 Hello and welcome to NewsClick. Today we're going to discuss not directly COVID-19 issues as we do, but the larger issue of vaccines themselves because it's very clear that vaccines will be our first line of defense against the pandemic and whatever form it takes later on. We have with us Professor Satyajit Rattu discuss some of the complex issues of science which vaccines really lead us to. Satyajit, we all talk about vaccines as if we understand it, but as you've explained to us immune systems are complex and so are vaccines. So can you tell us that what differentiates the vaccines that we know? Of course the pandemic has introduced us to COVID vaccines of different kinds, but what are the different kinds of vaccines and if we want to go to a universal vaccine and we'll come to that later. How does it differentiate itself from the various vaccines that we have seen, whether it's COVID or it is for flu, influenza, polio and this holy grail if we may say so of the universal vaccine which you don't seem to have yet done for anything else. Coming to first the vaccines themselves, what are the different kinds of vaccines we have seen during the pandemic, assuming these are the generic vaccine technologies which are available for others, other diseases, other infections too. So let's first look at the vaccines that we've been reading about for COVID-19 as you point out. So we've discussed how the virus causes infection. Virus particles land in our throat, sink through the fluid, stick to the surfaces of cells through a very specific sticking of the viral spike protein and the ACE2 protein on the surface of cells. So it's very clear that if we can prevent the spike protein from sticking to the ACE protein, we will prevent the virus from sticking to cells and therefore everything downstream of that will be prevented. In effect, we will have prevented infection. In order to do that, what pretty much all the COVID-19 vaccines do that are currently available, they take the portion of the spike protein called the receptor-binding domain, meaning that part of the spike protein which sticks to ACE2 protein and one way or another, they formulate it into a vaccine so that the body makes antibodies that stick to spike protein. So then if there are antibodies circulating against spike protein, there are antibodies in the fluids, in the throat and in the respiratory tubes. So when the virus particle comes in and lands, antibodies will quote the appropriate part of the spike protein. Spike protein cannot stick to cells. So basically, you've dealt with the problem right at the root. This is the design. All the technologies that we are dealing with, whether we are dealing with the mRNA or the adenoviral vaccines or we are dealing with the protein or the inactivated virus vaccines, all of these are simply differing in how to show the protein to the immune system and to get the immune system to make antibodies. But the core of the idea is to get the immune system to make these blocking, covering sort of ducking antibodies that will prevent this sticking. The difficulty is really when virus variants get selected that, for example, stick to the ACE2 protein even more efficiently, which is what we have seen with the Alpha variant, the Delta variant, the Omicron variant and so on and so forth. Now, let's all keep in mind that the virus is virus variation is emerging because we have done physical distancing. So more transmissible versions are emerging. One way of making it more transmissible is for changes in the spike protein to allow the spike protein to stick even better, to stick even harder. A byproduct of that is that because the shape has changed a little bit, the antibodies against earlier versions no longer stick to the new version. If the antibodies against the earlier versions no longer stick to the new versions, they are not as good at protection. So what's our response? Our response is very straightforward. Let's now make an Omicron specific vaccine, which is what we've been seeing in the newspapers will be done. So a straightforward tactic that has been adopted by vaccine makers against many other diseases is to say, okay, how many variations are there yet? If there are three variations, five variations, let's take all of those, let's mix all those versions of this target together and let's make a multivalent vaccine. We have examples of this. Our polio vaccines, our triple drops frequently come as trivalent vaccines with three different versions of the virus. For a bacterial vaccine like pneumococcal vaccine against pneumococcal pneumonia, we started out with tetravalent, then we went to seven valent, then we went to 10 or 12 and 14 valent vaccines. That means 14 different strains of the pneumococcal there of the target shade. So you are giving the immune system 14 different versions to make 14 different kinds of antibodies. Essentially. And the immune system seems to do a reasonably good job. Here is the major limitation with that approach. That approach works if you think you actually have the entire list of variations, if you don't, if you're looking at another Omicron or Phi or Psi or Omega emerging, then as in when the new strains emerge, you are going to have to scramble and put together a new vaccine. This is actually what happens in the every winter for instance, we get this version vaccine being again released in the market, that it seems to be a kind of weapons versus shield race, that the more weapons the virus changes, produces new kinds of weapons quote unquote, we have to produce new kind of shields. And this is the flu race that every year we seem to WHO seems to release flu vaccines, which circulated in the southern hemisphere for the northern hemisphere, we get a sort of lead time because you can see what's happening in the other part of the world. Is that what is the how the sort of weapons to shield race goes on? Yeah, there's a small difference there, which is interesting. And that small difference is for the pneumonia bacteria, for example, we make this 14, 12, 15 valent vaccine because there are that many different variations stably in circulation at the same time. So you make this combination multivalent vaccine and you sell it and that's what you sell year after year. For flu what happens is because many all of us are immune to some degree against a prevailing strain of influenza. And because influenza is mutable, is quite rapidly changeable, it changes and throws up a new strain, which becomes the prevalent strain. So rather than 15 different strains circulating every couple of years, there is a new dominant strain of flu. So identifying it or at least guessing what it might be, making a just one valent vaccine against that is good enough. So depending on disease dynamics, either a stable multivalent vaccine, trivalent vaccine for polio or 10, 12, 14 valent vaccine for pneumonia or a changing version of the vaccine as for influenza, it has been how we approach this problem historically. Now the question, of course we can do what we are doing for either influenza or for pneumococcus that we can provide multivalent or a rapidly changing vaccine, every strain new vaccine and make that process faster. Does do we and particularly guys like you who sit in the lab have a solution for us that will give us quote unquote the holy grail as I keep on saying the of immunology that we can make a universal vaccine? What prevents you guys from making an universal vaccine the current state of knowledge? So my colleague immunologist, my fellow immunologists will berate me as a pessimist and as a naysayer because many of them are not only optimistic about the idea of the universal vaccine that you point to but are actively working on it for COVID and related Vita coronavirus infections. Here is the, so let me explain the problem. The problem is as follows. We have currently both the strategies that we discussed being designed for future COVID vaccines. There are research groups that are making multivalent vaccines with multiple strain versions of spike protein. There are also research groups that are beginning to link the community surveys identifying emerging new strains and linking those community surveys to the vaccine pipeline to develop new generation, new seasonal vaccines if you will. Both of those are being done. In addition, this notion, this what I consider a fanciful notion at the moment of the universal vaccine is being discussed and there are two different ways in which it is being approached. One is to say, hey, what are you saying? You're saying that the spike protein binds to the S2 protein. Now, what you're pointing out is that as it changes to bind better and better, it changes shape. So the antibodies generated by last year's strain no longer bind to this changed version of the spike protein. But surely because the spike protein is binding to the S2 protein all the time, there must be some common preserved features of that binding which are present on the spike protein. Can we identify those common conserved structural features and just make antibodies against those features? Then the virus has no way, it might change, but because the antibodies are being made against a sort of core stripped down essential version of the protein, of the viral protein, the antibodies will bind to any viral, any protein version of that virus which binds to the S2 target and therefore will always work. This has been tried for 30 years for HIV vaccine design. It has been tried for a similar 20-25 year period for influenza vaccine design and at the moment it's a little bit like energy from fusion reactions. We are getting closer and closer and closer but we are not quite there and if we don't as yet have the science, the structural understanding sufficiently nuanced then we are not quite going to manage the fact. I'm going to take a step back Satish. I'm going to take a step back. I'm going to take a step back on this for our audience, our viewers and ask you that essentially that shape of the spike protein and in fact the protein shape is the problem. How to predict a protein shape from what we know about the composition of the proteins that make the spike so to say that the folding, the shape it takes, exact shape it takes is a much more difficult exercise to predict with our state of knowledge. Would that be the problem? That is the problem but the vaccine problem is actually a compounded version of the problem you point out. The compounded version is here is a shape that binds to this complementary shape on the set. Now there are many versions of this shape. All of them bind to this. What is the common shape component amongst all these shapes that allows binding to this and can we purely generate antibodies against that common shape component? So there is two ways of looking at it. I'm asking purely from common sense since I fortunately do not have to get into this. That two ways of looking at it, look at all possible shapes and see what is conserved. Now that is the what would be called the cannon shot scatter gun problem. We find n number of shapes and say okay all these shapes that we have found say 10,000 of them, 5,000 of them and these are conserved. That's one way of looking at it. Other ways to see what is morphologically necessary for a spike from doing what it does and then see that therefore what it that shape is and that second as well as the first, both approaches are being tried or it is really first approaches to broad. You are absolutely spot on. Both approaches are being tried. The first is the brute force computational approach. The second is the knowledge driven computational approach and both of these have been are being tried and as I said they're being tried for HIV, they're being tried for influenza, they're being tried for COVID. As yet there isn't sufficiently dramatic success for us to feel optimistic about such a vaccine coming out in the next six months or a year. Whether we will get there or not is a little bit like as I said fusion energy. For viewers, this in fact if we look at as a computational problem, we are looking at really a computational problem which does not get easily solved by our current state of computations and the machinery which does the computations. If of course we get to quantum computers, maybe we'll have a much easier solution for people who deal with the immune system and complexities of the protein folding exercise we talked about. So we have two hard problems and maybe we can marry them together if we have a solution for either. Yes, except that there is yet another problem that is emerging even as we are struggling with the core problems that you describe and that is all of us are getting exposed to or vaccinated against current versions of the strain. Which means that our immune systems have prior experience of a certain kind. Does that now skew the response of the immune system such that even when we come up against this ideal core universal vaccine, our immune systems will recalcitrantly say no, I have the old version of response and that's what I'm going to make more of is yet another problem and that problem has been dragged by our colleagues in the Global North into Christian theology and is called the original antigenic sin problem. Mercifully the rest of us outside the Christian world don't need to deal with ideas of original sin but it's a problem nonetheless. You are saying that even if we solve this problem, you guys will or gals will find some more problems for us to tackle science will still have problems. What I'm saying is that a solution under ideal circumstances much like the physicist's version of the cow may not correlate well enough to the real life messiness to be an actual practical solution and this is why there is a very large number of difficulties with the reasonable rational and worthwhile idea of a universal vaccine. So listening to Satyajit, let's accept this premise. I think this is where he's coming from and that's where his pessimism that he shared with us right in the beginning that we have, yes, we have a theoretical possibility of a universal vaccine but with the state of knowledge that we have and with the continuously changing equilibrium between the virus in our immune system such a universal vaccine itself may not be the optimal answer to the problems of infection, to the problems of future epidemics or set of epidemics shall be said. Satyajit, really good for you to try and explain a rather difficult exercise for us to comprehend what a virus is, what the immune system is and how do they fight each other and the complexities of evolution of both. I think this is a really a difficult exercise and we will trouble you to explain to us such complexities which are not dealing with public health and epidemiology which we have been dealing with till now but the future of science itself. This is all the time we have for news click today do keep watching us and we'll continue with Professor Satyajit Rath to focus on some of these areas which may be of larger interest not of immediate interest but nevertheless which we should engage with.