 So let's talk about the inactivated virus vaccine as the simplest technology, the oldest technology, the simplest technology. The obvious limitation is you're growing a disease causing virus. You're growing it at industrial scale. A great deal of safety protocols need to be put in place for containment. That becomes a major industrial limitation on making these vaccines. Now, keep in mind that SARS-CoV-2, the COVID-19 virus, is not actually hugely dangerous at the individual level in the same way that say Ebola virus is dangerous. Out of 100 people catching SARS-CoV-2 infection, maybe a, well, out of 400 people catching it, maybe one will die. Out of 100 people catching Ebola infection, more than 30 are likely to die. Now, and welcome to Talking Science and Tech. In today's episode, we are joined by Dr. Satyajit Rath. And what we want to discuss today is this life-saving technology, which has been pretty much the only thing on our mind since the pandemic broke out, that is vaccinations. So, Satyajit, before we get into specifically the COVID-19 vaccinations, can you tell us about the science behind vaccines in general? How do they work? All right. So, let's think about vaccines as a way of tricking the immune system of the body. Why do we want to trick the immune system of the body? So, ordinarily, the idea is that when we are exposed to an infection, to a microbe, the body responds with an immune response to the microbe that specifically recognizes and works against the microbe. So, if we want to make ourselves immune, one argument would be simply take the infection and take the risk. This is an argument that world leaders of Little Brain had made about COVID-19 in another era, if you remember. But the risk that all the rest of us pointed out was that you would become seriously ill as a result of this infection. So, the question for the technology is how does one expose the body to the microbe without risking disease? And the core of all vaccine technologies is this. How do we fool the immune system into thinking that it has met the microbe so that it makes a response to the microbe when it in reality has not met the microbe? So, clearly, there are two components that we need. One is some bits of the microbe that are specifically recognizable as belonging to that microbe. And the second is the kind of damage the microbe causes in the body, some mild version of that damage. And these two together will get the immune system worked up saying, hey, something's causing damage and hey, I see what the target is, I'm going to respond to that. Every vaccine technology is a variant on this tricking of the immune system. How exactly we design different vaccine technologies for this trickery, I'm assuming we will come to when we talk about COVID-19 vaccines. But this is the core of all vaccine technologies starting from Edward Jenner onwards. Right. So now, coming to the different types of technologies centered on the principle that he just talked about, of course, we see that there are well over 200 vaccines in development against COVID-19. Most of these are in preclinical trial stage, but I think around 60 of these are in clinical development phase. And we see, I think there are four different types of vaccines overall, which we have seen so far. This includes the inactivated virus-based vaccine, the RNA-based vaccine, then the viral vector and protein subunit. So let's talk about these technologies maybe starting with the ones we're more familiar with, which is the inactivated virus and the viral vector type vaccine. So can you first tell us about them? So forgive me, but before we talk about those technologies specifically, let's get a broader view of what the categories are that the technologies belong to. So remember what I said about we should be putting microbial bits into the body along with a little bit of damage. Remember, every time we take vaccine shots, there's swelling and pain locally, so just a little bit of damage enough to persuade the immune system to make a response to the bits that we've introduced. So now all the 200 vaccine making efforts that you referred to that are being undertaken globally, all of them fall into two separate technical categories of how to introduce microbial bits into the body. So microbial bits by and large are proteins. So proteins of SARS-CoV-2, the COVID-19 virus. What is the method to introduce the protein into the body? And the two major categories are either you make the protein in a test tube and then inject it or you take the genetic code of the protein, inject the genetic code into the body so that you get the body to make the protein and to make a response to it. Those are the two major technological separations because you can imagine that making a protein in a manufacturing process will be quite different from making a genetic code in a manufacturing process. So those are the categories that we should think about. In the first category, the make the protein outside and then inject it, we have the inactivated virus. That's the simplest way of making the protein outside. You just make the whole damn virus, which of course includes the protein that you're interested in and the protein that we are interested in will come to in a minute. But you therefore just take the virus and you inject the virus except that you don't want the virus to actually cause the disease. So you inactivate the virus so that it is no longer infectious. You do it by chemical inactivation, by enlarge, by a variety of chemical interventions and you can inject that. And there's three, four different COVID-19 vaccines with inactivated virus as the approach in advanced phase three clinical trials, including the ICMR-Bharat biotech co-vaccine that there is so much of conversation about. But there are already, I think two or maybe three vaccines from China that are in phase three clinical trials. One of the odd vaccines maybe from Kazakhstan or somewhere is also in clinical trials. And certainly one of the Chinese vaccines has already shown fairly good evidence for protection, early evidence for protection. So you can inject the whole virus or you can actually take the genetic code of the particular protein that you are interested in. And since we are interested in stopping the virus from getting in, the target of the immune response that we want is that particular protein of the virus that allows the virus to bind, to stick to cells. So that's the spike protein and therefore the spike protein is what all 200 vaccine making efforts are using as the target. So you can take the genetic code for the spike protein, but instead of injecting the genetic code, you can use so-called genetic engineering industrial technology and get bacteria or yeast to make the protein in industrial scale fermentation methods, purify the protein and inject that. Those are what are called protein subunit vaccines or virus-like particle vaccines and so on and so forth. In the inject the genetic code technologies, either you can put the genetic code in the backbone of a virus because what you need to inject along with the genetic code is an instruction for the body cells to make a lot of the protein. So the simplest way of doing that is to use the instruction, the genetic instruction from some other virus. So that's why adenoviral vector-based vaccines such as the Oxford AstraZeneca serum Institute vaccine or the Gamalai Institute vaccine or a whole bunch of other vaccines that are in development use a whole adenoviral backbone, but the adenovirus is defective, so it's not really a virus infection, it's just that the backbone is being used to give the instruction to make a lot of proof. Or you can use a very pure instruction hooked to the genetic code and that's what's being referred to as the DNA vaccine, which is what Zidus Cadillai in Amdabad is in phase 3 clinical trials for. Or keeping in mind the old classical high school biology that DNA is made into RNA and RNA is made into protein, so far we've been talking about injecting DNA-based genetic code, but we can also make the RNA of the genetic code and directly inject the RNA and that's what the BioNTech Pfizer vaccine or the NIH Moderna vaccine which are called RNA vaccines is doing injecting the RNA. But the end result of all of this is introducing viral protein into the body for the immune response to target and to be activated. In all of these remember the second part we need to cause a little bit of damage so that the immune response wakes up and begins to act efficiently and with high magnitude of response and all sorts of so-called adjuvants, additives that cause just a little bit of inflammation will be added and that's been one of the controversies regarding the bioNTech vaccine about what adjuvant has been added and so on and so forth. But that's the gamut of vaccine technologies. In technological terms there are very interesting pros and cons but maybe we can take another question and then talk about that. Yes that is what I was going to come to. We have all these different types but really so for instance we have this mRNA-based vaccine which is for the first time that this type of technology has been approved against any disease. So really what makes this technology better? What were the challenges of using it? Why was it not approved before and what disadvantages it has and can you tell us about that and also a general comparison of all of these different types of vaccines. Okay so let's talk about the inactivated virus vaccine as the simplest technology, the oldest technology, the simplest technology. The obvious limitation is you're growing a disease causing virus. You're growing it at industrial scale. A great deal of safety protocols need to be put in place for containment. That becomes a major industrial limitation on making these vaccines. Now keep in mind that SARS-CoV-2 the COVID-19 virus is not actually hugely dangerous at the individual level in the same way that say Ebola virus is dangerous. Out of 100 people catching SARS-CoV-2 infection maybe a well out of 400 people catching it maybe one will die. Out of a hundred people catching Ebola infection more than 30 are likely to die. So we're talking about dramatic differences but even so a disease causing vaccine virus being grown at the industrial scale needs a lot of containment. So that's a limitation if you like of the technology. Secondly viruses, live viruses are grown in tissue culture of human cells that again is a technology that's not easy to scale up to massive amounts. So there is a scale limitation with an activated virus vaccine and we will see this playing out in the Indian market today based on the straightforward calculation about comparing the number of doses that the serum institute of India can provide of the adenovirus based vaccine called Covishield versus how much Bharat biotech can provide of the inactivated virus vaccine called Covaxin. So that's one limitation. The second way is to make proteins in a test tube and then inject them. Now the trouble with making proteins in a test tube is it doesn't have any of these limitations of the inactivated virus but it acquires a different limitation and that is proteins are huge molecules in terms of in a chemist type perspective proteins are enormous molecules and proteins need to fold in appropriate shapes in order to look like themselves. So the immune system needs to see a properly folded protein if it's going to make an immune response that will also recognize the same protein on the virus and this folding of the protein is industrially a little tricky. So optimizing protein folding as an industrial step of the technology is not as simple and straightforward as it sounds and that becomes a limitation and in fact that and its variations have been the limitations for for example Novavax which is making this kind of a protein vaccine having gotten a little bit delayed in its clinical trials. They needed to figure out the technology the scale of technology at the laboratory it's not difficult but the scale of technologies tend to be a little tricky. So those are the kinds of problems that those technologies have on the other hand the genetic code doesn't actually because it's being read as a sequence it doesn't need to be folded into anything we can synthesize huge quantities of the genetic code and it's therefore easy and simple and this is why the mRNA based the adenoviral vector based and the DNA based vaccine technologies have come into play much more rapidly because they don't need to worry about the folding problem as as protein chemists call it at the industrial scale. So then the obvious question is then why haven't we seen RNA and DNA and adenovirus vector based technologies deployed? Why are they the first time they're being deployed? And the short answer is that we really came to them being industrially viable only over the past 15 or 20 years and over the past 15 or 20 years we haven't really made and deployed a lot of vaccines the world over. So let me give you therefore a an example that connects science and technology to industrial manufacture in politics. So over the past 15 or 20 years let's remind ourselves of the viral infections that have caused major concern and all of us will remember this even you in your youth will remember some of this. We've had Zika virus, we've had the original SARS virus, we have yet we have had yet another cousin coronavirus that is the MERS virus, we've had Ebola and interestingly over the past 20 years against all of these incipient dangers we've had RNA vaccines developed, we've had DNA vaccines developed, we've had adenovirus vaccines developed. So the obvious question is then why didn't we see them deployed for all those diseases and the answer to that is that vaccine development is a quintessentially capitalist process and as a consequence the question was not for deployment of these vaccines against those diseases the question was not is there a need out there? The question was is there a sufficiently large need out there to provide a sufficiently large profit to justify the investment in deployment and the answer so far has been no for the first time in COVID-19 the answer is yes and that's why in a science tech political landscape we are seeing the first time deployment. Right thank you Dr. Satyajit for joining us today for this very enlightening and interesting discussion that's all the time we have for today keep watching this clip.