#160 - Paul Offit, M.D.: The latest on COVID-19 vaccines and their safety, herd immunity, and viral variants

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay, here's today's episode. I guess this week is Dr. Paul Offit. That may be a familiar name to some of you because Paul was previously on the podcast In November of last year. At the time we spoke about the COVID 19 vaccine just prior to their first approvals. I wanted to have Paul back to get an update on the vaccines and to get a sense of what the next year is going to look like. As a refresher. Paul's a pediatrician specializing in infectious diseases and an expert on vaccines, immunology and virology. He is the Director of the Vaccine Education center and professor of Pediatrics in the Division of Infectious Diseases at the Children's Hospital of Philadelphia, chop and he is a Professor of Vaccinology at the Perelman School of Medicine at the University of Pennsylvania. He serves on the FDA Committee for Biologics Evaluations and Research Vaccines and Related Biologic Product Advisory Committee, evaluating not just the COVID 19 vaccines, but vaccines for influenza and other infectious diseases. He is the co inventor of the rotavirus vaccine. In this episode, we start with an update of all four major classes of vaccines, specifically talking about the two that are most utilized, which are the MRNA vaccines and the adenovirus vaccines delivering DNA. We then talk about some of the safety concerns that still remain around both of these and Paul does a very eloquent job, in my view, of explaining what is and is not a legitimate concern, both in the short term and the long term. We talk about the variants and what the implications are of variants, and we get into what herd immunity actually means. In other words, how much of it is going to require breadth of natural infection versus how much is going to require immunization. And we get into then what's going to happen with respect to other populations being immunized, most notably people under the age of 18. Something that I think Many of you will find interesting in this discussion was a deeper dive into the nature of immunology and how the short term immune response, usually mediated by what's called the humoral system, differs from the longer term immune response, which we call the cellular immune response, the memory immune response, how these two function together, and the importance of the latter in providing durable immunity. We also talk a little bit about the origin of this virus. I think there is a very interesting discussion around whether this virus originated in a lab or it originated, quote, unquote, naturally. And while a year ago people who suggested it originated in a lab were viewed as sort of conspiracy theorists, I don't think that's necessarily the case today. And we talk a little bit about that. Finally, we talk about the future. I think most people, Paul included, would agree that it is not a question of if, but rather when we see another major coronavirus outbreak. Given that this is the third one we've seen in 20 years, what can we do to be better prepared for it? Neither of us pull punches on what we think went wrong here, and most importantly, how would you need to remedy that in the future? So my hope is that you'll find this podcast to be accretive to knowledge you've already gained through the recent podcasts I've done on this topic, along with whatever else you're listening to on this topic. So without further delay, please enjoy my conversation with Paul Offit. Hey, Paul, it's great to have you back. Thank you so much for making time. Obviously, at the time that we're recording this, I know you're busy with some news that we'll. We'll get to later, but nevertheless, it seems like it's about the right time for us to pick up this discussion again, because the last time we spoke, we were just on the cusp of watching a number of vaccines hit that first phase of early use authorization. As we stand here today, I actually can't tell you the numbers, but tens of millions of people have been vaccinated, and in some ways there are still a lot of questions. So let's start with just an update. The lay of the land for people, broadly speaking, right? Four strategies, four scientific strategies in place to create vaccines. One of them is an MRNA vaccine, which we'll talk about. The second, something that's a little more tried and true, at least something that's been done a number of times before, using an adenovirus to deliver DNA. The third is delivering directly purified protein of the virus. And the fourth, probably the oldest trick in the book is using live attenuated virus. Can you give us just a broad overview of where each of those four are and maybe what it says about the scientific challenges of the approval process for each?

At least in the United States, the messenger RNA vaccines are the farthest along. The FDA vaccine Advisory committee approved the Pfizer messenger RNA vaccine on December 10, the Moderna messenger RNA vaccine on December 17, and they then rolled off the assembly lines and into the arms of the American public, such that now you have more than 120 million people who have received at least one dose of an MRNA containing vaccine. So that's the farthest along certainly in this country in terms of the adenovirus vectors, the replication defective adenovirus vectors. There's the replication defective simian adenovirus vector, which was put forward by the Jenner Institute at the University of Oxford in states the United UK that it's partnered with AstraZeneca and then the Johnson and Johnson product, which is Janssen, that is the wholly owned subsidiary of Johnson Johnson and that's a replication defect of adenovirus type 26. The AD26 vector had been used fairly extensively to try and slow the Ebola outbreak in West Africa. So about 200,000 doses had been administered in West Africa. That vaccine now we have more than 6 million doses of that that's been given in the United States. And then with regard to the AstraZeneca vaccine, tens of millions of doses have been given in the United Kingdom as well as in Europe. Certainly more than 20 million doses overall have been given of that vaccine. In terms of the purified protein vaccine, probably the company that's the farthest along is novavax. They use a baclovirus expression system. So basically you have a bacalovirus into which you insert, in this case the gene that codes for the coronavirus spike protein. And that's grown up in butterfly cells, basically Spedoptera frugipara cells. It's the exact same way we make flu. So there's a lot of experience using that technology to make a vaccine. Those studies have been largely completed, but novavax has been fairly slow to gain any sort of approval yet to my knowledge, anywhere. Yet live attenuated viral vaccines, they're still in the works. I don't know of any live attenuated viral vaccine that is now being routinely given to anybody in any country in this world. But I could be wrong. I haven't heard that. I know people were working, a number of groups were working on it. Then there's the Whole killed viral vaccine, which is the. The product that's used by China, which has been extensively given to now again, tens of millions of people, which is the way that we make the polio vaccine, the inactivated polio vaccine, or the hepatitis A vaccine, or the rabies vaccine. So again, a lot of experience with that product that there's some question about how effective it is. I should also add that the Russian vaccine is also a replication effect of adenovirus vaccine, in that case AD 26, human AD 26, followed by human AD 5. So those are the strategies that are currently wending their way through the world.

And is it safe to say, Paul, that either. That the whole killed is probably. I actually mistakenly said that the attenuated, because I tend to lump that in with whole killed. But really whole killed is the first play that's really initiated vaccination. Is that kind of the oldest trick?

Well, the oldest, oldest trick is a live non human virus. I mean, the cowpox was the first vaccine in the late 1700s, which. So basically the thinking there was that. Not that it was stinking at all, since this was the late 1700s, before we actually knew what viruses were. I mean, it was just phenomenology. But now we know that the cowpox virus is antigenically related, close enough to human smallpox, that immunization with one can protect you against disease caused by the other. But you're right, the second strategy was the whole killed virus strategy that was 100 years later in the late 1800s in France with Louis Pasteur making the whole killed rabies virus.

The rabies, right.

Yeah, that's right.

I remember my mom reading me that story when I was a little boy. Actually, I could listen to that story every single night because it had pictures of him taking the serum from the dog and killing the virus and giving it to the boy. I can still actually see every part of that book. One of the things that I hear a lot of is that MRNA thing is crazy. This is totally sci fi. It's completely experimental. Why would anyone subject themselves to something that is so risky and so unproven? A little while ago I wrote something on this topic, trying to make the point. I don't know how convincing it was that actually it's not as experimental as people think. And that this technology has been around for decades, plural. And that the only thing that's new is that this is the first time the final step has been made, which is actually taking a virus that is of concern to humans, sequencing it and then putting it into a Clinical practice. But this notion of using mRNA, this didn't just come out of nowhere. This wasn't something that was developed in 12 months, as one might believe, if they weren't really following the science too closely. Do you find yourself confronted with the same type of question?

Yes, and they're reasonable questions. It is a new era of vaccinology. I mean, we just went through that briefly, but it's arguably the fifth era. I mean, you go to initially sort of animal strains that are related to humans, then you go to the inactivated vaccines, then you go to the live attenuated viral vaccines, then you go to purified protein vaccines. What all those four strategies have in common is that you're giving the viral protein that you're interested in. I mean, in this case, we're interested in the SARS CoV2 spike protein. And when you give that protein, in one form or another, whole virus or live attenuated virus, or just purified protein itself, you're giving that protein the viral protein. Then the person makes an antibody response to that protein. You're not doing that here. You're giving the gene that codes for the viral protein that's translated in the cytoplasm to the viral protein. So your body makes the viral protein, then your body makes an antibody. And you can see why people are concerned because it's the term that is used correctly as it's a genetic strategy. You're giving a gene. And the minute you say that to people, that's often interpreted as something that could interfere with your genes or, you know, reorient or re engineer your genes. That's the way people hear that. They hear it as gene therapy. And in a sense it is kind of gene therapy, but not in the more traditional way that it's meant.

What is the best answer you have to someone that says, look, I'm not worried about acute toxicity or even subacute toxicity, because given how many tens of millions of people have received both the Moderna vaccine and the Pfizer vaccine, I think anybody can say unequivocally there can't be any complications in the short run that are clinically relevant. I mean, we just. There have been too many people vaccinated to know that, oh my gosh, you know, 0.001% of people are gonna suffer some horrible complication. But it's not necessarily clear that there can't be some really long term complication that doesn't show up for a year or two years or three years. And therefore, I think to your point, it is a reasonable point of concern to say, well, this is still very new and we don't have 10 years of data the way we would if this strategy were deployed through a traditional non emergency use approach for something like influenza, where we didn't have to rush because we have so many other strategies. So my question is, what would you say to reassure somebody that in five years we're not going to learn something horrible about inserting coronavirus MRNA into our cells?

All right, so there's two ways I would answer that. The first is can the messenger RNA in any way alter our DNA? Because I think that's at the heart of what people are worried about. And then that comes up later in some form or another. That's not possible for three reasons. First of all, when the messenger RNA is taken up by cells in our body, it's primarily something called dendritic cells, which is the major antigen presenting cell in your body that presents cells, presents antigens to the immune system, to the rest of the immune system. So it's taken up, it's in a lipid nanoparticle, the lipid nanoparticle is taken up in the cell, it's stripped away, and then that messenger RNA enters the ribosomal system where like the other couple hundred thousand copies of messenger RNA that are in your cytoplasm, it's then translated to a protein and that happens over days. And then the messenger RNA, like all messenger RNAs, breaks down and is no longer making that protein. So the question then is, can the messenger RNA get into the nucleus and in any way alter the DNA, which it cannot do for three reasons. First of all, it has to be able to cross the nuclear membrane, which requires a nuclear access signal that it doesn't have. Secondly, even if it got into the nucleus, it's rna, it's not DNA. So in order to affect DNA, it has to be converted to DNA, which requires an enzyme like reverse transcriptase, which it also doesn't have. Even if it was converted to DNA, which it can't, because it can't cross the nuclear membrane and it can't be basically reverse transcribed back to DNA, it still has to insert itself into the DNA, which requires an integrase enzyme that it also doesn't have. So it's not possible. You have a better chance of developing X ray vision after you've gotten this than you have of the MRNA in any way altering your DNA. Although I never understand why people, when they say that it alters your DNA, doesn't think it can alter your DNA for the good, like making you Spider man for example, or something like that. People never talk about that. So that's one thing I think that's not possible. The second thing is long term effects. I guess I would challenge. We have these discussions at the CDC a lot with people who have a lot of experience with this name, that serious adverse event that's associated with vaccines that has not been picked up within two months of getting a dose. And there are, I mean vaccines like any medical product that have a positive effect and have a negative effect, including a severe negative effect. And so for example, the squalene adjuvantin influenza vaccine that was used in Europe for the 2009 pandemic, one of those vaccines, so called pandemics, could actually cause narcolepsy. I mean it was rare, it was about 1 per 55,000 people, but it was real. And it again occurred within six weeks of getting a dose. The oral polio vaccine that was created by Albert Sabin to basically eliminate a polio from this country could itself cause polio. It could actually revert to essentially neurovirulent or wild type virus and cause polio again would happen within a few weeks of a dose. The influenza vaccine is a rare cause, roughly 1 per million. For polio, it's about 1 per 2.4 million doses. But influenza, about 1 per million doses can cause Guillain Barre syndrome, which is an ascending paralysis which can be severe and occasionally fatal. Again occurs within six weeks of a dose. The yellow fever vaccine in roughly 1 per million people, depending on which strain you use, can cause something we call viscerotropic disease, which is a nice way of saying yellow fever. I mean the yellow fever vaccine can cause yellow fever much the same way the oral polio vaccine could cause polio again within a week or so of getting the dose. So I don't know of that serious side effect that causes long term problems. Now it is true that some of these, most of these side effects, all of these side effects are so rare that when they occur, they only occur when they're in tens of millions of people. And then you can see that. But that's why for every vaccine you have to wait for two months after the second dose or whatever the last dose is to make sure it's still safe. And that was true of all these vaccines going out. I mean we're going to get to the issue I think later in this broadcast with Johnson Johnson vaccine. But again, that issue came up within two weeks of a dose.

Yeah, I just want to make sure. That for the listener, we really highlight the salient point here, which I think is actually the first point that you made, because I do think that for most people who are, I think, hearing a lot of misinformation, it's coming through the channels of people who don't really understand enough biology to sort of explain exactly how messenger RNA is translated into protein. And of course, that's what we want here and how we don't have any of the machinery to enable the reverse. Let's talk a little bit about HIV as a virus, because HIV actually can undergo some of this process. So maybe use HIV as a counterpoint. And also let's dovetail that into how failed attempts to create a vaccine for hiv. Why is that not possible? And what has that taught us about the current strategy here? A lot packed into that question, I realize.

Yeah, I would say if I had to pick what I think is the most heinous virus that was ever created, it would be hiv, because it does two things. First of all, when you're first infected with human immunodeficiency virus and it begins to reproduce itself, you make an antibody response to that virus that neutralizes and kills that virus. Does. Kills it effectively, efficiently. But what happens is it continues to evolve during a single infection so that the surface protein, the so called glycoprotein of that virus, to which you make an antibody response to prevent the virus from binding itself, continues to mutate again and again and again. Here we talk about how influenza virus, for example, mutates so much from one year to the next. The natural infection or immunization from the previous year does infect you, hence the need for a yearly vaccine. This virus does that during a single infection. It just continues to mutate and mutate and mutate and mutate, number one. Number two is where does it grow? It reproduces itself primarily in something called T helper cells, which is the major orchestrator of your immune system. It's T helper cells that help B cells make antibodies. It's T helper cells that help stimulate cytotoxic T cells which kill virus infected cells. So it paralyzes the orchestrator of your immune system at the same time that it continues to mutate so that your immune system never catches up to it. It is a remarkably effective virus at being able to kill us. I mean, we have, you know, in the late 90s we had finally developed a highly active antiretroviral therapy as a treatment. So we were able to do what we wanted to do, which was to make HIV a chronic disease. But that vaccine has remained elusive and it is not because of lack of money or lack of effort. I know Merca put several billion dollars into that project and was unsuccessful again with actually with a adenovirus vector into which they then inserted either the group antigen or the envelope protein or the glycoprotein genes. And it didn't in any sense work. In some ways it was actually worse for those who were vaccinated.

Yeah, I used to sort of explain it to people as imagine you were up against a foe, an army was up against another army, and the army knew how to strategically target the general, and the General being the CD4 cell, the helper T cell, and all of a sudden you could just sort of abolish any chance of there being a coherent strategy to fight back. But you're right, those two things, the constant mutation and the ability to infect again, at least if you come at this from the cellular side, the most important cell in the arsenal, is pretty remarkable. What is it about those failures that maybe actually sped up the development of vaccines against SARS CoV2, if anything?

No, I think you always learn. I mean, the replication defective adenoviruses that were used. It was an adenovirus, human serotype 5 that was used in the Merck trial. Certainly. We learned about replication defective adenoviruses for the Ebola vaccine. Not only the J and J vaccine, but also there was a replication competent of viral vector we using something called vesicular stomatitis virus, which is sort of a cousin in many ways of rabies, but obviously doesn't cause any of the symptoms of rabies or symptoms at all. So, yeah, sure. I mean, we've learned as we've gone here and with hiv, it's like Jonas Salk's strategy was to try and take the whole virus and kill it. That obviously it was never going to work. That was the strategy he had used. He thought it could apply to other things. It clearly doesn't apply here. That vaccine has failed and failed and failed. I put that sort of in the same category as like the universal flu vaccine. I mean, it's not for want of money and it's not for want of effort. I trained in a flu lab actually in the early 1980s at the Wistar Institute here in Philadelphia. I was working on rotaviruses, but I was trying to make monoclonal antibodies to rotavirus surface proteins. And I was learning to do it in a flu lab. And it was just these brilliant researchers, you know, People like John Udell and Walter Gerhardt and Lou Stout all in one place. I don't think I realized how lucky I was at that time to be around such amazing scientists. But the head of that lab at the time said something to me I'll never forget. And now for 40 years later, it's still true. He said, quote, if you want a research career that lasts for the rest of your life, study influenza. I think that's a virus where it's going to take a long time to catch up to.

So let's actually talk a little bit about influenza because there's something sort of strange about this coronavirus that fits in between the one and done viruses and influenza. And let's just put HIV in its own category because I think you've appropriately described it as the single worst virus that's ever been shat into the civilization of mankind. I mean, it is truly fortunately an anomaly with regard to how difficult it is. But on the one end of the spectrum you have influenza, which has so much genetic drift that every year you have to get a new vaccine if you want to have any chance of being vaccinated. Of course you could say, I don't want to be vaccinated, but because, you know, it's generally not a very lethal virus. But it's bad enough and certainly in high risk populations a vaccine makes a ton of sense, but you know, we can't hold our natural immunity to it from year to year to year. At the other end of the spectrum you have polio, smallpox, pertussis. Pick your favorite of these things where they don't seem to mutate, or if they do, I shouldn't say they don't seem to mutate. Whatever mutations they have don't seem to impact our body's immune system from reacting to them so far. Am I correct on those two ends of the spectrum?

Yes.

Okay, now we have this coronavirus, which seems to be neither of those. It's not clear that it has the genetic drift of an influenza where every year it's basically a new virus. But it also appears that it ain't one of the other guys too, where you're going to be one and done strategy with your vaccine. In fact, even though B117 looks like it is going to be managed through current vaccination strategies, it is not clear that the South African variant, the South American variant, Brazilian variant, are going to respond in that way, given significant changes in their binding properties. What does that say about this virus, if anything? Or is that simply just the luck of the biologic draw. Right.

So I'm not sure I can explain why these viruses act the way they act. But your assessment was exactly right. On the one hand, once end of the spectrum, you have flu, which you said correctly, year to year, probably you could argue minute to minute. I mean, we, I'm on the FDA's vaccine advisory committee the first week in March, we always pick flu strains. And the way that works is we, the Department of Defense, the World Health Organization, the cdc, all present data about these flu strains that are circulating in all areas of the world. So we can see how these clades of influenza and subclades and sub subclades are constantly sort of moving around. So we can try and predict which strains to include. And we certainly work hard to try and get the strains right. We usually get them right, but it's amazing we get them right given how much this virus mutates. And flu is a single stranded RNA virus, therefore, like all single stranded RNA viruses, its replication isn't highly faithful. But then you have a virus like measles, which is also a single stranded RNA virus, which also mutates, but mutates in such a confined way that the vaccines that you introduced or we introduced in the early 1960s continue to work now, you know, 50 plus years later, that virus has never mutated away from the vaccine, even though it is also a single strand RNA virus. So then you have this virus, also the SARS CoV2 virus, also a single stranded RNA virus, and also those mutates, but much more slowly actually than influenza, and in many ways in a manner that is between those two, between say measles and influenza. So it does mutate, all for the purpose primarily of becoming more contagious. That's really the main goal of viruses, is to continue to reproduce themselves. They don't necessarily want to make themselves more virulent, more likely to kill you, because then they can't reproduce anymore. So their goal is to be more contagious. So the bat virus, which was largely a bat virus that sort of first started in China and swept through China, was not the virus that left China. The virus that left China was the first variant, the so called D614G variant. That was the first variant. That's the virus that swept through Europe, that's the virus that swept through the United States. That's the virus that's killed 570,000 people. That's the virus to which all vaccines are made to try and prevent the D614G strain. But now these other variants come up, you know, the B117 UK variant, the Brazilian variant, the South African variant, now the New York variant, the California variant. So there's always going to be variants that are made as the virus tries to be more confused. And so the critical question then is to what extent will it drift away from immunity caused by vaccination? And the answer so far is that the B1.1.7 is close enough to that initial virus that left China, the D614G variant, that immunization with one protects against the other. Well, I mean really. Well, they're close enough where there's not really a critical immunological distinction between those two viruses. But the South African and Brazilian strain, now the New York strain, all the so called variants of concern are different, but not so far critically different in this sense that I think natural infection or immunization still protects against severe critical disease, meaning still protects against hospitalization and ICU admission and death. That's still true. When we've crossed the line with these variants is when you see, when you see, and we haven't seen this yet, people who are either naturally infected or fully immunized that nonetheless are hospitalized or killed by a variant virus, that line hasn't been crossed yet. Now we're looking because now as people are getting hospitalized and dying of this virus, we always have to look at the virus they're getting infected with. And there's an NIH group that's specifically designed to do that, to make sure that these people aren't being infected with variants and they're critically different, that now you're not even protected against severe critical disease.

How do we know in the situation you just described where someone who's been previously infected or vaccinated becomes infected with a variant of concern and goes on to have a bad adverse outcome, either, you know, ICU and or death. How do we know that it's because their existing immunity was incapable of responding versus they simply had lost immunity. Are you also checking for some quantitative or qualitative assessment of their existing immunity?

What you can say, if you isolate a virus, sequence it and realize it is just the D614G strain or the B117 strain, something that should have been fully susceptible to immunity induced by natural infection or immunization, then one of those two things is true. Either you had an adequate immune response and lost it, or you never really developed an adequate immune response. I'm not sure how easy those two things would be to figure out at that point.

Right. It's tough to distinguish Those two. Yep.

Yeah, that's the issue. Right.

But then what happens if they are confronted with the Brazilian variant? How will we know if indeed it's the latter problem which you just described, or frankly, the more frightening problem, which is actually no amount of current immunity either acquired from D614 or through any of the vaccines is going to save you. And basically we are back to square one of a pandemic.

Right. So I think when we isolate those variants, the question is you take it to the laboratory and see whether or not then the number of mutations that have occurred have occurred to the point that when you take sera from people who are adequately immunized or people who are naturally infected, that it doesn't neutralize that virus in the lab. I mean, that'll be the first clue that has now escaped recognition by natural or vaccine induced immunity.

And we're confident that an in vitro assay to look at neutralizing antibodies in the presence of a new variant is pretty sufficient to give us that insight. We won't have to rely on epidemiology to give us the answer.

No, I think it's pretty sufficient. I mean, it does ignore T helper cell responses, which tend to be broader and are of value in that they do offer that sort of broader immunity where even though there have been mutations in the receptor binding domain or the N terminal domain, that you still would get some evidence of immunity. That's why T helper cell response response are so critical here. But no, I think we, we can figure, for the most part figure that out.

Okay, so the good news about what you're saying, Paul, is you're holding us to a higher and more conservative standard because what you're basically saying is I can test in vitro what a B cell can do through neutralizing antibodies. I can't test what a T cell can do. But if it passes the B cell test, I don't need to worry about it. Now, if it fails the B cell test, we still don't know about the T cell test and that can only be played out in the real world. But if it's failing the B cell test, we're going to take action. Presumably, we're not going to wait and assume that this is going to be worked out on the side of T cells.

I think that's right. I mean, I think that's right. Yeah. I mean, if you look at the work that was done by Shane Crotty and others in La Jolla, looking at people who are naturally infected, and then, you know, if re exposed to A virus. Again, we're protected. They did find that while antibody responses fade over time and can fade over five, six, seven months later, that memory B cells are still there and memory T helper cells or memory cytotoxic T cells are there. And that's good. You know, you have. This is a virus that has an incubation period of around six days, meaning from the time you're first exposed to, when you develop symptoms is about six days. That's between sort of the typical mucosal infection like rotavirus or influenza, where incubation periods are very short, one to two days, and a virus like measles or German measles, which have or chickenpox, which have incubation periods of 10 to 14 days. The longer incubation period diseases are better in the sense that you really can induce sterilizing immunity and therefore you really can eliminate those viruses. We eliminated measles from this country by the year 2000. We eliminated rubella from this country by the year 2005. The only reason measles has come back is because a critical number of parents have chosen not to vaccinate their children. But those are eliminate able viruses. This is not because it's virus in the bloodstream is not an important part of pathogenesis. So when you have long incubation periods, all you need is immunological memory because there's plenty of time for activation and differentiation of memory B cells to become effector cells, meaning antibody producing cells. And therefore you're good for the shorter incubation periods. Your hope is to modify disease because a disease like rotavirus, which has an incubation period of two to four days, you can stimulate then those memory cells which are long lived to become antibody producing cells. But you've already started to sort of replicate because the incubation period so short and it takes about days to get activation and differentiation memory cells. So when incubation periods are short, the best you can hope for is to modify disease associated with infection. That's true of flu, it's true of respiratory syncytial virus, it's true of rotavirus for measles. On the other hand, where you have this long incubation period, as long as you have memory cells which are generally long, you have plenty of time for activation and differentiation of those cells to become antibody secreting cells. And that's why you can eliminate those diseases. This is actually somewhere in between. That's about a six day incubation period. So and again, virus in the bloodstream is really not an important part of pathogenesis of IgG, memory cells become a little less important. But I do think that we can control this infection. But I think that like all mucosal infections, your two choices basically as we move forward, are immunization or natural infection. Those are your two choices.

So Paul, that's a, that's actually an amazing insight about how the SARS CoV2 has that sort of gestation period that puts it into kind of an intermediate zone between the short and the long. Maybe let's take a moment to just explain to people how the cellular immune system comes into play here. So I think by this point, folks who have been paying attention to this understand how the neutralizing antibodies can work on first contact and how that can provide immunity in the weeks and months following an infection. But to your point, at some point down the line, call it six months later, 12 months later, a year later, you know, or whatever, 18 months later, those neutralizing antibodies may not be there in sufficiently high enough titers. What is the actual process by which that virus now gets presented to the cellular immune system such that we can re engage B cells to come out and make more neutralizing antibodies under the instruction of T cells. It's maybe walk people through how that works through antigen presentation, et cetera.

The virus would be then picked up by major antigen presenting cells in the body, like dendritic cells, macrophages, and to some extent B cells broken down into small sort of 10 to 15 mer peptides, put on the surface of the cell of these antigen presenting cells and then they travel to T helper cells where they then stimulate T helper cells to do two things. One is to stimulate T B cells to make antibodies too, is to stimulate cytotoxic T cells to kill virus infected cells. But as long as you have immunological memory, as long as you have memory, B cells, memory, T helper cells, memory, cytotoxic T cells, and those are generally longer lived, then you can at least have activation and differentiation of those memory cells to become effector cells. In this case of B cells, antibody producing cells, in the case of cytotoxic T cells, T cells that kill virus infected cells. So memory is what you want. And I think, I guess I was encouraged by the work of Shane Crotty and others that memory cells here do, at least after natural infection, appear to be fairly long lived. I'm also encouraged by the messenger RNA data where after that second dose you clearly get stimulation of T helper cells and cytotoxic T cells, which suggests that you'll have also somewhat longer lived responses. I mean, I'd like to think that these responses would be durable enough after natural infection or immunization to protect you for a couple years, three years, four years. I'd like to think that's true. I mean, we'll see whether or not it ends up being true. But the good news about the MRNA strategy is it's a powerful image. I mean, I'm amazed at how effective it is. And one thing that people at least can notice is that many people get shots in their arms for a variety of vaccines. This vaccine often causes lymph node enlargement under your arm, so called ipsilateral lymphadenopathy. That's not common. You see it with smallpox vaccine, which is another powerful immunogen. And you see it with this vaccine. Those antigen presenting cells travel to the local lymph node and then stimulate that response to the extent that your lymph node actually enlarges. It is a powerful image in these MRNA vaccines.

It's so funny that you bring that up, Paul. I was going to bring that point up later. So both my wife and I had whole body MRIs. We do this every once in a while for sort of a cancer screening protocol. And we had them four days ago. And the radiologist said, hey, I assume you guys have been vaccinated. And we said, yep, both vaccinated, such and such a time. He said, okay, let me show you something on the mri. The radiologist is a very close friend. And he said, look at the extent of lymphadenopathy under your arms. This is normally something that in a case of a woman would make me think she potentially had breast cancer. That's how inflammatory how concerning these nodes are. He said, look, I've now looked at enough of these in the past couple of months to realize that it's almost always people responding to the vaccination of this virus. And he said he is seeing it more with the RNA viruses, the Moderna and Pfizer. I didn't ask, and I should have asked, to what extent is he seeing it with the adenoviruses? But I think what you said is very interesting and I only knew of it literally four or five days ago. I want to ask you another question about this, which is why is it that the J and J virus is able to provide such a benefit after only one injection, whereas the RNA viruses needed that second injection?

Right. And if you look at these replication effective neurohuman adenoviruses the J and J vaccine, the replication effect of AD 26, human adenovirus 26, they induce cellular immunity after a single dose. That's really not true with the MRNA vaccines. You need that second dose. I'm not sure why one is more powerful in terms of, of one dose versus two doses, but that is true, which is why it's all the more important to get that second dose of MRNA vaccine. There are a lot of people that people who I actually really respect and are well known in the field of epidemiology or virology who have written op ed pieces that have gotten a lot of national play on why it is that one dose of MRNA vaccine gives you 80% effective protection, whereas the second dose gives you 90% or 95% and that let's get as much first dose out there as we can. I think as long as people realize you need that second dose, I mean, I just worry that people are going to hear, well, 80% protective after one dose, 90% after two doses. You know, that's not that big of a deal. I know that with the second dose there's more side effects. So I'm just going to go with one dose and then confuse it with the fact that J and J's vaccine, Johnson and Johnson's vaccine is one dose. This is a two dose vaccine, the MRNA vaccines. And the choice not to get that second Joe's is a choice probably to get less durable immunity, less complete immunity and likely less effective immunity against these variants that have drifted farther away from the original strain.

One other point on that, Paul, that I think is a real mistake that the press has made and frankly I think that the vaccine companies have made is they have not communicated clearly the difference between relative risk reduction and absolute risk reduction. So when the JJ vaccine received its emergency youth authorization, I think the headline grabbing statement was, hey, we just heard that Pfizer is 96% effective and Moderna 95% effective, but JJ looks like it's only 66% effective. Those numbers are probably off by a couple of percent, but directionally they are correct. And at the surface you would say why in the world would you take the JJ vaccine even though it's only a single shot? Or you might ask another question, which is why? Well, what happens if you took two shots of the J and J? Wouldn't that put it on par, et cetera? And it turns out I actually had to go back and look at the data to actually see what the true risk reduction was. Now I won't go into it here for people because it would take too long. But we'll link to it in the show notes. We have an entire post I've written about the difference between absolute risk reduction and relative risk reduction. But you must talk about this in terms of absolute risk reduction. And when you look at the absolute risk reduction, it turns out that the JJ vaccine has a 1.7% absolute risk reduction versus a 1.2% absolute risk reduction for Moderna. And I believe Pfizer is actually less than 1% risk reduction. These are all great vaccines, but it turns out that JJ gets the most bang for its buck. Now, I wanted to talk with you about why you think there is that discordance between the lowest relative risk reduction in the mid-60s and the highest absolute risk reduction, which is the number that matters, approaching 2%. Do you believe that the Pfizer and Moderna vaccines were tested on less susceptible populations and that J and J was just tested on a sicker population that was therefore going to benefit more greatly?

Well, so there are different strategies. So it is interesting how both MRNA strategies had very similar, at least relative risk reduction. But you're right, I mean, it is interesting how we don't talk about that way. We also don't talk about that with regard to safety issues. So if you look, for example, I'm trying to remember the specific numbers for the Pfizer trial, but there were like 165 cases of disease in the placebo group in like eight cases in the vaccine group. So that's 165 cases per. In the case of the Pfizer trial was a roughly 40,000 person trial. So you roughly strike 165 cases, you know, per 20,000 people that got placebo as compared to like 8 cases per 20,000 people who got the vaccine. So when you actually divide that all up, the absolute difference is much less dramatic than is, you know, the sort of the relative risk.

Right. The Pfizer absolute risk difference was like 0.9%. And you're right, the total number of cases was about 170 total cases in 20,000 or 40,000. I'm sorry, but you're right, the difference was 8 versus like 165 or something like that.

Right.

Which again makes me just think like these are people who were either less exposed, more healthy. There was something in these populations that differed dramatically from the JJ population where, I mean, we're talking about 500 infections versus a hundred infections directionally. So the relative reduction wasn't as high. But the absolute reduction, like I said 1.7%, which we're going to come back to in a moment. It's worth keeping in the back of your mind. When you have a 1.7% absolute risk reduction, that means your number needed to treat, to prevent a negative, a bad outcome is very low. I mean, we're talking about, what, 60 for an NNT?

No, you're right. It's interesting that. I mean, the way I think of it, just because it's easier for me to conceptualize it, is if I walk on the street in front of my house, I have a certain risk of being hit by a car. Just stand in front of my house, in the lawn in front of my house, I have another risk of being hit by a car. The risk is much greater if I cross the street than if I just stand on the grass in front of my house. But I cross the street all the time and never get hit. So the chances of my being hit are still extremely small. Even though I cross the street, even though the relative risk is much higher, the absolute risk is still very low of being hit by a car. And I think that's. That's what people don't quite understand.

Let's talk about the kind of the elephant in the room today, at least, which is as of yesterday. And by the time this podcast come out, this might even be irrelevant news. So I don't want to dwell on it too much, but as of yesterday, the news came out that J and J's vaccine, which as of this moment has been given to 6.9 million people in the United States, has resulted in six serious clotting episodes, all in women. Interestingly, probably not a coincidence, but it's too soon to tell. And one of whom has died, so obviously very easy to believe that these side effects are the result of the vaccine, given what we saw in the AstraZeneca case. Not clear if it's a coincidence that it's also in an adeno virus vector. But regardless, let's just think about this for a moment through the numbers. Six out of 6.9 million people have had a side effect that is completely undesirable, one of whom has died, which is the ultimate undesirable side effect. But contrast that with the nnt. Now, the data in the JAMA paper that I looked at, which is where I saw the most robust data on the vaccine, at least I couldn't extract from it what the NNT was to save a life. Do you know that? So the NNT data that I quoted, which is about 60 based on the reciprocal of the ARR. So if you take 100 divided by 1.7, whatever that number is, I'm doing the math in my head, it's about 60. That's for all reactions. So serious reactions, hospitalizations, death. But if you just do it on death, I don't know what that is, do you?

I think it's something like, if you, let's assume just for the purpose of this discussion, that and it's roughly one case of this so called cerebral vascular sinus thrombosis, or you know, blood clot in a vein of the brain per million people who got this vaccine, for a million people who would get the vaccine Otherwise, something like 1,850 or so would be prevented from having, I think would be prevented from dying. This was presented this morning.

Okay, that's the number I'm asking for. Yeah, what's the difference? So we can do it for how big that number is, will be prevented from going to the hospital, but to actually be prevented from dying, if it's about 2000, you're talking about a trade off of 2000 to one. And that's why I've got to be honest with you, I looked at the reaction of the federal, if I read it correctly, Paul, the federal government basically said we're going to stop this and let states decide. And New York and California immediately said we're going to stop it. And again, that's not the worst thing in the world if we have enough other vaccines in the pipeline to keep going. But my thinking is that's an overreactive strategy if it's going to actually prevent people from being vaccinated, isn't it?

Oh, and it's going to prevent people from being vaccinated. I mean, I just think that the minute you did that, the minute you paused that vaccine, you sent a chill through people in this country. I think that would affect not only this vaccine, but I think even it would spill over to any COVID vaccine, which is, I think what, what worries me the most about this pause. I mean, I understand why they did it. I think they wanted to say to people, at the very least, this is an unusual phenomenon. And typically when you see, for example, thrombotic events, you invariably treat them with heparin, don't treat this with heparin. So thinking maybe is that intravenous immunoglobulin is the best treatment, but if heparin is the worst thing you could do for this, and so to alert the physicians of that, also to alert physicians of the fact that if any, anybody's gotten the JJ vaccine and within two weeks of getting that vaccine had signs and symptoms of severe headache, chest pain, shortness of breath, leg pain, to pay attention to that, I think that all makes sense. But by pausing it now, the city of Philadelphia is not giving that vaccine anymore. I think in San Francisco they've decided not to give that vaccine. And I just think that the point you made earlier is exactly right. If it doesn't matter, meaning if we have enough of the Pfizer Moderna vaccine, that this is not going to going to in any sense slow our ability to vaccinate this population and get to the level of population immunity that creates herd immunity, then it's not that big of a deal. But I think that there's two ways to look at that. One is that we have enough vaccine that makes it not a problem. But the other thing is that people may now be scared. That's what scares me the most in this. If you ask me the question, what do I fear most about this whole pandemic, it's actually not the variance. It's not. It's that there would be a significant percentage of the population that is going to choose not to vaccinate. So much so that we can't get to that 80 plus percent of population immunity. We need to slow this virus and then what do we do? And we're going to know that by the middle of the summer when we have enough vaccine, and then we're going to figure out just what percentage of this population doesn't get vaccinated. Because it's not small. I mean, I was at the doctor's office yesterday. The nurse who checked me in told me she was not going to get a vaccine. This is a nurse. You know, these are people in the medical profession. So you can imagine what it's going to be like out there in the real world. And we already know those numbers to some extent. You know, we know that, for example, 46% of Republican men say that they don't want to get a vaccine. 30% of Christian evangelists say they don't want to get a vaccine. 14% of those in the black community say they definitely don't want to get a vaccine. So there are groups out there that are going to be making this choice. We'll see how this plays out.

So let's talk about what herd immunity means. Because even something that conceptually makes sense when it comes to the details we're seeing lots of experts disagree on what it's going to take to achieve herd immunity. What is your best explanation for not what it means conceptually, I think we understand that, but for specifically what is going to be required? And that includes both among children, adults, very susceptible populations, like, what is it? What does a world look like in which we have herd immunity?

Right. So I define herd immunity for mucosal viruses like rotavirus, for example, as distinct from non mucosal viruses, systemic viruses where the virus spreads into the bloodstream, like polio and measles and rubella, where you can eliminate that virus. We're not going to eliminate this virus. I think the best we can hope for is to significantly slow its spread as we did for rotavirus. I mean, when the rotavirus vaccine was introduced in the United States, there would be several million cases every year of rotavirus. There'd be about 75,000 hospitalizations and roughly 60 deaths every year from rotavirus. But no child got to age 5 without being infected with that virus. That virus came into the United States in 2006, and within a few years, you started to see a dramatic drop in the spread of that virus. It's still out there, but it's much, much less. Many residents have never seen a case of rotavirus induced diarrhea and dehydration, whereas it dominated my residency. So you can control it, but you're not going to eliminate it. So I think that's number one. Number two is if you look at sort of the contagiousness index and the efficacy of the vaccine, there's a formula for this, you would figure that you probably would need at least 80% of the population to be immune, either from natural infection or immunization to slow the spread of this virus. But this virus, I think, is going to be with us forever. I don't see it going away. I think it's just going to slowly get under control. Assuming we can get the 194 countries in this world to get a significant percentage of their population vaccinated. But know this, we're going to be giving a coronavirus, a SARS CoV2 vaccine, continually until it happens that other countries have gotten it under control. Because, you know, we give a polio vaccine every year to children in the United States. We haven't had a case of natural polio in this country since the 1970s. The reason we do that is polio still exists in Pakistan and Afghanistan. And so international travel is common. So polio could always come back in this country. And I think that's going to be True here, too. We're going to see how long immunity lasts. We're going to see whether the variants get to the point where they escape immunity from natural infection or immunization. But all that is going to play out over years, and we're going to be dealing with this for years. But I do think we can get control of this virus if we can get at least 80% of the population immunity to the point that we can go back to the things we normally do, like going to Eagles games and screaming and booing without a mask. That is my goal.

Well, as a person who really can't stand the Eagles, you'll have to forgive me that I have no interest in you going to Eagles games unless you are booing because your team is doing poorly. Now, that said, let's go back to the person, like this nurse who you saw at the doctor's office the other day who says, I'm not going to get the vaccine. Now, my view is there's going to be a subset of the population that will never be convinced that that is the right strategy, or more to the point, that getting a vaccine is a safe alternative to getting Covid. So that's fine. I think we do live in a world where medical freedom for adults exists, and I support that. So I do support a person's right to choose to not get a vaccine. Can't we still get to herd immunity when enough healthy people who have refused vaccination survive the infection? Because we certainly have seen that natural infection is going to be a great way to develop immunity. So I don't know what the numbers are, but is it safe to say about 30% of American adults don't want to get vaccinated?

I don't know. If I had to guess, I think it's probably that about 30%, maybe more. And you're right in terms of natural immunity in that if you look on the reports on this Covid Tracker, it says 32,000 people. Sorry, 32 million people have been infected with SARS COV2 and have Covid. But that's only people who've been tested and found to be infected. If you do antibody surveillance studies, that number is probably all that could be much. It's probably more like the CDC estimated last I saw, which was a few weeks ago, was 85 million. It's probably closer to 100 million people who've been infected with this virus and are naturally immune.

And then we don't know the overlap between those people and then who's been vaccinated. There's obviously gonna be a Venn diagram. You can't add these things up. I guess the way I look at it is even with a modest success of the vaccine and those, let's just say those 30% of people who say I'm not gonna be vaccinated, someone's gotta be able to come up with a reasonable estimate for how many of those people were knowingly infected in the past, were unknowingly infected in the past. In other words, those people, you could argue, don't need a vaccine. Then you've got the group who have not been infected, who don't want to get vaccinated. Well, a subset of those people are going to get infected and therefore will develop natural immunity for those of us who choose to get vaccinated. Paul, is it really that big a concern at the number of people who don't want to get vaccinated?

Well, first of all, we're also assuming that natural infection induces a durability and control completeness of protection that is the same as vaccine. That may not be true. I mean, the vaccine, there are certainly a number of vaccines. The human papillomavirus vaccine is one example. Tetanus is another. The conjugate inhibitor and pneumococcal vaccines are another example where the vaccination is better than natural infection in terms of the immunity to do that may also be true here. While I think it's perfectly reasonable to give then a dose of vaccine, dose of the MRNA containing vaccines, sort of.

The booster strategy for those who are naturally infected, you and I are going.

To differ on one thing, which is a person's right to choose not to be vaccinated. I think if I cut my foot on a rusty nail, for example, go to the doctor's office, get it washed out and the doctor says, I would recommend a tetanus vaccine and I choose not to get a tetanus vaccine, that only affects me. I mean, if I get tetanus, nobody's going to catch tetanus for me. That's not true here. I mean, when you make a choice not to get a vaccine, you are making a choice potentially to catch and transmit a potentially fatal infection. And see, I don't think that's your choice. I think that that should not be your inalienable right as a US citizen to affect others. I mean, if you're, if you're going to stay in your house and the only time you ever walk outside is you're going to be really good about wearing a mask and making sure you're four to six feet away from somebody else, great. But that's not the way it's going to play out. And I think we're dealing with that in our hospital. Now is the issue of mandating a vaccine. You know, we have a population of vulnerable hospitalized children. Certainly viruses like this can spread in a hospital. And is it your responsibility as someone who works in a hospital in a group of vulnerable hospitalized children to get a vaccine? We think the answer is yes.

Well, I would agree with you on that. So, I mean, obviously these things are nuanced. I'll tell you where my view is. There are going to be some people for whom there is a privilege that comes from your existence. So for me, healthcare is a privilege. To be a doctor or a nurse is a privilege, not a right. And so I would agree with you. If you are going to work in a hospital and take care of patients, I do not believe you should have the right to refuse vaccination for exactly the reasons you've stated. Furthermore, I would agree that, and this is getting way off topic, but when it comes to mmr, I don't think the parents should be able to refuse that for their child because I don't think it's fair to the children. In other words, I don't think a parent should be able to make a decision that's going to negatively impact a child. I will go one step further. This is going to, I'm sure, make. I'm sure every statement I'm making is making a newer and newer faction of people I rate. So the last one I'll say is I think that society may have to make decisions about who can and can't have other certain privileges such as travel. So I think that there should be a day when, if we decide, you know, what, like people who haven't been vaccinated or haven't conferred natural immunity through some other means and can demonstrate it. Maybe we don't want to have all those people traveling on airplanes, or maybe certain countries are going to say you can't enter unless you've done those things. So I think you and I would probably be aligned on everything I just said. I think where we do differ is if John Smith, who works in whatever he does, doesn't want to get vaccinated, provided his society, his network, is okay with that, you know, and he's not lying about it or something, which, again, I think there are ways around that. You have to live with the consequences of your choice. When people say to me, why would you, Peter, as a healthy roughly 50 year old get vaccinated when your odds of dying are so low from a natural infection, I say frankly, my concern is not death. I think my odds of dying from this virus are so low that I'm much more afraid of dying in a car accident. What I'm afraid of are the long term consequences of this that don't seem trivial even in young people. And you know, there was an article in JAMA maybe two months ago that talked about some of the long term neuropsychiatric complications that are being seen in up to a quarter of people 6 and 12 months out. And to me those are the things that are of grave concern. And again, when you weigh the risk of that versus the risk of vaccination, which I think you very eloquently spoke to at the outset, to me it's personally a no brainer. But that said, there are gray areas in between. That said, of course I agree with you about in the hospital. I think it's a tragedy that a high risk patient would be cared for by someone in a hospital who has willingly or knowingly chosen not to be vaccinated.

This is probably the one area we're going to disagree. But I think, see, I see the hospital as a microcosm of society. I mean, if I There are probably about 500,000 people or so in this country who can't be vaccinated because they're getting biologicals for their chronic disease, because they're getting chemotherapy for their cancers. They depend on those around them to protect them. I mean, I remember when California suffered its measles epidemic and Richard Pan, who was a Democratic state senator out of Sacramento, basically eliminated the philosophical exemption, leaving California with only medical exemptions. They never had a religious exemption. Now that you only had medical exemptions if you went to school in California, you had to be vaccinated or you could homeschool. There was a little boy who showed up at those meetings because certainly the anti vaccine folks were all over those meetings, meetings. They didn't want this exemption eliminated. And he was great. I just wish there was a videotape of him because I've heard what he said and I've seen pictures of him. But he's a little kid named Luke who was five years old and he was in the induction phase of his chemotherapy for acute lymphoblastic leukemia. And he would get up to the microphone, they'd have to give him a stool so he could reach the microphone and he would say, what about me? I depend on you to protect Me, don't I count? And I think that that's how I see the hospital in some ways, as society. You don't know who you're running into when you're getting on a subway or a bus or whatever. And those could be the Lukes out there. So I just don't think if it's a contagious disease, that's where I sort of draw the line.

So love to discuss this more over Emile. Let's talk about the implication of it though. Do we believe? Because I don't think it's going to happen from a practicality standpoint. Is there any chance this is going to be mandated at the private level?

There already is at some level, in a carrot not stick sort of way, where, you know, a number of universities now said, want to come back to campus. Great. Love to have you get vaccinated. If not, you're going to continue to do remotely.

Sure. And just as travel restrictions may only open up to those who are vaccinated, I mean, I completely, I think that's exactly the right way to do it. But my point is we'll never do what California did, which is say you don't get to send a kid to school without vaccination, which, by the way, I think was the right thing to do 100%. But I don't see how you would enforce or make something like that happen in society. So assuming we don't, what do you think is the duration of time from now until we achieve herd immunity? Based on what you know about the speed with which the vaccines are rolling out and the limited information we have about the rates of natural infections, which are obviously challenging to comprehend.

Right. So let's assume the following. Let's assume that about 25 or maybe as many as 30% of the population has been naturally infected. We know that about 22 to 23% of the general population has also been now fully vaccinated with the adult population. So it may be a little more than that. And you're right, there's overlap in terms of having been infected or having been vaccinated. So let's assume we're getting close to 40%. To get to 80%, you're probably going to need to fully immunize another 120 million people. We're vaccinating more than 3 million people or 3 million doses of vaccine a day. These are mostly two dose vaccines. So if you just play out the math, it's possible that within, if we continue to get 3 million doses a day out there, that within three or four months, we could have vaccinated that other 120 million people. I think by mid summer, when there's enough vaccine for everybody, that's when you're going to really find out what percentage of the population doesn't want to get vaccinated.

Vaccinated.

And then we'll see what we're going to do. And the way that you'll test, you'll know whether or not we've succeeded with herd immunity is what happens next winter. This is still at its heart, largely a winter respiratory virus. And if you look at what happened when the virus came into the US in early March and started to kill people, it quickly shot up. You would have 2,000, 2,500 deaths. Just looking at deaths, deaths a day. And then it started to come down. As you went to sort of April, May, June, you started to see the number of deaths per day come down. This, this was in a wholly susceptible population without a vaccine. And then you, for the summer months, you were sort of at hundreds of deaths a day. Then once you hit November, December, it took off again. 2000 deaths a day, 3000 deaths a day, 4000 deaths a day, 4500 deaths a day. And then now it started to come down again. And I think that there's several reasons. Either one, because a larger percentage of population is immune from natural infection, because a larger percentage of population is immune now with vaccination. But I think also the weather has something to do with this. So it's now started to come down. What happens then next winter? If we're at population immunity that is effective, then I will see, you will see a bump in the winter month. If we're not, you are going to see a surge just like we saw this winter in the winter month, and that's how you'll know. But we're going to be vaccinating this population for my lifetime because I just think this is a virus that's not going to go away. We're going to continue to need to keep up that population that's immune and that's also going to involve children. So now we've got an approved vaccine down to 12 years of age. I think by early next year we'll probably have it down to six years of age. And then we're going to need to, I think, vaccinate children as well.

Will that be because children are vectors or because we actually fear harm to the kids themselves?

Both. But I was on service for two weeks in a row about a week ago and it's the same thing that you mentioned earlier in terms of like fear of long term disease. You should see what MIS C looks like up close. I mean this so called multi system inflammatory disease in children which is not uncommon and they all tell the same story or very similar story which is that they had an incidental infection, something that was picked up often because a family member or friend got sick. And so then they had, they were tested to be PCR positive but were asymptomatic a month later. They come now to our house with high fever, involvement of heart, liver, lung, kidney, you know, heart enzymes spilling out into the bloodstream with high fever. And they're PCR negative and they're antibody positive. I mean their immune system has been induced to make an inflammatory response against themselves. I mean primarily against the cells that line vessels. And so this is a largely a vasculitis. And because every organ in your body has a blood supply, virtually every organ can be affected. It's pretty frightening to see. And do I think that some of these kids are going to have long term problems? I absolutely do. For the same reason Kawasaki's did that. I mean also another multi system inflammatory disease that could cause long term heart problems. I think that is likely to be true here. We're going to learn as we go. But if a parent sat across from me in my office and asked me why should I vaccinate my child? These are the stories I would tell. The MIS C stories.

Yeah. I mean I wish I had a crystal ball that would show us the data we're going to have a year from now. When you think about how much we have learned in 12 months, it has been a geometric outflow of knowledge. And the next 12 months will offer I think even more insight because as you said, we're going to be laying over the natural infection, the vaccine, immunology. We'll also, as you basically alluded to really have a true sense of what steady state is going to look like societally with respect to vaccine refusal. And so we will be able to incorporate that into models of how close we are going to get to that herd immunity. But let's talk about it through the two scenarios. There's a scenario clearly where enough people refuse vaccination that we never truly achieve herd immunity. And in that sense the real tragedy is for the vulnerable people who can't be immunized. Correct. I mean I think that's a very clear thing to acknowledge is there's going to be a subset of people who because of their cancer treatment or RHEUMATOLOGIC treatments can't be vaccinated and the disease is still spreading like crazy. Then there's a scenario under which we get to herd immunity on the backs of people who are naturally infected and or are willing to be vaccinated, inclusive of children. And have you done the math on how far down you need to go in kids ages to almost assure that happens? In other words, if you go down to six years of age, is that pretty much a fait accompli?

Oh, for sure. You may not even have to get down that far. I mean, it's something like 20% of the population is less than 18 years of age. So you're assuming all adults got vaccinated, which isn't going to happen. You know, you're already talking about 80%. But the other reason I think that deaths are down. You look at Michigan, for example, clearly there's been a surge of cases in Michigan, but not really a surge in deaths. And I think the reason is, is that it's something like 55% or 57% of people over 65 now have been vaccinated fully and something 75% have gotten at least one dose of vaccine. So we're starting to pull out of this. Of the group, the group, those that are most likely to die, it's something like 92% of those over 55 or those over 55 account for 92% of the deaths. So, you know, we're now pulling them out. And so that's, I think it's one. One of the several reasons why the deaths are clearly coming down now.

Paul, how long do you think it'll be before we know the frequency with which people need to be given a booster shot? And is this going to be a single booster shot? That should be one more than enough to make sure that the memory T and B cells are rocking and rolling. Or do you think that. And by the way, I'm putting aside for a moment mutation, so let's put that aside for one second. But just on the basis of B1 1.7 D6 1 4, is it your immunologic expectation that if you've had your two RNAs, you'll need one more? If you've had your one Adeno, you'll need one more and that should be it, or are we talking about an annual or biannual process?

I think we'll know in two years. I think we'll have a much better idea in two years how this plays out. There were studies done with human coronaviruses Human challenge studies done with human coronaviruses in the early 1990s where they would, you know, someone would be infected with a serotype of one of the four serotypes of human coronavirus that circulates, and then a year later they were experimentally challenged with that virus to see, answer the question, were they protected against symptoms associated with illness? And they were a year later. But they never did those studies. Beyond that, I'm optimistic that it would be for a few years, but I don't think we're talking about decades.

Okay, let's pivot to another question that has come up a lot. And when it first arose, which was a year ago, if not more than a year ago, the people who were raising it sounded crazy, and today it doesn't sound so crazy, which is the origin of this virus. So there are largely two competing theories. The first is the theory that was proposed at the time of the pandemic's arrival, which is that this was a virus that escaped from a bat or left a species of a bat via some intermediary mammal and made its way to humans. This originated in a wet market in China, and that's kind of the story everybody knows, but with increasing, I don't want to say veracity, but certainly with more and more reason behind it. There are lots of people offering explanations for the idea that this was actually an accidental escape of a virus in a lab that happened to be near Wuhan. So I guess there were three labs near Wuhan that would do this type of research. This theory does not suggest biological warfare, that this was deliberately unleashed, but rather that any lab can have a breach in protocol that could result in a virus leaving. How much have you examined this theory?

Certainly it is not unheard of that laboratories have done so called gain of function studies to see what would happen if they alter a virus and then cause it to be able to do things it couldn't do before. So for example, you could take rabies virus. I'm not saying you should do this or how easy it would be to do this, but you could take rabies virus, which is essentially universally fatal virus, but not easily transmitted. I mean, in order to get rabies virus, you usually have to be bitten by a rabid animal and make it such that it is spread by the respiratory route. So now you have a contagious virus that is highly fatal, which I think was basically the story behind the movie Contagion. I think it was a Nipah virus that killed Gwyneth Paltrow in that movie. And Others, because they showed an electron micrograph of it. And I think it was, this was a Nipah virus, which is, you know, it's not easily transmitted. And they made it easily transmitted. It's something, it affects the brain. They made it easily transmitted. Certainly gain of function studies have been done. Is it possible that somebody in Wuhan was doing these kinds of gain and function studies? I'm telling you though, this is like the world's smartest human. I honestly don't think humans were smart enough to make this virus, given all the things that it can do. The only way to really know the answer to the question, because I think this is a knowable question, is to go back and look at all the sequences of those early strains and go back and as early as you can and look at sera from people in China from well before this virus was said to have spread. I mean, think about it. We really depended on a whistleblower in Wuhan to tell us what was going on, which was China not acting like a good neighbor here? And that's the way, that's the way we did it with hiv. I mean, when we finally got all the sequences that we needed with hiv, as we go back further and further and further to see when exactly it evolved from so called simian immunodeficiency virus, I mean the chimp virus, you could see that it happened in Cameroon in the 1930s, presumably when a hunter cut the chimp and then cut himself and introduced the virus into himself. So it's knowable. I just don't think we know. So now we're left with sort of postulates as to how it happened. My, my bias is that it jumped from a bat to humans, presumably from an intermediate host that remains unidentified. You know, people have suggest maybe it's pangolins, but that's knowable. If we can just have all the sequence data we need. And China has not been great about opening its doors and letting us see all that information.

If you assume that it occurred naturally, it begs the question if versus when this occurs. Again, because coronaviruses have been around longer than we have, there's no reason to believe that SARS CoV2 is the last of them. So what is the implication for SARS CoV3?

Oh, we can assume this is going to happen. I mean, we had SARS 1, which was largely a bad virus. We had MERS which came out of Saudi Arabia, which was also at least in part of that virus. And now you have SARS CoV2, three viruses all within roughly 20 years. Right. SARS one was around 2002, MERS around 2012. It'll happen. I mean, I'd like to think what we've learned from this is that it will happen. That we need a level of international collaboration that where the minute there's evidence that this is going on, that there's an international surveillance system where all countries are open to this, where we can identify it, do the kinds of works we need to do, not just to make a vaccine but to have personal protective equipment and ventilators or anything else that you're going to need so that we're not overwhelmed. Overwhelmed by this. I mean this. Unless you're 130 or 140 years old and live through the 1918, 1919 flu pandemic, no one has lived through this. And I'd like to think this has sobered us up as to what needs to be done moving forward.

Do you think that there's a chance that if the next variant of this comes along, which is even worse than this one. So pick. So either it's more virulent but has the same degree of transmissibility, or it's similar virulence but an even greater transmissibility, either of those would make for a much worse pandemic. Do you think that there's a chance that such a virus emerges? Let's just say it originates in the United States. That a given population locally could be shut down enough to identify quickly, patient zero, the first 50 people and immediately quell this thing. Or do these types of things never result in. In a local shutdown that is effective and they will always turn into something bigger? Because the difference between SARS 1 and MERS is not so much that the response was amazing. I mean, in the case of mers, I think the thing was just such a deadly virus that it didn't have a high enough reproductive rate because it was killing people too quickly. It's not like we did such a great job with those viruses. It was really the biology of the viruses.

Right, right. I think both SARS 1 and MERS did not have this level of asymptomatic transmission. I think that that's what makes this virus so awful and that when you walk past somebody in the street who's perfectly fine, they could be shedding this virus. That really wasn't true with SARS 1 and MERS, where most of that disease was either moderate or severe. So it was much easier to put a moat around those infections than you can here because everyone could be infected. It's actually many ways reminds me of polio. I mean, I am a child of the fifth. I'm much older than you are, but I remember polio. But part of the heinousness of polio was that only about one of every 200 people who was infected with polio virus was paralyzed. There was a lot of asymptomatic transmission of that virus.

So what does that mean though, Paul? How confident are you that 10 years from now we're not going to have another worldwide pandemic? That, you know, the analogy I used to describe this to somebody the other day was when you're driving a race car, the worst thing you can be doing is braking too late because then you have to brake much harder than you want to and the dynamics of the car become really unstable and you're probably going to crash. And in some ways I sort of feel like that's what happened in the United States, which is we didn't brake soon enough. And when we did break, we had to brake way harder than we should have and we crashed. And I want to believe we could learn from that first.

Such a great analogy. I do think that at the heart of that question is how much do I have faith in human nature that we can learn from these things, that we will have the kind of heart, big heartedness, that will allow us to have international collaborations and more open borders regarding sort of scientific inquiry. We haven't been very good at it so far. If we don't learn our lesson here, I mean, we're never going to learn it. So I don't know, I don't have an enormous amount of faith in human nature that we're going to learn from this. But I hope you're right.

Yeah, I wasn't suggesting I was right. I was wondering what would need to happen. Right. What would. Let me pose it to you this way, Paul. If someone came to you and said, hey, I want to put you in charge of thinking about the next pandemic, you're doing a great job helping us with this one, but we've got a lot of people thinking about this one. I want you to go on vacation for two weeks, recharge, shake the dust off a little bit, and I want you to come back and the only thing I want you to do is think about how we're going to prepare for the next one. What would be some of the ideas you put forth?

It's an international collaboration. That's an international question. So you have to get the governments and the scientists from every nation in this world in line with what are we going to do collectively to monitor for the next pandemic potential virus and there will be a next pandemic potential virus in terms of surveillance, how are we going to do that? How are we going to do the sequencing? Who's going to do it? And then once in hand, when we see that that's true, how are we going to collaborate to do this, to make sure we all have what we need? Because we're all dependent on each other, because we're only as strong as our weakest nation out there. How are we going to do that? But even with the vaccines, you see a certain level of nationalism, right? There's sort of the Chinese have their vaccines, the Russians have their vaccines, we have our vaccines. The fact of the matter is, I think Dr. Fauci is amazing. He's a phenomenal science communicator. He's a brilliant man. The only time he's ever said anything that bummed me out a little bit was when somebody asked him about whether or not there would be another vaccine that would be submitted for licensure, like the UK AstraZeneca vaccine being submitted for UA approval here. And his response to that was, we don't need another vaccine. We have enough vaccine for our country. But I think our country has a responsibility to all countries in this world. We're economically and technologically advanced to provide vaccine for everyone if we can. And we can. You know the Pfizer. Look at these MRNA vaccines. They're given at 30 micrograms or 100 micrograms. Micrograms a dose. A microgram is a millionth of a gram. That's 10 to the minus six. Right. You can make kilograms, that's 10 to the third. Right. That's a nine log difference. That's a billion fold difference. Can you make billions of doses of MRNA vaccine? Absolutely. Should you? Absolutely. And if it means restricting sort of the intellectual property and allowing that to happen, it should happen because it's the right thing to do for these companies and for the the world.

This is an unrelated question to where I want to go, but while we're here on the topic, do you have any idea what vaccine hesitancy rates are like outside of the United States? I actually haven't looked at those data.

Right. So there's a woman named Heidi Larson at the London School of Public Health who does this. She has something called a vaccine confidence project. So she goes throughout countries in this world to see sort of what she measures vaccine confidence. She recently had a book out that came out called stuck. But interestingly, we're not the least confident country in this world. The least confident country in this world for vaccinations is France. Don't know why. Yeah, France is number one. So we're not actually that bad. But see, I sort of divide this into two categories. I think there's the skeptics and I'm a skeptic. I think you should be skeptical of anything you put in your body. I think you should want to see the data to make sure that what you're being given has been adequately tested and vetted. I think skepticism at this point, certainly for the MRNA vaccine, should melt away. You've got a highly effective vaccine that doesn't even appear to have a rare serious side effect problem. And it's been in 120 million people in the United States, skepticism should be gone. And I think largely among that group, it has. When you look at sort of percentage of people who said they would definitely get a vaccine, say last September, it was about 30%. Then by December it was 40%. The University of Washington, Washington came out with recently a survey that suggested it's about 70% that said they would definitely get a vaccine. And then there's the second group, which are the vaccine cynics. And they just don't trust the government or trust pharmaceutical companies or trust the medical community. They just don't believe you. They don't believe you. It's amazing to me that some of those people are also in the medical profession. But that's been the experience, so you can't convince them. Neil Degrasse Tyson has just a great quote on this, which, which is if people don't use reason or logic to come to a specific conclusion, reason and logic are not going to talk them out of it. So then what do you do? And then this is what we were talking about earlier. Do you compel them either with the carrot or the stick to get vaccinated? Because what they do affects others.

When I think back looking at the past year, Paul, this is my opinion, which I'm only stating so you can contrast it with something that's probably much more thoughtful. My view of the greatest single failure in the past year was how long it took to get testing up and running. When I think about the absolute buffoonery on the part of. I think it was frankly mostly on the part of the government, but I'm sure there were others at hand. It was the inability to make testing readily available. Now, I don't think it was at the obvious Level. I mean, I think there are things that probably weren't in place. In other words, how much reagent existed for PCR to begin with. But you'd like to think that in a future pandemic or in preparedness for a future pandemic, you would have enough PCR machines, you would have enough reagent, you would have enough other critical infrastructure such that the moment you had a sequence, because getting the sequence of this virus was not the rate limiting step, the moment you had a sequence, you would be able to rapidly deploy tests to contain this thing. And I think a lot of the things that have happened since that time have been actually pretty good. Like, I mean, the speed with which the vaccine has been developed has been remarkable. I think the evolution of insight into critical care has actually been pretty darn impressive. So I think a lot of things have gone kind of well. But boy, that testing thing is really what goes back to my analogy of coming, you know, waiting way too deep in the corner to hit the brakes and then slamming on the brakes and crashing the car. What's your assessment of where we really lost things this time around? And therefore where we'd want to really make sure we had it right the next time around? Right.

I completely agree with you. I mean, we had the sequence in hand by January of 2020. The virus started to kill people in this country two months later. Was that enough time to be able to create, produce and distribute enough tests that we could have done what South Korea did? We're not South Korea in many ways. I think we are a much more diverse population that is much less corrallable, if you will. And so. But I do think that we put all our eggs in the CDC basket. It was just CDC that was making the test, whereas there should have been many, many groups that were making those tests initially and quality controlling for them. Because what happened was then CD screwed up. They did, they screwed up the testing so that their negative control ended up being positive. Therefore, those tests were useless. And so by the time that all got sorted out, South Korea had done 500,000 tests where we had done fewer than 5,000. It was pathetic. Pathetic. And if we had done that, and again, I just don't think we didn't have great federal leadership either. That's today's understatement in terms of this, where you could have said, let's get things in place to do the testing, do the quarantining due to the restriction of international travel. That would have allowed us to be much better off. I mean we are roughly a 4% of the world's population and 20% of the world's deaths when we have a technologically and economically advanced society. So there's really no excuse for doing it as badly as we did it. But I think the testing was one big reason. I agree.

Well, Paul, there are actually several things I want to talk with you about more, but I also know that given that the news of JJ's vaccine just hit you are probably being dragged in a million different directions. So I want to let you get on with those obligations. And I'm incredibly grateful that you made time to still speak with me today. Obviously far less important than speaking with all the other people that are clamoring at your door today. So thank you again for making time, as was the case last time, just a phenomenally interesting discussion to me. I learned a lot and I know that the folks watching this did as well.

Well, thank you. I can tell you that you'll be the most interesting, smartest person was clamoring at my door as I go through the rest of my day. But no, I really appreciate this. It was a lot of fun.

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