we are interested in, we will fund you to do your trials. In some ways, what you would like is for everybody to be a good global citizen and share resources so that people around the world who need them the most get them quickly, but that clearly is not happening. We need to do our best but then the way to think about it is, there aren’t 800 million people in the US, so if we do wind up with the US having 800 million doses of successful vaccines, they are not going to be able to use it all. So I am assuming that they will give it away and at least some countries in the region will get access to those products.
It’s a worry and something that we need to be thinking about. We have one of the largest populations in the world, there is no way that the Indian population is all going to be able to get the vaccine quickly, so we need to be thinking about our populations and coming up with a clearly communicated strategy about how we will vaccinate, whom we will vaccinate and when. I believe the committee that is chaired by Dr Vinod K Paul is doing precisely that.
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On whether every vaccine needs a phase-3 trial in India before it is made available
When you have a product that is licensed in a different country and that country has what is known as a stringent regulatory authority, then getting a vaccine licensed in India requires a very small trial in India. These are called bridging studies. You can do it in less than 100 participants and if the immunogenicity data from that study is similar to what was done in the place where the vaccine was licensed, the vaccine can be accepted. When the vaccine is a novel product that has not been licensed elsewhere, then you will need larger-scale studies. Given that the ChAdOx1 vaccine is in phase-3 studies… it’s likely that by the time the studies are done in India, there may be phase-3 efficacy data and the data that Serum generates now from their 1,600 participants can be used for submission for Indian licensure.
On implications of future vaccine development
I think many of the new vaccines we are developing are actually based on pretty old technologies. In the 1950s we got cell culture that allowed us to make polio vaccine, rotavirus vaccine. In 2010 when we got DNA sequences and… that was the first time we started to use new technologies, reverse vaccinology approaches to make vaccines. Since then, in terms of licensing vaccines, the new technology has really been the Ebola vaccine where we had the first viral vectored vaccine being licensed. We have not so far had an RNA vaccine or a DNA vaccine licensed. We have not had new adjuvants available, we have not tried prime-boost strategies, so if these are all learnings from this pandemic, I think that is what is going to change the face of future vaccine development.
Transcribed by Mehr Gill