Pushkin from Pushkin Industries. This is Deep Background, the show where we explore the stories behind the stories in the news. I'm Noah Feldman. Coronavirus cases are surging across the country. Cities and states are responding with new regulations on social gatherings, but another potential solution is at least on the horizon and maybe a little closer than that. Last week, the drug company Visor announced in a press release that it's coronavirus vaccine seems to work. According to a preliminary analysis, Visor's vaccine is ninety percent effective at preventing COVID nineteen. Maderna's vaccine, which operates on similar principles, has produced similar numbers reported by that company as well. To discuss the science behind these developments and what's going to happen in practice, we are joined by doctor Paul Offen. He's a professor of vaccinology and pediatrics at the University of Pennsylvania. He's also importantly a member of the FDA's Vaccine Advisory Panel. Among his other distinctions, he is also the co inventor of the rhodavirus vaccine. Paul, thank you so much for joining me. The immediate impetus for our conversation is the good news that mRNA vaccines like Visors and Maderna's shows efficacy in trials. So let's just start with the very basic question. The Visor vaccine is an RNA vaccine. There's never been one of those that worked before. Why is this appear to be working? So what we think we know is we think we know that we want to make antibodies to the protein that emanates from the surface of the virus that is responsible for attaching the virus to cells. If you can then make antibodies to that protein, you can prevent the virus from attaching the cells. In the past, when we've wanted to make an about it to the spike protein, we would do things like give sort of a whole killed form of the virus which would have the spike protein on it, or we would give a live we can form of the virus which would have the spike protein on it, or we would purify the spike protein, or we would use recomment at DNA technology to make the spike protein. What we're doing now is we're saying we're not going to do any of that. We're going to take a small gene that essentially codes for that spike protein, and then we'll inject that and hope that it gets into muscle cells and will then be translated to the spike protein. So, in other words, the person makes the spike protein, then the person makes in about it's the spectro protein. We've never done that before. Just like you said, there's no commercial equivalent for that for any vaccine. It should theoretically work, we just never knew that it could. That was a spectacularly clear explanation. I want to just dive into a specific part of it. The part I want to dive into is the idea that historically, the way we've done vaccines and by Weime and you the scientific community, is by introducing a version of the spike protein in this case that we want to block, and then having the body produce antibodies to it. And that what makes the mRNA approach, which is characteristic of the Fiser approach and of the Maderna approach, distinctive, is that it actually introduces a genetic code to produce the spike protein, which the body then produces, which we don't want in principle a body to produce. But then the body produces antibodies to the spike protein that the body has produced. So you're saving a step, as it were, you don't have to introduce the spike protein in some form from the outside. First of all, am I getting that right? That's exactly right. But if for example, you gave a live attenuated viral vaccine, that virus would then enter the cell, reproduce itself, and it would make the spike protein inside that cell. So it's not like a complete long shot. And we certainly have a wealth of experience using live weakened viruses to induce immune response, starting in the mid nineteen thirties with yellow fever vaccine. And is it a good thing that by encoding for the spike protein without introducing the virus, the virus actually doesn't in principle have a chance of arising within the cell with this kind of vaccine, correct, because we're not encoding for the virus, just encoding for the spike protein. That's right. It's just you're being infected, if you will, with one protein, so that's not the virus, that's right. So when we think about potential negative side effects, when we think about live attenuated viruses or killed viruses, sometimes we worry that they might produce, at least in some people, symptoms of the actual virus or the bad consequence of the actual virus. Is it correct to say that, at least in principle, the mRNA vaccine can't do that because there is no virus introduced into the system. There's just the genetic code for the spike protein, which is not itself the virus. Yeah, this is not sours cob two virus. This is just one protein from the virus that you will make. Therefore, the signs and symptoms that you develop will not resemble those of SARS cob two infection. So one of the best things about an RNA vaccine, if indeed it works, is that it avoids some of the potential downsides of more traditional vaccination. That's correct. Yes, Sometimes it's been said in the media and by the companies that it's easier to produce large numbers of doses of an mRNA vaccine than it is to produce large numbers of doses of a traditional killed or attenuated virus vaccine. Is that so, And if it is so, why is it so? I think there's a couple advantages for these genetic approaches. The so called genetic plug and play approaches are fast because they're very easy to construct. You just take the gene and in the case of mRNA, you give the gene, or in the case of some of these other so called viral vectors, you just insert the gene into that viral vector. So it's really very fast to be able to construct it, and then it's very easy to scale up rapidly. So MESSERNA, it's essentially synthetic. You're just manufacturing it, so it can be scaled up very quickly. I mean, I think Visor said that they would have fifty million doses by the end of twenty twenty, that they would have one point three billion doses in the year twenty twenty one. You mentioned the viral vector vaccines also sometimes called trojan horse vaccines. The Astroxenica approach, the Oxford approach is one of those. Could you describe how that works in relationship to the mRNA approach, right, So it's a little different. So the so called replication defective adnovirus vectors, which is the approach that's being used by Johnson Johnson, the approach that's being used by Astroxenica, the approach is being used by Russia. The approach is being used by Chin in part is the adnovirus is a human virus that can cause a variety of diseases. But by engineering the virus so that it's replication defective, that means that it cannot reproduce itself, that means that it cannot cause disease. But it's also genetically engineered so it has the gene that codes for the spike protein. So then you inoculate this replication defective viral vector into the person. It's taken up into muscle cells, and then that replication of vectivirus enters the cell nucleus, where then that gene that codes for the spike protein is transcribed into messenger rna, and then the messenger rna then enters the cytoplasm and then makes the protein, and then you make the protein. So it's sort of like a step back from the messenger RNA strategy, but essentially it's the same strategy. It's ultimately getting the cell to make sours covie to spike protein. And the reason that it's sometimes called the trojan horse vaccination approach is that the adnovirus is another virus that does in fact, in effect the cell, though not with the possibility of replication. And once it's in there, it delivers the genetic code for the spike protein exactly right, and then the human body makes the spike protein and then develops the antibodies to it, and we're off to the races, as it were, off to the races. Are those viral vector vaccines just as easy to produce in large numbers of doses as the mRNA vaccine is. Well, the mRNA is synthetic at some level, so it's in that sense easier to make, but it can be rapidly killed up. And there's a lot of experience actually with replication effective add and ofvirus vectors, which was used actually as one of the e bowl of vaccines by Johnson and Johnson, the so called replication effective ad ofvirus twenty six, So millions of doses were administered in West Africa associated with that outbreak. Plus, interestingly, I think many people don't realize this that product who had to be maintained on dry ice and it was successfully maintained on dry ice in West Africa, because that's going to be also the story with the Fiser vaccine. So we'll see how this plays out, but there is at least some experience, some commercial experience with this approach. I'm glad you raised the temperature issue, which seems like it's going to be an important one going forward. The Fiser folks are saying that their vaccine needs to be kept at negative seventy degrees centigrade, which is around ninety four degrees below zero fahrenheit. Why does it have to be kept at that cold temperature? So? People who work with messenge drying in a laboratories usually stored in liquid nitrogen, which is like minus seventy to minus eighty degrees centigrade in order to be able to make sure that that molecule doesn't break down at least the fives are construct. You have to ship it and store it at minus seventy, which means that for the people who are taking care of it, they have to constantly replenish the dry ice, which is a lot to ask. And it gets worse than that. Then what happens is when you've thought it out and you put it in the refrigerator, that concentrated form of Messenger RNA can only stay in the refrigerator for twenty four hours. After twenty four hours you have to throw it out. Also, if you reconstitute it and it's just reconstituted with just a normal as salt water solution, after you reconstitute it, you have six hours to give it. So that's a lot to ask and I think when you do these trials, it's forty four thousand person trial, you can be sure that the company was very good about making that these study centers that were doing these trials knew exactly how to do it, and we're good at doing it. When a thing gets out into the real world, you worry that people are going to be as good at making sure they kept this ultra cold chain going as we did into trials, and that the efficacy may be a little less in a real world center. Because messenger RNA breaks down very quickly. It decentegrates very quickly, and although that would not be an issue, I think in terms of safety, it would definitely be an issue in terms of potency. Why does it break down so quickly? If in the human body, mRNA is tremendously necessary, and of course the human body is not negative seventy degrees centigrade, right, it does break down quickly in the human body, but you're constantly making messenger RNA and it's constantly breaking down. I mean, one thing, it's interesting just from a nerdy virologious standpoint, when you're infected with this virus, you usually shed infectious virus for about a week, meaning live virus for about a week, but you can be PCR positive for three months. Which interesting about that is when you're PCR positive, what that means is is that the virus gene is being detected in the back of your throw, so it's not the live virus necessarily, it's just the virus genome. Well, if messenger RNA breaks down so quickly, and it does, why is it that you're positive for three months after you're no longer making effect as virus. I mean, shouldn't the mRNA breakdown very quickly? And the answer as it does. So the only explanation for this is that the virus continues to make messenger rna, continues to make its genome, but doesn't make whole virus particles, which would be the first virus at least that I know about, has ever done something like that. It's just a very strange virus, this bad coronavirus. Can you think of any adaptive advantage genetically for an organism to continue to make its genome, maybe if it's not making the thing that enables it to spread in the population. That doesn't sound super efficient from a sort of classic evolutionary advantage standpoint. I know, I can't think of a reason, but you know what, I'm going to assume the virus is smarter than I am, and it's doing it for a reason, because why would it expand the energy that's needed to make message RNA unless there was some advantage to its survivability. Fascinating of the viral vector vaccines, the ones that Johnson and Johnson and Astra Zeneca are producing, will those also have to be kept at a comparable level of coldness. You mentioned that the vaccine that was used in Africa was stored on dry eye, so that's at the same kinds of low temperatures. My understanding is it's they'll be either kept at freezer or refrigerator temperatures, so they're not going to nearly require the kind of issues that are going to be required at least with the Fiser vaccine. Which interesting is that the modernist vaccine is also an mr anda vaccine, but it doesn't have to be shipped in stored at minus seventy to Minusa. It can be shipped in stored at minus twenty degrees centigrade, which is basically freezer temperature. They're both mr Anda vaccines. The gene sequence that determines the so called receptor binding domain on the Saurus CoV two spy protein is identical, but they are different. I mean, Fiser's vaccine is given at thirty micrograms per dose in two successive doses. Madernas is a hundred micrograms and two successive doses, And they don't have the same so called ducleoside analog, so they're not the same molecule. Obviously, there's there's stability differences, physical chemical differences between those two products, and I'm not sure exactly why, because obviously I'm sure if Fizer could ship in store at freezer temperature, which is much more doable, they would, so will that potentially turn out to be a determinative factor for governments that are making specific orders or for healthcare systems that are making specific orders. I mean, I'm sitting in I don't know, the Massachusetts Department of Health and Human Services, and I'm trying to figure out which one should I buy? Would that be ir relevant consideration for me? I'd rather buy the one, for example, that can be shipped at a slightly higher temperature or stored at us slightly higher temperature. You would think that the degree of ease, the degree to which administration and storage is idiot proof, it would be attractive what is currently required for the Fiser vaccine, which is, you know that you can't keep in the refrigerator from more than a day once we constuted, can't be kept for more than six hours, that you constantly have to replace with dry ice. I can't imagine how that is going to be done in a large retail pharmacy. I can't. I can't imagine how it's going to be done at our hospital, frankly, so, so then how would it be done? One way would be to have a series of centers that are distributed throughout a city that are like a testing center sept here that are specifically devoted to giving the vaccine. That would be one way to do it, and that may be the way it's going to be done. So yes, I think you're exactly right. How operationally or we get a vaccine that has these kinds of requirements out there. When you just described that you're not even sure your hospital, which is one of the best hospitals in the country and indeed in the world, could do it, that actually makes me wonder about viability altogether. I mean, you describe setting up these centers in different cities. That might be all well and good in big cities that have lots of resources, but it sounds like it would be hard to do in lots of parts of the United States, and definitely very hard to do in lots of parts of the world where such centers don't exist, and would then have to be built from scratch. From the way you formulated it there, I almost thought you were hinting that unless there is no other choice, the Fiser approach doesn't sound like it's going to be doable at scale. I think it's doable, and I think it's doable at scale. I just think it's going to require an enormous effort, which means an enormous expenditure as well as time. Yes, I think that's right, And understandings in the United States has contracted to by one hundred million doses of the Fiser vaccine, which means that they could vaccinate fifty million people. Now that the number of people that have been considered sort of first tier responders meaning essential workers like healthcare workers, people in transportation, law enforcement, etc. People over sixty five, people who have certain high risk medical conditions, added up to about one hundred and fifty million American adults, which is roughly half the adult population. This vaccine to be given exclusively at least for that hundred million, doses to the United States would be about a third of that. So the only way we're going to vaccinate the American population is if there's more than one vaccine. That's going to have to be true. We'll be right back. When I try to picture a center, a newly created center that becomes the vaccination center in a city, I guess we're down at getting into the nitty gritty, But I guess you have to set up appointments for people. You can have fifty million people lining up and waiting for vaccines, among other things, they would probably be too proximate to one another and that might spread the virus, right, and you have to identify whether or not these people really are the first tier for whom the vaccine is recommended. Because I think there are a lot of people who were going to get it who are not necessarily in that first tier group. So how do you identify who they are? How do you make sure they come back twenty one or twenty eight days letter depending on the vaccine, so to make sure they got their second dose. If you look at shing ricks, which is probably the best equivalent for this, which is an adult vaccine that's given in two doses roughly separated by a month, what percentage of people come back for that second dose. The answer is it's pretty high. It's about eighty five percent or so ninety percent. But still, you know, one out of ten or more people don't come back for that second dose because, first of all, the first dose of a shingles vaccine does cause side effect, as these vaccines will for different reasons. Mess Darna is an adgement. By adgement, I mean it stimulates the immune system so that you can give a lesser quantity of the active ingredient. And so you may get a first US and think, yeah, hey, this wasn't fun. I had fever, including high fever, I had headaches, chills, muscle eggs. I'm not signing up for that. Seconds, which really is the shingle story. I mean, it's certainly nothing compared to what the benefit is, which is preventing a disease that could kill you. So it's certainly worth it. But you know, for some people, they may think, you know, I'm young and healthy, I'm probably not going to die from this, so I really have to go back for that second dose. This wasn't much fun. The fact that mRNA it can be used as an adjument, namely something that stimulates your immune system, does that mean that a high percentage of the population who takes the vaccine will have those kinds of quasi flu leg symptoms in response to taking the vaccine. Yes, I think that's right. I think probably as much as half of people will have fever, including high fever, and then the symptoms associated with fever, headache, chills, muscle as I think that's likely. And how long do those symptoms typically last When you've administered just an agement a day or two. I mean, it'll go away again. So people will know they don't have COVID because they've just taken the vaccine, but they may be a little nervous about it. Well, the same thing actually applies for the vaccine trials. In theory, the participant doesn't know whether they're getting vaccine or placebo. But because the mRNA vaccines, and actually also true for the replication effect of adenovirus vaccines for a different reason, that too had a fairly high side effect profile. So if you didn't have side effects, you probably did have a placebo, and if you did have side effects, you probably did have the vaccine. So most people probably do know which they got. Interesting. Interesting. The second question I wanted to ask about that scenario is if one hundred and fifty million people aren't being described as first responders, and as you say, that's half of the US adult population, that on some level that first responder categorization isn't that meaningful, and it's going to have to be more narrowed down, especially if let's say we have fifteen million doses to begin with, and even among that there's the question of the order in which it will be given. Do you have a view about what would be plausible ways to narrow it down beyond that, or do you think that the governments involved are just going to duck the issue because it's so difficult to do allocation processes like this in a way that seems fair to people. I think you're exactly right. I think it is going to be difficult to do that, But I don't think they're going to duck the issue. I think both the Advisor Community for Communization Practice to the CDC and the National Category Medicine, which have been charged with trying to figure out exactly how these tiers are going to work out who's in the top top tier, who's just below that top tier, they won't duck it. The question is how it then is going to play out in the real world when the rubber meets the road, and we'll see I'm sure that the healthcare workers will be right up at the top, as will people who are older. For in terms of people who are over sixty five, we do need data to prove that the vaccine is effective in that age group. Hopefully we'll have enough people in these fisor trials, and we're during the trials, which are going to be the first ones to go through the FDA, we'll have enough data to be able to make that statement. Because although you know, obviously you want to make sure that both genders weekly represented, you want to make sure that there's an adequate representation of racial and ethnic minorities. There's no reason to believe that there would be really differences in the ability to respond with the accept for someone older and people who have various medical conditions, like you know, say obesity or diabetes. So that needs to be clear or as we do this. I thought of that specifically because I heard an interview on the radio with one of the fiser's spokespeople who was asked, of your forty four thousand people in your trial, were their elderly people? And the spokesperson responded by saying the trial group was demographically broad, which was not a direct answer, and of course it didn't say anything about whether the ninety percent efficacy level is you know, nearly one hundred percent of young people are finding it working and a very substantial number of older people are not discovering that it works. Do you have an instinct about that? I mean, would it be ordinarily the case that if you looked at a natural variation across a population, that older people would have a much harder time having the vaccine effectively generate successful protections for them, just because their immune systems are less responsive as they get older. Yes, and that's the flu story. I mean, influenza vaccine works. It's about sixty to sixty five percent effective to say, people less than eighteen years of age, but it's barely effective in people over sixty five. On the other hand, is shingles vaccine in those over seventy eighty years old works extremely well. So there are horses for courses. As they say at the track, I think we'll find that there are vaccines that may work well in one group but not another. And I thought, of you. I thought that the press release was pretty cajry. I think it made a statement that they had X number of people over fifty five, but it's really over sixty five that you care about. And I'm not just saying that because I'm over sixty five. Okay, I am saying that because I'm over sixty five. But you know you can't forget about us. Well, I don't think anyone is going to forget about people over sixty five. In the context of responding to a disease where most of the people whom it has killed were not just over sixty five, but over seventy or over seventy five, I think people are going to be extremely concerned about this. I guess there's the answer. Then we just have because of your horses for courses point, there's just no way we're going to know anything about this until we see the data. We can't assume what it's going to look like. The challenges here. If you look at that forty four thousand person trial and then you look at the instance of infection, it's actually much less than you would have predicted based on what the instances of outbreaks were as these trials were progressing. Which makes you wonder whether the people who were participants, because they may be more attentive to their health, were more likely to wear a mask, more likely to social distance, and therefore less likely to have been infected than an otherwise group. In other words, as compared to if they say, did the trials with bikers in Sturge of South Dakota who didn't wear masks, or you know, people who go to the Trump rallies or go to Rose Garden ceremonies, you know that you'd be more likely to have a higher rate of infections. And that matters because masks aren't one hundred percent effective, and so it may be that you were exposed to a lesser inoculum than someone who was less careful about their care. And you know, there's definitely an anoculum effect. The greater the enocuum, the more likely to have some modern secure disease. So there's a lot to work out. I don't think we're going to work a lot of it out before these vaccines are already introduced, because we have two hundred and forty thousand people that died of this virus this year. You're not going to do huge long term trials. You're not, and there's going to be whenever you do subsets, there's always going to be a loss of statistical strength, and so you're just going to take your best guests. I'm on the FDAs Vaccine Advisor Committee. These are the questions that are going to come before us, probably in the next few weeks when we're asked to approve these products through EUA, and I think we're going to be looking to approve both fisor in Maderna soon. And the other thing is I think although ninety four cases was reported by fives are in this press release, my sense was they're going to have at least one hundred and sixty by the time that our committee looks at this and it may be also drew from Maderna. So just to clarify the EUA as the emergency use authorization, your committee is a crucial step because the head of the FDA has said they're not going to issue an emergency use authorization unless your committee says go for it. So you're an important choke point in that structure. When you talk about the number ninety four or the number one hundred and sixty, clarify what that number refers to for us, Right, So what fives are said press releases that they had ninety four illnesses among participants and that the vaccine was ninety percent effective roughly, So we don't really know the numbers, yeah, but let's make them up. Let's assume then that there were eighty six cases in the placebo group in eight cases in the vaccine group, so that would be ninety percent protection. And just to clarify, that's out of forty four thousand people, twenty two thousand of whom got the vaccine, twenty two thousand of whom did not get the vaccine. Because it has to have been evenly divided, right, at least, that's a normal practice, that's right, so of forty four thousand people, twenty two thousand get the vaccine, eight of them get sick roughly on this reconstruction, and only eighty six people get the virus of twenty two thousand people who are not vaccinated. I mean that is stunningly small degree of the number of people, isn't it weirdly small? That's why I sort of had mentioned before that they may be much more likely to protect themselves by it. It It means because we're not helpless here, I mean hygienic measures who work, so that maybe that's what's going on. If that were true, if your hypothesis were correct, then maybe this vaccine is a lot less than effective. That's a good point. I think it was your point. I didn't mean it to you my point. Then I agree with my point. Let's assume, just theoretically, that there were eight people in the vaccine group who got sick. Those are the people you learn the most from, because you'll know whether or not they had an immune response what you thought was going to be an adequate immune response to the vaccine, if they didn't, if they had didn't have a very good neutralizing handibody response I e. And antibody response that neutralized virus and effectivity. Then you may have an immunological marker. You can say that, look, if you don't have this sort of level of immunity in response to the vaccine, you may not be protected. On the other hand, they may have had an a perfectly adequate neutralizing antibode response, in which case you can say, maybe the immune response that we thought was associated with protection isn't clearly associated with protection. And then it's a matter of looking at who those people were the god sick. Were they more likely to be over sixty five, did they have other healthcare problems, were they of a particular racial or ethnic background. That's where you learn the most people that got the vaccine still got sick. Should we, on the more positive front, have a pretty good indication of the lack of bad side effects if twenty two thousand people have gotten the vaccine, because presumably if there were any really meaningfully bad side effects, we would have seen them in this population. That's right. And if you look historically at the side effects that have been associated with vaccines, whether it's sort of polio from the ro polio vaccine or so called vicerotropic disease, which is to say, yellow fever following the yellow fever vaccine, or Gambera syndrome, which is the ascending paralysis that occurs very rarely after flu vaccine, and all of which are extremely rare, and they all occur really within six weeks of getting a dose. So and the way these trials are now being set up is that you can't get in EUA unless you follow at least half of the population who was vaccinated at least two months after dose two. So what that'll tell you is that at least as far as you know that you don't have a relatively uncommon severe side effect. But twenty thousand people isn't twenty million people. I once you put the vaccine out there in twenty million people, there may be a very rare side effect that the cursent say one in a million people or one in five hundred thousand people, that you're not going to pick up pre approval. But the good news is there are systems in place, like the Vaccine Adverse Events Reporting System, or like the Vaccine Safety Data Link, which will pick that up and have picked that up in the past. So I think people can be reassured that you're looking to remember a choice not to get a vaccine. It's not a risk free choice. It's just a choice to take a different risk. And the question is when do you know enough to say that I think that we have mitigated a critical amount of risk associated with this vaccine. Should I feel better say, as an over sixty five year old that ten thousand people are five thousand people who are three thousand people who've been vaccinated with the vaccine safely knowing that if I get infected with this virus, I have a higher chance of dying. It's always a matter of risk benefit, and I don't think people see it that way. They think that I'm just going to take the conservative thing and I'm just going to wait, And you know, while you're waiting, you may get infected. Now, as you wait, more and more people will get vaccinated, and then you have a much bigger platform in which to say, I think there really isn't a safety issue here, but while you wait, you might suffer the consequences. You've just replicated the conversation I have had with my parents recently, who are definitely over sixty five. And so I want to ask you if you're willing to share what your view is of the cost benefit here. I mean, my takeaway, and this is what I said to my parents, is that because you're in an age group, and they also live in New York where if you were to become infected, your health outcomes are not great, even with the new treatments that are available. I mean, I said it more bluntly like that. I said, you know, if you're infected and you're over this age, the danger that you could become sick and even die is really very high. Therefore, I argued, being conservative and waiting in this instance would make no sense at all measured by cost benefit, because although it's nice in general to be cautious about healthcare, in this instance, the side effects have not been shown to be particularly bad, and if they were in existence, they would be of tiny probability, and it would be of very very very minuscule probability that you could be so ill as to die from those side effects, whereas if you get the virus the possibilities are much greater. So that was my argument. I'm wondering was I right? I mean, I hope I was right, But if I wasn't, I want to know that. So I can take it back. What would you say to someone in that situation. No, I agree with you completely. I think that's exactly the argument. You know, when you do vaccine trials and you go from phase one trials of twenty two hundred people to face through trials of several hundred people, to face three trials of tens of thousands of peach people. Every time you do that, you mitigate risk, you lessen the risk. You never eliminate the risk, you never know everything. I mean, one of the real dangers here is that we could have a scenario where we have a pretty darn good vaccine that's pretty darn safe, and yet there's some significant part of the population that refuses to take it. I think what's going to happen Because this vaccine, it's not going to be recommended for the general population. Initially, it'll be recommended for certain groups like healthcare workers and transportation workers, etc. Those groups will start to get that vaccine, and then you'll see millions of people have been vaccinated, and then you'll see that they're happy they've been vaccinated, that there's no serious side effect. You may start to see an instance of cases and hospitalizations and deaths start to decrease, and people will see that the vaccine is having a positive effect, and that, I think, which assure people that there doesn't seem to be a problem, and there'll be more and more confident in getting the vaccine overtime. So that's the happy story, and I desperately hope that you're right. One of the reasons I always think that anti vaccination people manage to have the effect that they do have is that they're often free riding. You know that, in effect, there are some diseases that are the prevalences which is so low as a result or broad vaccination that some people say, well, I'm not going to get the vaccine and watch, I'm not going to get sick, And they might not get sick because the vaccine has effectively reduced the prevalence of the disease such that they're not very likely to be exposed. Is there a danger of that kind of a perceived free rider effect if the first responders and others and healthcare workers get the vaccine, if numbers start to go down, and then some people say, well, now that it's going down, I don't need to be vaccinated. I mean, we eliminated measles in the United States. By the year two thousand, it's come back because a critical number of parents have chosen not to vaccinate their children for just that reason. I think they figure, what the hell everybody around me is being vaccinated, Why should I take the risk and I'll still be protected. When enough people make that decision, then the virus thrives. And you had a handful of children who were in the Intensive care Union in New York hospitals because of severe measles, because the parents had made the decision to frankly put their children unnecessary risk. And you know, you are a member of society. I don't think it's your right to catch and transmitted potentially fatal infection. I think you owe it not only to yourself or to your children eventually, but to the people with whom you come in contact. We're remembering that there's five hundred thousand people in this country who can't be vaccinated. There can't be vaccinated because they're getting cancer chemotherapy, and then some instances now they're not going to be vaccinated because they're too young. They can't be vaccinated because they're getting biologicals for their chronic diseases. So do you have a responsibility to them the answer to I mean, in our hospital Children's Hospital of Philadelphia, every year we ask our healthcare workers to get a flu vaccine. Not just healthcare workers, anybody who could walk in the room, dietary, environmental services, anybody. Because you are working in a hospital of vulnerable children and it is therefore your responsibility to make sure that you protect them. Well, you could make the same argument in society. As a member of society, it's your obligation to protect those around. Could you just say a word about the half a million people who we can't vaccinate and what the reasons are, what's not safe for them to have their vaccine. Five hundred thousand people in this country are receiving biologicals, you know, things like monoclonal antibodies, because they have chronic disease, because they have psoriasis or arthritis or whatever. And a lot of people who are on chemotherapy for cancer, they too can't get vaccines because it wouldn't work in them because their immune systems are suppressed. Some people are born with immune systems that don't work. So that involves about five hundred thousand people in this population. Roughly three hundred and thirty million, And they depend on the herd. They depend on those around them to protect them. And when the herd says I don't care about you, they're the ones who are often the first to suffer these diseases. Last, but not least. What's it kind of feel like in the room when your committee meets? What does it usually feel like when you're committee meets. I guess it'll be virtual because of COVID. Well, we've never had a meeting like this, I mean normally, what does it feel like in the room. Normally it's it's a group of sort of you know, nerdy virologists like myself sitting around talking about what flu strange we're going to pick for the vaccines for next year. So we haven't at least in the last couple of years, licensed a new vaccine that's going to be what's happening here, and it's opened to the public. Anybody can come to those meetings. But if you went to our flu meeting, you'd be bored to death. Most likely. We don't have big crowds there. On the other hand, when we had our first meeting of the FDA's Vaccine Advisor committee regarding these vaccines. It was on October twenty second, just to see what criteria we would be happy with for approving a vaccine under emergency use authorization, and that was televised. I mean, that was on c SPAN because there was a lot of interest in seeing it. And here again, when we meet, and I suspect we're going to be in December, and I suspect we're going to be meeting more than once in December and January, that too will be televised and people can have public comment, because that's true of any federal advisory committee meeting. Those have to be open to the public, which is great because I think then the public will see the data in the same way we see the data, so it shouldn't be an issue of transparency. Paul, I just want to thank you for your important work with you luck in these meetings, and really I just deeply appreciate the clarification and the listeners do too, so thank you. Thank you very much. That was fun. I appreciate it. I learned many fascinating things in the course of my conversation with doctor Offitt. The first had to do with the basic science, which we've talked about before on this podcast. To me, they takeaway here is that mRNA vaccines like visors and madernas do not pose the traditional risk of actually infecting people with the virus because they're not introducing the virus at all into the human system. That seems like a very positive fact. Simultaneously, it is true that these vaccines may have the side effect on many people of giving them twenty four hours of fever and chills, and we need to be aware of that and recognize that will not be a symptom of COVID. To the contrary, it's a symptom that the vaccine is actually doing its work. Another crucial takeaway is that the difficulty of delivering at least the Fiser vaccine, which has to be stored at seventy degrees below zero centigrade, will be very significant. The practical difficulty of administering a vaccine that has to be kept so cold is going to require, according to doctor Offit, the development of new delivery systems and potentially even new facilities for doing this. Mr Anda vaccines can be produced extremely fast, but their distribution is going to be a more subtle matter. A further consequence of my conversation with Doctor offit is that I learned that there are half a million people in the United States. I didn't know that number who are not able to take a vaccine of any kind, and therefore are dependent on the rest of us to make sure that we take the vaccine, to reduce the prevalence of the virus, and to protect them via protection of the herd. Last, but by no means least, is Doctor Office assessment that if the data turn out to be what we've heard from the press release, the cost benefit analysis will indicate clearly that people should take the vaccine, and that that will be especially true of older people who would be very vulnerable to serious, serious illness and even death should they catch the stars Cove two virus. For me and from my family, that takeaway is hugely significant, and I intend to repeat it to anyone who will listen. We at Deep Background will be taking a Thanksgiving break, so we won't have an episode for you next week, but we will be back after Thanksgiving. Until the next time I speak to you, be careful, be safe, and be well. Deep back Ground is brought to you by Pushkin Industries. Our producer is Lydia Gencott. Our engineer is Martin Gonzalez, and our showrunner is Sophie Crane mckibbon. Theme music by Luis Gera at Pushkin. Thanks to Mia Lobell, Julia Barton, Heather Faine, Carlie mcgliori, Maggie Taylor, Eric Sandler, and Jacob Weisberg. You can find me on Twitter at Noah Arfeld. I also write a column for Bloomberg Opinion, which you can find at bloomberg dot com slash Feldman. To discover Bloomberg's original slate of podcasts, go to Bloomberg dot com slash podcasts, and if you liked what you heard today, please write a review or tell a friend. This is deep background

Pushkin from Pushkin Industries. This is Deep Background, the show where we explore the stories behind the stories in the news. I'm Noah Feldman. Coronavirus cases are surging across the country. Cities and states are responding with new regulations on social gatherings, but another potential solution is at least on the horizon and maybe a little closer than that. Last week, the drug company Visor announced in a press release that it's coronavirus vaccine seems to work. According to a preliminary analysis, Visor's vaccine is ninety percent effective at preventing COVID nineteen. Maderna's vaccine, which operates on similar principles, has produced similar numbers reported by that company as well. To discuss the science behind these developments and what's going to happen in practice, we are joined by doctor Paul Offen. He's a professor of vaccinology and pediatrics at the University of Pennsylvania. He's also importantly a member of the FDA's Vaccine Advisory Panel. Among his other distinctions, he is also the co inventor of the rhodavirus vaccine. Paul, thank you so much for joining me. The immediate impetus for our conversation is the good news that mRNA vaccines like Visors and Maderna's shows efficacy in trials. So let's just start with the very basic question. The Visor vaccine is an RNA vaccine. There's never been one of those that worked before. Why is this appear to be working? So what we think we know is we think we know that we want to make antibodies to the protein that emanates from the surface of the virus that is responsible for attaching the virus to cells. If you can then make antibodies to that protein, you can prevent the virus from attaching the cells. In the past, when we've wanted to make an about it to the spike protein, we would do things like give sort of a whole killed form of the virus which would have the spike protein on it, or we would give a live we can form of the virus which would have the spike protein on it, or we would purify the spike protein, or we would use recomment at DNA technology to make the spike protein. What we're doing now is we're saying we're not going to do any of that. We're going to take a small gene that essentially codes for that spike protein, and then we'll inject that and hope that it gets into muscle cells and will then be translated to the spike protein. So, in other words, the person makes the spike protein, then the person makes in about it's the spectro protein. We've never done that before. Just like you said, there's no commercial equivalent for that for any vaccine. It should theoretically work, we just never knew that it could. That was a spectacularly clear explanation. I want to just dive into a specific part of it. The part I want to dive into is the idea that historically, the way we've done vaccines and by Weime and you the scientific community, is by introducing a version of the spike protein in this case that we want to block, and then having the body produce antibodies to it. And that what makes the mRNA approach, which is characteristic of the Fiser approach and of the Maderna approach, distinctive, is that it actually introduces a genetic code to produce the spike protein, which the body then produces, which we don't want in principle a body to produce. But then the body produces antibodies to the spike protein that the body has produced. So you're saving a step, as it were, you don't have to introduce the spike protein in some form from the outside. First of all, am I getting that right? That's exactly right. But if for example, you gave a live attenuated viral vaccine, that virus would then enter the cell, reproduce itself, and it would make the spike protein inside that cell. So it's not like a complete long shot. And we certainly have a wealth of experience using live weakened viruses to induce immune response, starting in the mid nineteen thirties with yellow fever vaccine. And is it a good thing that by encoding for the spike protein without introducing the virus, the virus actually doesn't in principle have a chance of arising within the cell with this kind of vaccine, correct, because we're not encoding for the virus, just encoding for the spike protein. That's right. It's just you're being infected, if you will, with one protein, so that's not the virus, that's right. So when we think about potential negative side effects, when we think about live attenuated viruses or killed viruses, sometimes we worry that they might produce, at least in some people, symptoms of the actual virus or the bad consequence of the actual virus. Is it correct to say that, at least in principle, the mRNA vaccine can't do that because there is no virus introduced into the system. There's just the genetic code for the spike protein, which is not itself the virus. Yeah, this is not sours cob two virus. This is just one protein from the virus that you will make. Therefore, the signs and symptoms that you develop will not resemble those of SARS cob two infection. So one of the best things about an RNA vaccine, if indeed it works, is that it avoids some of the potential downsides of more traditional vaccination. That's correct. Yes, Sometimes it's been said in the media and by the companies that it's easier to produce large numbers of doses of an mRNA vaccine than it is to produce large numbers of doses of a traditional killed or attenuated virus vaccine. Is that so, And if it is so, why is it so? I think there's a couple advantages for these genetic approaches. The so called genetic plug and play approaches are fast because they're very easy to construct. You just take the gene and in the case of mRNA, you give the gene, or in the case of some of these other so called viral vectors, you just insert the gene into that viral vector. So it's really very fast to be able to construct it, and then it's very easy to scale up rapidly. So MESSERNA, it's essentially synthetic. You're just manufacturing it, so it can be scaled up very quickly. I mean, I think Visor said that they would have fifty million doses by the end of twenty twenty, that they would have one point three billion doses in the year twenty twenty one. You mentioned the viral vector vaccines also sometimes called trojan horse vaccines. The Astroxenica approach, the Oxford approach is one of those. Could you describe how that works in relationship to the mRNA approach, right, So it's a little different. So the so called replication defective adnovirus vectors, which is the approach that's being used by Johnson Johnson, the approach that's being used by Astroxenica, the approach is being used by Russia. The approach is being used by Chin in part is the adnovirus is a human virus that can cause a variety of diseases. But by engineering the virus so that it's replication defective, that means that it cannot reproduce itself, that means that it cannot cause disease. But it's also genetically engineered so it has the gene that codes for the spike protein. So then you inoculate this replication defective viral vector into the person. It's taken up into muscle cells, and then that replication of vectivirus enters the cell nucleus, where then that gene that codes for the spike protein is transcribed into messenger rna, and then the messenger rna then enters the cytoplasm and then makes the protein, and then you make the protein. So it's sort of like a step back from the messenger RNA strategy, but essentially it's the same strategy. It's ultimately getting the cell to make sours covie to spike protein. And the reason that it's sometimes called the trojan horse vaccination approach is that the adnovirus is another virus that does in fact, in effect the cell, though not with the possibility of replication. And once it's in there, it delivers the genetic code for the spike protein exactly right, and then the human body makes the spike protein and then develops the antibodies to it, and we're off to the races, as it were, off to the races. Are those viral vector vaccines just as easy to produce in large numbers of doses as the mRNA vaccine is. Well, the mRNA is synthetic at some level, so it's in that sense easier to make, but it can be rapidly killed up. And there's a lot of experience actually with replication effective add and ofvirus vectors, which was used actually as one of the e bowl of vaccines by Johnson and Johnson, the so called replication effective ad ofvirus twenty six, So millions of doses were administered in West Africa associated with that outbreak. Plus, interestingly, I think many people don't realize this that product who had to be maintained on dry ice and it was successfully maintained on dry ice in West Africa, because that's going to be also the story with the Fiser vaccine. So we'll see how this plays out, but there is at least some experience, some commercial experience with this approach. I'm glad you raised the temperature issue, which seems like it's going to be an important one going forward. The Fiser folks are saying that their vaccine needs to be kept at negative seventy degrees centigrade, which is around ninety four degrees below zero fahrenheit. Why does it have to be kept at that cold temperature? So? People who work with messenge drying in a laboratories usually stored in liquid nitrogen, which is like minus seventy to minus eighty degrees centigrade in order to be able to make sure that that molecule doesn't break down at least the fives are construct. You have to ship it and store it at minus seventy, which means that for the people who are taking care of it, they have to constantly replenish the dry ice, which is a lot to ask. And it gets worse than that. Then what happens is when you've thought it out and you put it in the refrigerator, that concentrated form of Messenger RNA can only stay in the refrigerator for twenty four hours. After twenty four hours you have to throw it out. Also, if you reconstitute it and it's just reconstituted with just a normal as salt water solution, after you reconstitute it, you have six hours to give it. So that's a lot to ask and I think when you do these trials, it's forty four thousand person trial, you can be sure that the company was very good about making that these study centers that were doing these trials knew exactly how to do it, and we're good at doing it. When a thing gets out into the real world, you worry that people are going to be as good at making sure they kept this ultra cold chain going as we did into trials, and that the efficacy may be a little less in a real world center. Because messenger RNA breaks down very quickly. It decentegrates very quickly, and although that would not be an issue, I think in terms of safety, it would definitely be an issue in terms of potency. Why does it break down so quickly? If in the human body, mRNA is tremendously necessary, and of course the human body is not negative seventy degrees centigrade, right, it does break down quickly in the human body, but you're constantly making messenger RNA and it's constantly breaking down. I mean, one thing, it's interesting just from a nerdy virologious standpoint, when you're infected with this virus, you usually shed infectious virus for about a week, meaning live virus for about a week, but you can be PCR positive for three months. Which interesting about that is when you're PCR positive, what that means is is that the virus gene is being detected in the back of your throw, so it's not the live virus necessarily, it's just the virus genome. Well, if messenger RNA breaks down so quickly, and it does, why is it that you're positive for three months after you're no longer making effect as virus. I mean, shouldn't the mRNA breakdown very quickly? And the answer as it does. So the only explanation for this is that the virus continues to make messenger rna, continues to make its genome, but doesn't make whole virus particles, which would be the first virus at least that I know about, has ever done something like that. It's just a very strange virus, this bad coronavirus. Can you think of any adaptive advantage genetically for an organism to continue to make its genome, maybe if it's not making the thing that enables it to spread in the population. That doesn't sound super efficient from a sort of classic evolutionary advantage standpoint. I know, I can't think of a reason, but you know what, I'm going to assume the virus is smarter than I am, and it's doing it for a reason, because why would it expand the energy that's needed to make message RNA unless there was some advantage to its survivability. Fascinating of the viral vector vaccines, the ones that Johnson and Johnson and Astra Zeneca are producing, will those also have to be kept at a comparable level of coldness. You mentioned that the vaccine that was used in Africa was stored on dry eye, so that's at the same kinds of low temperatures. My understanding is it's they'll be either kept at freezer or refrigerator temperatures, so they're not going to nearly require the kind of issues that are going to be required at least with the Fiser vaccine. Which interesting is that the modernist vaccine is also an mr anda vaccine, but it doesn't have to be shipped in stored at minus seventy to Minusa. It can be shipped in stored at minus twenty degrees centigrade, which is basically freezer temperature. They're both mr Anda vaccines. The gene sequence that determines the so called receptor binding domain on the Saurus CoV two spy protein is identical, but they are different. I mean, Fiser's vaccine is given at thirty micrograms per dose in two successive doses. Madernas is a hundred micrograms and two successive doses, And they don't have the same so called ducleoside analog, so they're not the same molecule. Obviously, there's there's stability differences, physical chemical differences between those two products, and I'm not sure exactly why, because obviously I'm sure if Fizer could ship in store at freezer temperature, which is much more doable, they would, so will that potentially turn out to be a determinative factor for governments that are making specific orders or for healthcare systems that are making specific orders. I mean, I'm sitting in I don't know, the Massachusetts Department of Health and Human Services, and I'm trying to figure out which one should I buy? Would that be ir relevant consideration for me? I'd rather buy the one, for example, that can be shipped at a slightly higher temperature or stored at us slightly higher temperature. You would think that the degree of ease, the degree to which administration and storage is idiot proof, it would be attractive what is currently required for the Fiser vaccine, which is, you know that you can't keep in the refrigerator from more than a day once we constuted, can't be kept for more than six hours, that you constantly have to replace with dry ice. I can't imagine how that is going to be done in a large retail pharmacy. I can't. I can't imagine how it's going to be done at our hospital, frankly, so, so then how would it be done? One way would be to have a series of centers that are distributed throughout a city that are like a testing center sept here that are specifically devoted to giving the vaccine. That would be one way to do it, and that may be the way it's going to be done. So yes, I think you're exactly right. How operationally or we get a vaccine that has these kinds of requirements out there. When you just described that you're not even sure your hospital, which is one of the best hospitals in the country and indeed in the world, could do it, that actually makes me wonder about viability altogether. I mean, you describe setting up these centers in different cities. That might be all well and good in big cities that have lots of resources, but it sounds like it would be hard to do in lots of parts of the United States, and definitely very hard to do in lots of parts of the world where such centers don't exist, and would then have to be built from scratch. From the way you formulated it there, I almost thought you were hinting that unless there is no other choice, the Fiser approach doesn't sound like it's going to be doable at scale. I think it's doable, and I think it's doable at scale. I just think it's going to require an enormous effort, which means an enormous expenditure as well as time. Yes, I think that's right, And understandings in the United States has contracted to by one hundred million doses of the Fiser vaccine, which means that they could vaccinate fifty million people. Now that the number of people that have been considered sort of first tier responders meaning essential workers like healthcare workers, people in transportation, law enforcement, etc. People over sixty five, people who have certain high risk medical conditions, added up to about one hundred and fifty million American adults, which is roughly half the adult population. This vaccine to be given exclusively at least for that hundred million, doses to the United States would be about a third of that. So the only way we're going to vaccinate the American population is if there's more than one vaccine. That's going to have to be true. We'll be right back. When I try to picture a center, a newly created center that becomes the vaccination center in a city, I guess we're down at getting into the nitty gritty, But I guess you have to set up appointments for people. You can have fifty million people lining up and waiting for vaccines, among other things, they would probably be too proximate to one another and that might spread the virus, right, and you have to identify whether or not these people really are the first tier for whom the vaccine is recommended. Because I think there are a lot of people who were going to get it who are not necessarily in that first tier group. So how do you identify who they are? How do you make sure they come back twenty one or twenty eight days letter depending on the vaccine, so to make sure they got their second dose. If you look at shing ricks, which is probably the best equivalent for this, which is an adult vaccine that's given in two doses roughly separated by a month, what percentage of people come back for that second dose. The answer is it's pretty high. It's about eighty five percent or so ninety percent. But still, you know, one out of ten or more people don't come back for that second dose because, first of all, the first dose of a shingles vaccine does cause side effect, as these vaccines will for different reasons. Mess Darna is an adgement. By adgement, I mean it stimulates the immune system so that you can give a lesser quantity of the active ingredient. And so you may get a first US and think, yeah, hey, this wasn't fun. I had fever, including high fever, I had headaches, chills, muscle eggs. I'm not signing up for that. Seconds, which really is the shingle story. I mean, it's certainly nothing compared to what the benefit is, which is preventing a disease that could kill you. So it's certainly worth it. But you know, for some people, they may think, you know, I'm young and healthy, I'm probably not going to die from this, so I really have to go back for that second dose. This wasn't much fun. The fact that mRNA it can be used as an adjument, namely something that stimulates your immune system, does that mean that a high percentage of the population who takes the vaccine will have those kinds of quasi flu leg symptoms in response to taking the vaccine. Yes, I think that's right. I think probably as much as half of people will have fever, including high fever, and then the symptoms associated with fever, headache, chills, muscle as I think that's likely. And how long do those symptoms typically last When you've administered just an agement a day or two. I mean, it'll go away again. So people will know they don't have COVID because they've just taken the vaccine, but they may be a little nervous about it. Well, the same thing actually applies for the vaccine trials. In theory, the participant doesn't know whether they're getting vaccine or placebo. But because the mRNA vaccines, and actually also true for the replication effect of adenovirus vaccines for a different reason, that too had a fairly high side effect profile. So if you didn't have side effects, you probably did have a placebo, and if you did have side effects, you probably did have the vaccine. So most people probably do know which they got. Interesting. Interesting. The second question I wanted to ask about that scenario is if one hundred and fifty million people aren't being described as first responders, and as you say, that's half of the US adult population, that on some level that first responder categorization isn't that meaningful, and it's going to have to be more narrowed down, especially if let's say we have fifteen million doses to begin with, and even among that there's the question of the order in which it will be given. Do you have a view about what would be plausible ways to narrow it down beyond that, or do you think that the governments involved are just going to duck the issue because it's so difficult to do allocation processes like this in a way that seems fair to people. I think you're exactly right. I think it is going to be difficult to do that, But I don't think they're going to duck the issue. I think both the Advisor Community for Communization Practice to the CDC and the National Category Medicine, which have been charged with trying to figure out exactly how these tiers are going to work out who's in the top top tier, who's just below that top tier, they won't duck it. The question is how it then is going to play out in the real world when the rubber meets the road, and we'll see I'm sure that the healthcare workers will be right up at the top, as will people who are older. For in terms of people who are over sixty five, we do need data to prove that the vaccine is effective in that age group. Hopefully we'll have enough people in these fisor trials, and we're during the trials, which are going to be the first ones to go through the FDA, we'll have enough data to be able to make that statement. Because although you know, obviously you want to make sure that both genders weekly represented, you want to make sure that there's an adequate representation of racial and ethnic minorities. There's no reason to believe that there would be really differences in the ability to respond with the accept for someone older and people who have various medical conditions, like you know, say obesity or diabetes. So that needs to be clear or as we do this. I thought of that specifically because I heard an interview on the radio with one of the fiser's spokespeople who was asked, of your forty four thousand people in your trial, were their elderly people? And the spokesperson responded by saying the trial group was demographically broad, which was not a direct answer, and of course it didn't say anything about whether the ninety percent efficacy level is you know, nearly one hundred percent of young people are finding it working and a very substantial number of older people are not discovering that it works. Do you have an instinct about that? I mean, would it be ordinarily the case that if you looked at a natural variation across a population, that older people would have a much harder time having the vaccine effectively generate successful protections for them, just because their immune systems are less responsive as they get older. Yes, and that's the flu story. I mean, influenza vaccine works. It's about sixty to sixty five percent effective to say, people less than eighteen years of age, but it's barely effective in people over sixty five. On the other hand, is shingles vaccine in those over seventy eighty years old works extremely well. So there are horses for courses. As they say at the track, I think we'll find that there are vaccines that may work well in one group but not another. And I thought, of you. I thought that the press release was pretty cajry. I think it made a statement that they had X number of people over fifty five, but it's really over sixty five that you care about. And I'm not just saying that because I'm over sixty five. Okay, I am saying that because I'm over sixty five. But you know you can't forget about us. Well, I don't think anyone is going to forget about people over sixty five. In the context of responding to a disease where most of the people whom it has killed were not just over sixty five, but over seventy or over seventy five, I think people are going to be extremely concerned about this. I guess there's the answer. Then we just have because of your horses for courses point, there's just no way we're going to know anything about this until we see the data. We can't assume what it's going to look like. The challenges here. If you look at that forty four thousand person trial and then you look at the instance of infection, it's actually much less than you would have predicted based on what the instances of outbreaks were as these trials were progressing. Which makes you wonder whether the people who were participants, because they may be more attentive to their health, were more likely to wear a mask, more likely to social distance, and therefore less likely to have been infected than an otherwise group. In other words, as compared to if they say, did the trials with bikers in Sturge of South Dakota who didn't wear masks, or you know, people who go to the Trump rallies or go to Rose Garden ceremonies, you know that you'd be more likely to have a higher rate of infections. And that matters because masks aren't one hundred percent effective, and so it may be that you were exposed to a lesser inoculum than someone who was less careful about their care. And you know, there's definitely an anoculum effect. The greater the enocuum, the more likely to have some modern secure disease. So there's a lot to work out. I don't think we're going to work a lot of it out before these vaccines are already introduced, because we have two hundred and forty thousand people that died of this virus this year. You're not going to do huge long term trials. You're not, and there's going to be whenever you do subsets, there's always going to be a loss of statistical strength, and so you're just going to take your best guests. I'm on the FDAs Vaccine Advisor Committee. These are the questions that are going to come before us, probably in the next few weeks when we're asked to approve these products through EUA, and I think we're going to be looking to approve both fisor in Maderna soon. And the other thing is I think although ninety four cases was reported by fives are in this press release, my sense was they're going to have at least one hundred and sixty by the time that our committee looks at this and it may be also drew from Maderna. So just to clarify the EUA as the emergency use authorization, your committee is a crucial step because the head of the FDA has said they're not going to issue an emergency use authorization unless your committee says go for it. So you're an important choke point in that structure. When you talk about the number ninety four or the number one hundred and sixty, clarify what that number refers to for us, Right, So what fives are said press releases that they had ninety four illnesses among participants and that the vaccine was ninety percent effective roughly, So we don't really know the numbers, yeah, but let's make them up. Let's assume then that there were eighty six cases in the placebo group in eight cases in the vaccine group, so that would be ninety percent protection. And just to clarify, that's out of forty four thousand people, twenty two thousand of whom got the vaccine, twenty two thousand of whom did not get the vaccine. Because it has to have been evenly divided, right, at least, that's a normal practice, that's right, so of forty four thousand people, twenty two thousand get the vaccine, eight of them get sick roughly on this reconstruction, and only eighty six people get the virus of twenty two thousand people who are not vaccinated. I mean that is stunningly small degree of the number of people, isn't it weirdly small? That's why I sort of had mentioned before that they may be much more likely to protect themselves by it. It It means because we're not helpless here, I mean hygienic measures who work, so that maybe that's what's going on. If that were true, if your hypothesis were correct, then maybe this vaccine is a lot less than effective. That's a good point. I think it was your point. I didn't mean it to you my point. Then I agree with my point. Let's assume, just theoretically, that there were eight people in the vaccine group who got sick. Those are the people you learn the most from, because you'll know whether or not they had an immune response what you thought was going to be an adequate immune response to the vaccine, if they didn't, if they had didn't have a very good neutralizing handibody response I e. And antibody response that neutralized virus and effectivity. Then you may have an immunological marker. You can say that, look, if you don't have this sort of level of immunity in response to the vaccine, you may not be protected. On the other hand, they may have had an a perfectly adequate neutralizing antibode response, in which case you can say, maybe the immune response that we thought was associated with protection isn't clearly associated with protection. And then it's a matter of looking at who those people were the god sick. Were they more likely to be over sixty five, did they have other healthcare problems, were they of a particular racial or ethnic background. That's where you learn the most people that got the vaccine still got sick. Should we, on the more positive front, have a pretty good indication of the lack of bad side effects if twenty two thousand people have gotten the vaccine, because presumably if there were any really meaningfully bad side effects, we would have seen them in this population. That's right. And if you look historically at the side effects that have been associated with vaccines, whether it's sort of polio from the ro polio vaccine or so called vicerotropic disease, which is to say, yellow fever following the yellow fever vaccine, or Gambera syndrome, which is the ascending paralysis that occurs very rarely after flu vaccine, and all of which are extremely rare, and they all occur really within six weeks of getting a dose. So and the way these trials are now being set up is that you can't get in EUA unless you follow at least half of the population who was vaccinated at least two months after dose two. So what that'll tell you is that at least as far as you know that you don't have a relatively uncommon severe side effect. But twenty thousand people isn't twenty million people. I once you put the vaccine out there in twenty million people, there may be a very rare side effect that the cursent say one in a million people or one in five hundred thousand people, that you're not going to pick up pre approval. But the good news is there are systems in place, like the Vaccine Adverse Events Reporting System, or like the Vaccine Safety Data Link, which will pick that up and have picked that up in the past. So I think people can be reassured that you're looking to remember a choice not to get a vaccine. It's not a risk free choice. It's just a choice to take a different risk. And the question is when do you know enough to say that I think that we have mitigated a critical amount of risk associated with this vaccine. Should I feel better say, as an over sixty five year old that ten thousand people are five thousand people who are three thousand people who've been vaccinated with the vaccine safely knowing that if I get infected with this virus, I have a higher chance of dying. It's always a matter of risk benefit, and I don't think people see it that way. They think that I'm just going to take the conservative thing and I'm just going to wait, And you know, while you're waiting, you may get infected. Now, as you wait, more and more people will get vaccinated, and then you have a much bigger platform in which to say, I think there really isn't a safety issue here, but while you wait, you might suffer the consequences. You've just replicated the conversation I have had with my parents recently, who are definitely over sixty five. And so I want to ask you if you're willing to share what your view is of the cost benefit here. I mean, my takeaway, and this is what I said to my parents, is that because you're in an age group, and they also live in New York where if you were to become infected, your health outcomes are not great, even with the new treatments that are available. I mean, I said it more bluntly like that. I said, you know, if you're infected and you're over this age, the danger that you could become sick and even die is really very high. Therefore, I argued, being conservative and waiting in this instance would make no sense at all measured by cost benefit, because although it's nice in general to be cautious about healthcare, in this instance, the side effects have not been shown to be particularly bad, and if they were in existence, they would be of tiny probability, and it would be of very very very minuscule probability that you could be so ill as to die from those side effects, whereas if you get the virus the possibilities are much greater. So that was my argument. I'm wondering was I right? I mean, I hope I was right, But if I wasn't, I want to know that. So I can take it back. What would you say to someone in that situation. No, I agree with you completely. I think that's exactly the argument. You know, when you do vaccine trials and you go from phase one trials of twenty two hundred people to face through trials of several hundred people, to face three trials of tens of thousands of peach people. Every time you do that, you mitigate risk, you lessen the risk. You never eliminate the risk, you never know everything. I mean, one of the real dangers here is that we could have a scenario where we have a pretty darn good vaccine that's pretty darn safe, and yet there's some significant part of the population that refuses to take it. I think what's going to happen Because this vaccine, it's not going to be recommended for the general population. Initially, it'll be recommended for certain groups like healthcare workers and transportation workers, etc. Those groups will start to get that vaccine, and then you'll see millions of people have been vaccinated, and then you'll see that they're happy they've been vaccinated, that there's no serious side effect. You may start to see an instance of cases and hospitalizations and deaths start to decrease, and people will see that the vaccine is having a positive effect, and that, I think, which assure people that there doesn't seem to be a problem, and there'll be more and more confident in getting the vaccine overtime. So that's the happy story, and I desperately hope that you're right. One of the reasons I always think that anti vaccination people manage to have the effect that they do have is that they're often free riding. You know that, in effect, there are some diseases that are the prevalences which is so low as a result or broad vaccination that some people say, well, I'm not going to get the vaccine and watch, I'm not going to get sick, And they might not get sick because the vaccine has effectively reduced the prevalence of the disease such that they're not very likely to be exposed. Is there a danger of that kind of a perceived free rider effect if the first responders and others and healthcare workers get the vaccine, if numbers start to go down, and then some people say, well, now that it's going down, I don't need to be vaccinated. I mean, we eliminated measles in the United States. By the year two thousand, it's come back because a critical number of parents have chosen not to vaccinate their children for just that reason. I think they figure, what the hell everybody around me is being vaccinated, Why should I take the risk and I'll still be protected. When enough people make that decision, then the virus thrives. And you had a handful of children who were in the Intensive care Union in New York hospitals because of severe measles, because the parents had made the decision to frankly put their children unnecessary risk. And you know, you are a member of society. I don't think it's your right to catch and transmitted potentially fatal infection. I think you owe it not only to yourself or to your children eventually, but to the people with whom you come in contact. We're remembering that there's five hundred thousand people in this country who can't be vaccinated. There can't be vaccinated because they're getting cancer chemotherapy, and then some instances now they're not going to be vaccinated because they're too young. They can't be vaccinated because they're getting biologicals for their chronic diseases. So do you have a responsibility to them the answer to I mean, in our hospital Children's Hospital of Philadelphia, every year we ask our healthcare workers to get a flu vaccine. Not just healthcare workers, anybody who could walk in the room, dietary, environmental services, anybody. Because you are working in a hospital of vulnerable children and it is therefore your responsibility to make sure that you protect them. Well, you could make the same argument in society. As a member of society, it's your obligation to protect those around. Could you just say a word about the half a million people who we can't vaccinate and what the reasons are, what's not safe for them to have their vaccine. Five hundred thousand people in this country are receiving biologicals, you know, things like monoclonal antibodies, because they have chronic disease, because they have psoriasis or arthritis or whatever. And a lot of people who are on chemotherapy for cancer, they too can't get vaccines because it wouldn't work in them because their immune systems are suppressed. Some people are born with immune systems that don't work. So that involves about five hundred thousand people in this population. Roughly three hundred and thirty million, And they depend on the herd. They depend on those around them to protect them. And when the herd says I don't care about you, they're the ones who are often the first to suffer these diseases. Last, but not least. What's it kind of feel like in the room when your committee meets? What does it usually feel like when you're committee meets. I guess it'll be virtual because of COVID. Well, we've never had a meeting like this, I mean normally, what does it feel like in the room. Normally it's it's a group of sort of you know, nerdy virologists like myself sitting around talking about what flu strange we're going to pick for the vaccines for next year. So we haven't at least in the last couple of years, licensed a new vaccine that's going to be what's happening here, and it's opened to the public. Anybody can come to those meetings. But if you went to our flu meeting, you'd be bored to death. Most likely. We don't have big crowds there. On the other hand, when we had our first meeting of the FDA's Vaccine Advisor committee regarding these vaccines. It was on October twenty second, just to see what criteria we would be happy with for approving a vaccine under emergency use authorization, and that was televised. I mean, that was on c SPAN because there was a lot of interest in seeing it. And here again, when we meet, and I suspect we're going to be in December, and I suspect we're going to be meeting more than once in December and January, that too will be televised and people can have public comment, because that's true of any federal advisory committee meeting. Those have to be open to the public, which is great because I think then the public will see the data in the same way we see the data, so it shouldn't be an issue of transparency. Paul, I just want to thank you for your important work with you luck in these meetings, and really I just deeply appreciate the clarification and the listeners do too, so thank you. Thank you very much. That was fun. I appreciate it. I learned many fascinating things in the course of my conversation with doctor Offitt. The first had to do with the basic science, which we've talked about before on this podcast. To me, they takeaway here is that mRNA vaccines like visors and madernas do not pose the traditional risk of actually infecting people with the virus because they're not introducing the virus at all into the human system. That seems like a very positive fact. Simultaneously, it is true that these vaccines may have the side effect on many people of giving them twenty four hours of fever and chills, and we need to be aware of that and recognize that will not be a symptom of COVID. To the contrary, it's a symptom that the vaccine is actually doing its work. Another crucial takeaway is that the difficulty of delivering at least the Fiser vaccine, which has to be stored at seventy degrees below zero centigrade, will be very significant. The practical difficulty of administering a vaccine that has to be kept so cold is going to require, according to doctor Offit, the development of new delivery systems and potentially even new facilities for doing this. Mr Anda vaccines can be produced extremely fast, but their distribution is going to be a more subtle matter. A further consequence of my conversation with Doctor offit is that I learned that there are half a million people in the United States. I didn't know that number who are not able to take a vaccine of any kind, and therefore are dependent on the rest of us to make sure that we take the vaccine, to reduce the prevalence of the virus, and to protect them via protection of the herd. Last, but by no means least, is Doctor Office assessment that if the data turn out to be what we've heard from the press release, the cost benefit analysis will indicate clearly that people should take the vaccine, and that that will be especially true of older people who would be very vulnerable to serious, serious illness and even death should they catch the stars Cove two virus. For me and from my family, that takeaway is hugely significant, and I intend to repeat it to anyone who will listen. We at Deep Background will be taking a Thanksgiving break, so we won't have an episode for you next week, but we will be back after Thanksgiving. Until the next time I speak to you, be careful, be safe, and be well. Deep back Ground is brought to you by Pushkin Industries. Our producer is Lydia Gencott. Our engineer is Martin Gonzalez, and our showrunner is Sophie Crane mckibbon. Theme music by Luis Gera at Pushkin. Thanks to Mia Lobell, Julia Barton, Heather Faine, Carlie mcgliori, Maggie Taylor, Eric Sandler, and Jacob Weisberg. You can find me on Twitter at Noah Arfeld. I also write a column for Bloomberg Opinion, which you can find at bloomberg dot com slash Feldman. To discover Bloomberg's original slate of podcasts, go to Bloomberg dot com slash podcasts, and if you liked what you heard today, please write a review or tell a friend. This is deep background