#137 - Paul Offit, M.D.: An expert perspective on COVID-19 vaccines

1. 0:00 – 1:29

   Intro

   1. PAPeter Attia0:01

      [upbeat music] 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 wanna 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 wanna learn more now, head over to peterattiamd.com/subscribe. Now, without further delay, here's today's episode. [upbeat music] My guest this week is Dr. Paul Offit. Paul's a pediatrician specializing in infectious diseases, and he's an expert on vaccines, immunology, and virology. He's the director of the Vaccine Education Center and a professor of pediatrics in the Division of Infectious Diseases at CHOP, the Children's Hospital of Philadelphia. He's also a professor of vaccinology at the Perelman School of Medicine at the University of Pennsylvania, and he's on the FDA Committee for Biologics Evaluation and Research Vaccines and Related Biological Products Advisory Committee. In other words, he's on the FDA committee that is overseeing the basically unprecedented scale with

2. 1:29 – 3:30

   45 - Why vaccine development can be challenging and risks of current COVID-19 strategies

   1. PAPeter Attia1:29

      which vaccines are being put into a pipeline to be evaluated for COVID. He's also the co-inventor of the rotavirus vaccine, as if all of the above were not enough. I've wanted to talk with Paul for a couple of months, but I wanted to wait until the time was right, and I kinda define that as a moment when we had enough certainty in terms of what was going on with COVID vaccines that we could speak about it in less abstractions and more straightforward terms with respect to likely releases and approvals of various vaccines. And so I'm re- I'm really glad that actually we waited until this time, because I, I do think we're at that point where we have a pretty clear line of sight into the pipeline of a number of companies and also a number of strategies that are being employed. And that's, that's basically what we go into. I mean, we, we, we certainly talk about Paul's background, which is fascinating and, and why he's sort of the perfect guy to have this discussion. But the meat of this discussion really focuses on delineating the four strategies with which one can pursue a vaccination against the virus that causes COVID. And then we talk about basically who the major companies are in each of those categories, where they are in their life cycle, what that actually means, and what it implies as far as vaccination approval. We talk a lot about what the potential risks are in each of the categories and more broadly, and ultimately, we talk about what 2021 could look like and what the unknowns are. So I learned a lot in this episode [chuckles] actually, more than I expected. I was just completely riveted by Paul's insights, and I think we all have a little bit of COVID fatigue at this point. That's understandable. But I think anybody who's got questions about, "Will a vaccine change my life? What should I expect next year?" I think, and I hope at least, most of your questions are going to be answered here, and I, and I don't suspect this is the last time that Paul and I will speak. So without further delay, please enjoy my conversation with Paul Offit. [upbeat music]

3. 3:30 – 8:00

   How Paul’s experience as a child in a chronic care hospital as child informed his path in pediatrics and vaccine development

   1. PAPeter Attia3:34

      Paul, thank you so much for making time to sit down with me today. I know that you are someone who a lot of people wanna talk with, especially now that people are really starting to come to grips with the fact that a vaccine for the coronavirus is going to be a very important part of the story. I guess before we get that, though, I think it's important for people to understand why your thoughts on the subject are important. In other words, you're not just someone like me who's been thinking about the coronavirus for less than a year. You're someone who has spent essentially a lifetime thinking about this type of a problem. There's a story about how you were a very young boy, you were hospitalized, and that experience at such a young age kind of shaped the way you thought about going into medicine and, and ultimately even being a pediatrician. Can you share a bit of that?

   2. POPaul Offit4:21

      Sure. So I was born with club feet, which means that my feet turned sort of inward and down. Typically, that's treated with casting, so I was casted within the first few hours of life, really. And then, so for months, I was casted, but it seemed to work. I mean, my feet seemed to straighten out. But at the age of five, my father decided that he didn't like the way that my heel didn't, or my right foot didn't hit the ground as well as he would have liked. So he was able to find a surgeon to do a surgery, frankly, that was perfected about 40 years later. We should have never done that surgery. There was no clubfoot surgery. He, he was able to find a guy who was a son of a friend of his who had just finished his residency in orthopedics and thought, "Great, I get to do this surgery," which went badly. My father was a shirt manufacturer. Medicine wasn't really his strength, but he didn't like the way the heel hit. Interesting as a side part of the story is that my great uncle, my grandfather's brother, was a bookie. He was really Baltimore's bookie. He didn't print books. He made book. My mother initially had trouble getting me into the clubfoot clinic at Johns Hopkins Hospital, but she just called my great uncle, who called the guy who was head of the foot clinic, who was a gambler, apparently, so we got in within a week. And when the guy, this physician, saw me, he said, "I-- if you do nothing, don't operate on this foot." Nonetheless, my father insisted that the foot be straighter, and so I had an operation that was a complete failure. And as a consequence, I ended up in a chronic care facility called Kernan's Children's Hospital, although I think, I think then it may have been called Kernan's Hospital for Crippled Children, when you could use words like crippled and feeble-minded. I was there for about six weeks, and this was the 1950s. Polio was king, and I remember just a lot of children in that ward with polio. It was probably about 20 kids in the ward, some in iron lungs, some in traction. And there was one visiting hour a week. That was it. Sundays from two to three. My mother had a complication with pregnancy with my brother, so she never came. My father had tried to sneak in once. to see me. Gus was re- prohibited from seeing me again. So he traveled a lot, so he couldn't do the hours that they had wanted him to do. So I just remember sort of seeing those children as vulnerable and helpless, and wanting to frankly see myself the same way. And I, I remember looking, there was a-- my bed was next to a window. This was when you had one visiting hour a week, polio days, so people were scared to death of having anybody else come into that hospital. Sundays from two to three. It wasn't like they had, like, therapy dogs or, you know, iPads or televisions or anything. You just pretty much laid there, and in my case, looked out the window that was right next to my bed, which looked out into the front door. And I kept waiting for my parents to come rescue me, to walk through that front door of the hospital. Never happened. When I was a, um, medical student at the University of Maryland, we rotated through Kernan's Children's Hospital, and that room was still there. It wasn't a polio ward anymore, it was a group of secretaries, but that window was still there.

   3. PAPeter Attia7:07

      That facility is still there, isn't it?

   4. POPaul Offit7:09

      Yeah, Kernan's Children's Hospital is still there.

   5. PAPeter Attia7:11

      I did my residency at Johns Hopkins, and I remember we would sometimes get transfers. I was in surgery, so kids that would get infections that would need to be transferred to Hopkins for surgical care. That's funny, I didn't think I'd hear that name again.

   6. POPaul Offit7:24

      So I remember as a student then, walking-- I was at Maryland Medical, but I remember walking up to, uh, that window and looking out of it and seeing that front door, and, you know, I cried. So I think that's it. I mean, I think that we are motivated by the scars of our youth. For me, a choice to go into pediatrics, a choice to go into pediatric infectious diseases, a choice to write a book about polio, specifically about a sort of a tragic event associated with the making of the polio vaccine, a choice to make vaccines, I think, enter the world of science and stuff, probably all is motivated by the scars. Pretty much every book I've written, at its heart, child advocacy, at its heart, sort of standing up for children who are vulnerable, who can't stand up for themselves.

   7. PAPeter Attia7:59

      We're gonna

4. 8:00 – 17:00

   Addressing the anti-vaccination sentiment and explaining the fraudulent origins of the anti-vaccination movement

   1. PAPeter Attia8:00

      talk about vaccines today, and I don't think a discussion of vaccines would be complete without saying something about just the unbelievable disservice that has been done to so many people, so many vulnerable people, specifically parents who are looking for answers when maybe there are no answers, by sort of the fraud that was catapulted upon them in the late nineties in, in the form of that Lancet article that has been so thoroughly debunked as not just incorrect, but outright fraud. Of course, I'm referring to that Wakefield paper of 12 completely fabricated case studies that really, on some level, is kind of a big part of the anti-vaccine rhetoric and the vaccines cause gastrointestinal disease, which causes autism story that started at that time. And frankly, on some levels, there's a solid number of people who continue to believe this despite the efforts of people like Brian Deer, yourself, Peter Hotez, people who have so thoroughly debunked that type of nonsense. How do you process that? Do you process it? Or there are some people who are very angry about the anti-vaccine movement. There are others who I think speak to it more from a place of empathy. How do you manage your own emotions around that, especially when you see the children themselves are often the victims of parents who are themselves the victims, et cetera?

   2. POPaul Offit9:31

      Yeah, I guess I fall-- come out on the angry side. I think Andrew Wakefield was a fraud. I think at some level he was a knowing fraud. I mean, he misrepresented clinical data. He misrepresented biological data. That paper should have never been published. It was basically a story of 12 children, eight of whom had autism, presumably within a month of receiving MMR vaccine, when in fact, at least a couple of the children had developed signs and symptoms of autism before ever having received that vaccine, which he knew. He also, he had biopsies on all those children, and presumably measles vaccine virus was supposed to be destroying intestinal epithelial cells. He had biopsies on those children. He never did studies looking at, or at least never reported studies, looking at whether there was measles virus genome or measles virus vaccine proteins in those cells, which is to say he probably did do those studies, and they didn't come out the way that he wanted them to.

   3. PAPeter Attia10:17

      Actually, we'll go one step further. I think Brian Deer has actually done a very good job uncovering those biopsies were done and processed, and the amount of virus that was found in them was identical to that which was found in basically the formalin itself, demonstrating that it was a pure contaminant. So actually, there, there was no measles virus whatsoever in any of the colons of, or distal ileums of any of those children.

   4. POPaul Offit10:48

      And I talked to a person who did some of the serology with Andrew Wakefield for a meeting I had in England, and he refused to be on the paper because he felt that Andrew Wakefield had basically misrepresented sort of IgM, IgG response, immunoglobulin responses to measles. That was Andrew Wakefield. Brian Deer just wrote a book called The Doctor Who Fooled the World, which goes through all this.

   5. PAPeter Attia11:07

      I'll be interviewing Brian because I think it's such an important discussion. Clearly, there's no shortage of anger towards Wakefield because I agree with you. And by the way, fraud and knowingly is a bit of a tautology. By definition, if it's fraud, in my opinion, he was knowingly acting in bad behavior. And where are we today? Maybe just talk about it through the geography that you understand best, which I assume is the United States. Where are we at MMR vaccination levels? Are we above ninety-five percent?

   6. POPaul Offit11:37

      We were. I mean, I think what happened with the COVID-19 pandemic is that we had a dramatic drop in the instance of vaccines in general, including MMR vaccine. But I would say this, I think that this is gonna probably surprise you. I think in some way, Andrew Wakefield was good for science. Here's why. When he put that out there, he became a darling of the anti-vaccine movement. He was attractive, he was well-spoken, he had a British accent, which we all love. I think we're ready to give ourselves back to the Queen at this point. And he made the rounds in the United States. He was on everything, morning, evening shows. He was on 60 Minutes with Ed Bradley. Uh, he was a darling of the anti-vaccine movement. He was a physician, a scientist who now said all the right things, and I think the anti-vaccine folks attached themselves to his star When it was found out that he was not only wrong, but fraudulent and wrong, that he not only had misrepresented clinical and biological data, but in fact had basically laundered money, laundered legal claims through a medical journal, his star fell, and I think the mainstream media rejected him. His last, I think, appearance on mainstream media was on Anderson Cooper.

   7. PAPeter Attia12:40

      Where Cooper just destroyed him, yeah.

   8. POPaul Offit12:42

      Yeah, it was great. So at some level, he helped us marginalize to some extent the voices that were the anti-vaccine voices. Barbara Loe Fisher, Jeff Schwarz, J.B. Handley, et cetera, had a much bigger voice, I think, twenty years ago, fifteen years ago than they do now, because I think mainstream media anyway has chosen to set them aside. Now obviously their platform is social media, but so I think Wakefield in some ways helped us. I mean, we did the studies to answer the question whether you were more likely to develop autism if you got the MMR vaccine or not. That's been done eighteen times in seven different countries on three different continents. The question's been asked and answered. I do think, according to a study done by the Autism Science Foundation, about eighty-five percent of parents who have children with autism no longer believe that vaccines were the cause. So I do think that that good science did win out to some extent, and I think Andrew Wakefield has lost that. He's now, you know, he goes on Alex Jones' show, where all good conspiracy theorists go.

   9. PAPeter Attia13:35

      Yeah, it's interesting. There aren't many things in medicine we can say with a higher degree of certainty actually than the MMR vaccine does not cause autism. If you really stop to think about it, Paul, do statins cause Alzheimer's disease? I think the data's overwhelmingly convincing that it does not, but I think the data are more convincing that MMR does not cause autism based on the extent to which it's been studied, and maybe to some extent the negative attention that Wakefield has brought to this has actually forced so much scrutiny of those data, not just the eighteen studies you refer to, but also going back and really exposing the biological plausibility of the argument itself, and frankly exposing another issue that I think is very easy to understand, so I say this with a lot of empathy, but is nevertheless an issue, which is any of us are capable of misremembering facts. And so much of what I think gave Wakefield and his associate, Barr, the lawyer with whom you referred to earlier that he was basically in cahoots siphoning funds through his research organization, the ability to carry on for so long was effectively parents misremembering things. I actually believe most of those parents were not nefarious. I think there are some that who clearly were. I think there were some who consciously chose to sort of pursue legal action to get money knowing that what they were saying was false. But I don't think that that's the majority of them, 'cause remember, all of those parents in that case said little Susie got the vaccine on Tuesday, had a nosebleed on Wednesday, had a fever on Thursday, and started banging their head against the wall, and the rest is history. I actually think they believed that, although the medical records showed no, actually little Susie stopped talking six months before they ever got the vaccine, and here are the medical records to demonstrate it. I mean, it was unambiguous what had happened. But I just think that people, ourselves included, sometimes struggle when we go back to remember things, especially things that are painful.

   10. POPaul Offit15:51

       I think we look for reasons for why things happen. That gives us some level of control, even though the reason may not be the correct one. At least now we feel like we have some handle on it. What Andrew Wakefield offered at some level was hope. If you don't want your next child to get autism, separate the MMR into its three component vaccines. If you want to treat this child, here's a variety of intestinal treatments that will work, that will be magical. I mean, he, he was a charlatan of the first order because he took advantage of parents' desperate desire to do something for their children.

   11. PAPeter Attia16:22

       And not to get too far into Wakefield's psyche, but I actually believe there was probably a day when he was honest. I believe there was a day when he, like any scientist, had a hypothesis, set out to test it. The difference is he crossed a line. The difference between a good scientist and a bad scientist and a charlatan is that a good scientist can look at the data when they disagree with hypothesis and modify hypothesis.

   12. POPaul Offit16:47

       He had done some early work on sort of vasculitis associated with inflammatory bowel diseases, yeah. He tried to really make the case that measles, mumps, and rubella vaccine also was a cause of inflammatory bowel disease, and he was wrong, and he admitted he was wrong. And

5. 17:00 – 27:15

   Lessons and insights from 26 years studying rotavirus and creating a successful rotavirus vaccine

   1. POPaul Offit17:00

      then he went on to the next thing where he was wrong but didn't admit he was wrong.

   2. PAPeter Attia17:03

      Yeah, and doubled down, and that's where really the fraud got out of control. Let's take a step back to give people a bit of a sense of your work. What were you doing? What was a day in the life of Paul Offit a year ago, basically before SARS-CoV-2 was a known entity? What were you working on?

   3. POPaul Offit17:22

      I spent twenty-six years of my life working on creating the strains of virus that became the bovine human reassortant vaccine RotaTeq. That was my twenty-six year effort. Before that was done, about two thousand, we created the Vaccine Education Center at Children's Hospital Philadelphia, which sort of creates and distributes educational materials to educate the press, educate the public, educate doctors about vaccines so we can sort of meet this anti-vaccine movement, or at least the anti-vaccine sentiment that people have, so that we can answer their questions. What we're trying to avoid is, are those children who suffer needlessly by not getting vaccines that would protect them. So that's been the passion. I mean, I think the passion for me came because I think I saw how hard it was to make a vaccine, how hard it was to prove that a vaccine was safe and effective, and how easy it was to damn them. That paper was, was awful. Should have never been published. And yet it created a movement, or at least supported a movement. So I think that was it. Seeing how hard vaccines were to make, how easy it was to damn them got me interested in trying to fight with facts.

   4. PAPeter Attia18:21

      Let's talk a little bit about rotavirus. Can you tell folks a little bit about what that is and how often it afflicts children?

   5. POPaul Offit18:27

      Rotavirus is a virus that infects the small intestine. It causes fever, vomiting, and diarrhea primarily in children between six and twenty-four months of age. In the United States, before there was a vaccine, everybody would be infected by age five. All children would be infected by age five. It would cause about seventy-five thousand children to be hospitalized in this country every year with severe dehydration or water loss. It would also cause about sixty children to die every year. In the developing world or in the rest of the world, it was a killer. I mean, it was really the biggest killer of infants and young children, killing about five hundred thousand babies a year, typically children less than two years of age, about as many as two thousand a day. So there was always a lot of interest in trying to make a vaccine to prevent it. That's where I come in.

   6. PAPeter Attia19:09

      And obviously, the difference between why so few kids would die in the United States versus the rest of the world presumably had to do with supportive care, and these children in the developing world were gonna die of dehydration and/or electrolyte imbalance, whereas in the United States, despite how many were hospitalized, at least they could receive intravenous fluids and some form of nu- perhaps even parenteral nutrition if necessary. Is that the fundamental distinction?

   7. POPaul Offit19:33

      The story that I tell is that there was a friend of mine who was a PhD in chemistry. She actually worked for a pharmaceutical company. Her baby got s- rotavirus infection, so she took the baby to the doctor, and the child was severely dehydrated. The doctor said, "Let me call an ambulance and take this child to a local hospital." The mother said, "No, I can take her. I'll put her in the car and take her." So she gets her in the car, and then she's in a major traffic jam, which is why you get an ambulance. And so she was stuck, and she was much longer to get to the hospital than she would have others. By the time she got to the hospital, the child was out of it, so they whisk the child back into the treatment room. They were able to do a cut-down incision in the child's neck to thread a catheter down because that was the only vein they could find. That child dies in the developing world because you don't have the kind of equipment to do that cut-down because you're walking twenty miles to get to a clinic or hospital. So the difference between this country and other countries where children die is not severity of disease. It's as severe here. It's just that we have the resources here to keep children from dying.

   8. PAPeter Attia20:30

      So what type of a virus is a rotavirus? Is it an RNA or a DNA virus?

   9. POPaul Offit20:34

      It's a double-stranded segmented RNA virus.

   10. PAPeter Attia20:37

       Does that pose any challenges for creating a vaccine against it?

   11. POPaul Offit20:41

       The good news is when you're trying to make a vaccine, you wanna see clear evidence that natural infection can induce protection against at least moderate to severe disease. Then you know that you should be able to mimic that part of the immune response that's associated with that protection. Those studies were done in the '70s actually. Ruth Bishop published a paper showing that if you got a rotavirus infection in your first year of life, when you were then subsequently challenged with the virus again, just naturally, you could get mild infection or you could get asymptomatic infection, but you wouldn't get moderate to severe infection. The minute that paper was published, we thought, "Okay, we can make a vaccine. We just have to mimic that part of the immune response that's associated with protection."

   12. PAPeter Attia21:15

       And was that protection lifelong, Paul?

   13. POPaul Offit21:18

       No. [laughs] No. Like many mucosal viruses, rotavirus, influenza virus, parainfluenza, respiratory syncytial virus, those viruses which have generally short incubation periods, meaning time from when you're first infected to when you get sick, which generally don't have viremia as part of pathogenesis, their immuni- or natural infection and immunization induces a, a protection that is short-lived and incomplete, meaning decades and meaning protection against moderate to severe disease but not mild disease. These are the mucosal viruses, which I think brings us to SARS-CoV-2. I think that's gonna be the same story here.

   14. PAPeter Attia21:49

       Did that paper in the 1970s offer an insight into whether the immunity was provided more by the B cells or the T cells?

   15. POPaul Offit21:58

       The thinking was that it was gonna be an antibody response at the intestinal mucosal surface. We had to induce an antibody response that was active at the intestinal mucosal surface, which made us think it was gonna have to be an oral vaccine which stimulated then immunity at the intestinal mucosal surface and not a parenteral vaccine, which would stimulate systemic immunity.

   16. PAPeter Attia22:14

       So what was the approach you took then to do that? In the spirit of that, at the time, what were the options available? I mean, beginning with, say, a live attenuated virus, is that generally the first thought an, an individual has when pursuing a vaccine, or how did you guys problem solve around the different ways in which you could induce immunity?

   17. POPaul Offit22:32

       The way we saw it was that rotaviruses are ubiquitous. Every mammal that walks the face of this earth has its own unique strain of the rotavirus. And species barriers are pretty high, meaning that a cow rotavirus or calf rotavirus would cause disease in calves but not people, and vice versa. Human rotaviruses would cause disease in babies but not calves. So we basically took advantage of that. It was a Jennerian approach, if you will, an Edward Jenner-like approach. I mean, Edward Jenner basically used a cow virus to protect against human smallpox virus. So cow smallpox, essentially cowpox, would protect against human smallpox because they were antigenically related enough that immunization with one could protect you from a disease caused by another. That was our approach. So... And that was our initial approach, was just to take a cow virus, a calf virus, that had caused diarrhea, adapt it to growth in cell culture, and then use that as our vaccine. And it did work, but it was inconsistent. So then we had to modify that calf virus so that it included the genes that coded for the proteins that evoked what we found were neutralizing antibodies. There were two surface proteins of the virus, and we thought both independently evoked neutralizing antibodies. That's what we proved. So then it was a matter of just constructing these combination virus, so-called reassortant viruses between calf and animal strains that became the vaccine, thus summarizing 10 years' worth of work in about 35 seconds. It's a little depressing that you can do that, but that's what we did.

   18. PAPeter Attia23:55

       [laughs] What were the risks associated with the vaccine?

   19. POPaul Offit23:59

       You don't know. When any- ever you're dealing with something that's unknown, these are new calf viruses. Will they behave differently in people? Will they cause something that's untoward that you hadn't thought about? What we learned from other researchers was that, surprisingly actually, there was a vaccine that was introduced in the late 1990s. It was made by National Institutes of Health in collaboration with Wyeth called RotaShield, which was a simian rotavirus that was also a recombinant virus, simian human reassortant rotavirus, that was found to be a rare cause of intussusception, which is intestinal blockage. It occurred in, depending on who you read, between one in ten thousand to one in thirty thousand recipients. It wasn't picked up pre-licensure because the studies wouldn't have been big enough to pick it up pre-licensure. It was only picked up months after licensure, and then it was off the market within 10 months. So that was a sobering experience. Just to relate it to today, if you don't mind, that virus had... rotavirus had been studied for 50 years by that time. I mean, we-- it was known to be an animal pathogen in the '40s. Veterinarians studied it. We knew it was a human pathogen by the '70s. When that vaccine came out in the late 1990s, we had 50 years' worth of study. Nonetheless, it caused a side effect, intussusception, that would have never been predicted by all those studies.

   20. PAPeter Attia25:06

       Yeah, let me tell people what that is. So an intussusception is when usually a lymph node in the small intestine acts as a foci and allows the small bowel to telescope on itself, so it gets tugged probably through some sort of peristalsis action, and that can cause an obstruction. So if the piece of the bowel telescopes into another and comes back out, easy peasy, but if it telescopes and gets stuck, you now have a bowel obstruction. And I took care of many kids, as I'm sure you have, who had intussusception from lymphoid hyperplasia or various other things, but obviously in this case, it was a side effect of a vaccine, and an understandable side effect, meaning there's a biological plausibility of why giving a vaccine that has a GI mucosal effect could lead to lymphoid hyperplasia that could act as the tugging point. But you're right, you would never in a million years say, "I think intussusception could be a side effect here." And if it only occurs one in 10,000 cases, you're gonna easily miss that in phase one, two, and phase three. Again, it speaks to aftermarket surveillance and the absolute imperative of it, and it also speaks to the fact that as we start to talk about coronavirus, which we're going to get to very shortly, one has to be thoughtful about risk versus reward trade-off with small N, right?

   21. POPaul Offit26:24

       Yeah, I think that the surprise was that vaccine, which was sort of a simian rotavirus-based vaccine, that virus reproduced itself far less efficiently at the intestinal mucosal surface than did wild type virus, natural virus. There was no evidence that natural rotavirus caused intussusception, so why would this be true? And the reason is, is that intussusception really appeared to be a year-round phenomenon. It wasn't a winter phenomenon in the United States, which was what rotavirus was. You would expect to see a bump in the winter, which you never saw. So why would a vaccine do something that natural infection didn't do? I think what we know now is that natural infection probably was a very rare cause of intussusception, as was this vaccine. And I guess the COVID analogy is that here's a virus, COVID, for which we had at least the, the gene structure in early January of this year, which has already had a number of sort of clinical and pathological surprises, which we are now about to counter with a series of vaccine strategies with which we have no commercial experience. I think

6. 27:15 – 32:30

   Developing a new vaccine: the different phases of clinical trials, overall timeline, and financial costs

   1. POPaul Offit27:15

      it's fair to say there's gonna be a learning curve here, so there has to be real humility, I think, as we move forward.

   2. PAPeter Attia27:19

      Well, let's help folks understand a little bit about these different phases because you can't turn on the news without hearing Company X is in phase one or two or three, and I just want people to understand what those mean specific to vaccines 'cause they have slightly different meanings than, say, in drugs that treat blood pressure. So can you explain to people what a phase one vaccine trial aims to accomplish and what a typical size of that trial might look like?

   3. POPaul Offit27:50

      If you're trying to make a vaccine, you start in so-called preclinical studies, meaning studies done before you get to humans, and hopefully you'll have an animal model to study the disease. In the case of rotavirus, it was mice. If we inoculated baby mice with rotavirus, they got sick. Okay, great. So now we have a way to study this infection. Then you have your idea for how you want to make your vaccine. You give your vaccine, you then challenge the animal with the virus, and hopefully you can protect the animal from disease. And more importantly, you can frankly literally dissect out that part of the immune response that's associated with protection against challenge. So those preclinical studies are called proof of concept studies. So now you have your way of making a vaccine. Then you go to phase one, which are usually about twenty to a hundred people. Now you have your idea for how you want to make it, but you don't really know the dose. So you give a variety of different doses to these twenty to a hundred people to see whether or not you can safely induce an immune response that you think is gonna be protective based on your animal model work. Now you have a dose and a strategy.

   4. PAPeter Attia28:45

      What's the typical length of time to go from that preclinical where you've now filed an IND and you now would be applying to, you know, institutional review board to do a phase one? In the normal world, that takes how long usually?

   5. POPaul Offit28:59

      I think probably it's fair to say ten years, fifteen years.

   6. PAPeter Attia29:02

      Okay. We'll make sure everybody keeps that in mind when we pivot to coronavirus. The other thing I want to highlight that you just said there is twenty to forty people-ish.

   7. POPaul Offit29:11

      Yeah, twenty to a hundred.

   8. PAPeter Attia29:12

      We're not talking about ten thousand people.

   9. POPaul Offit29:14

      No, no.

   10. PAPeter Attia29:15

       And these are often done with a little bit of a dose escalation built in, so maybe the first ten people are gonna get a really, really small dose. We make sure nothing catastrophic happens. We then escalate the next ten, et cetera, right?

   11. POPaul Offit29:27

       They're dose ranging trials, exactly right. You go slow, and you work your way up to see what seems to consistently induce an immune response that is, and that is safe.

   12. PAPeter Attia29:36

       The third thing I want to highlight there is we're not actually able to assess whether or not the people have legitimate immunity. We're using a proxy, presumably, which is some form of serology. In other words, we're not actually testing their ability to resist an infection. We're measuring an antibody. Is that correct?

   13. POPaul Offit29:55

       That's right. You have a prediction based on your animal model studies that one aspect of the immune response is going to be associated with protection against challenge, as it was true in your animal models. You won't know that till you get to phase three.

   14. PAPeter Attia30:06

       So now let's go to phase two. You've established a dose, potentially a frequency. What do you do in phase two, and roughly how many people do you do this with?

   15. POPaul Offit30:15

       So phase two is typically hundreds of people. Now you've got your vaccine, you've got your dose, and you just want to make sure that it's consistently inducing an immune response that you think is protective and that it's at least safe and that it doesn't cause a relatively common serious side effect. That's phase two.

   16. PAPeter Attia30:31

       And again, the two points worth making sure people understand, still a relatively small clinical trial, hundreds of people, and you're still using surrogate markers. We don't actually know if this vaccine is providing immunity in the real world, its efficacy. We don't know if it's effective And we don't really have any way of knowing what very minor or in-- or I shouldn't say minor, infrequent negative consequences could look like because we're still dealing with a very small sample size.

   17. POPaul Offit31:01

       That's exactly right.

   18. PAPeter Attia31:03

       So now we go to phase three, and what does that look like?

   19. POPaul Offit31:06

       This is the definitive trial. This is the trial that you're going to use to submit information to the FDA, Food and Drug Administration, hopefully for licensure. These are tens of thousands of people. In the case of our rotavirus vaccine, it was seventy thousand babies. Thirty-five thousand got the vaccine, thirty-five thousand got placebo, which is just essentially the vaccine except no active ingredient, just the, frankly, sugar solution in which the vaccine virus was suspended. And then you just send people out into the real world. I mean, rotavirus is a common infection. It's the rare child who gets to age five without being infected. And then you just see whether or not children who got the vaccine were less likely to get rotavirus, or if they got it, that they were less likely to get it severely. And hopefully, you'll have-- We had sera on all those children, meaning we looked at the antibodies on all those children. Hopefully, that would provide a clear immunological correlative protection, which it didn't. We knew that the vaccine worked. We knew that it was safe, and so we could submit it for licensure to the FDA. But as you go along, things are much more expensive. You go from sort of millions to tens of millions to hundreds and hundreds of millions, and then you mass produce the vaccine after you've found out that it works.

   20. PAPeter Attia32:12

       And as a general rule, the process we just described, going from a preclinical model in animals to the completion of a phase three trial with the FDA approval of an agent, here's the rule of thumb I use. Please correct me on the vaccine side. I generally say that's twenty years and one billion dollars, and that's

7. 32:30 – 35:00

   Operation Warp Speed: the expedited process of creating a coronavirus vaccine

   1. PAPeter Attia32:30

      usually on the drug side. Is it about the same on the vaccine side?

   2. POPaul Offit32:33

      Yes, fifteen to twenty years with at least a billion dollars. That's right.

   3. PAPeter Attia32:37

      So let's now talk about coronavirus and just understand that in January of twenty twenty, when the sequence of the RNA identifying this as a novel pathogen, a coronavirus named now SARS-CoV-2 shows up, and by March, I guess, it becomes pretty clear this is not going to be contained, which means any strategy towards containment is going to fail, it became readily apparent that a vaccine was going to be a very important piece of the strategy. Basically, at that point, it was going to be herd immunity without vaccine or herd immunity aided by vaccine. If you're staring down the barrel of it's gonna take twenty years and a billion dollars, that's not a very appealing strategy because it basically says it has to be herd immunity without a vaccine, meaning this virus has to sort of rip through a population without it. If I could ask you to put yourself back in your mindset in February or March of last year, what would you have said if I asked you at the time, "Paul, how likely is it that a vaccine will be developed to at least thwart in some way this virus? And two, how long will it take?" What would you have said then?

   4. POPaul Offit33:48

      I would have said it would take years. You do have to give credit to the administration for one thing. Operation Warp Speed, what they did was they basically took the risk out of it for pharmaceutical companies. What the government said is both BARDA, which is part of Health and Human Services, the World Health Organization, the Gates Foundation, and others, but in this country, the government said, "Here's what we'll do. We'll pay for phase three trials. We'll pay for mass production at risk, meaning we'll mass produce this vaccine. We'll make millions of doses of vaccine without knowing whether the vaccine works, without knowing whether it's safe, and showing a willingness to, if it neither works or isn't safe, we'll throw out those tens of millions of doses." No pharmaceutical company would ever do that. So now you basically had phase one trials. You pretty much went right to phase three trials, which a company would never do. Went right to mass producing, which a company would never do. And that's what meant having a vaccine in hand in January. It is in all likelihood that we will have a vaccine that is rolling off the assembly line into the arms of Americans by early next year. I mean, so a year and a quarter to make a vaccine with only having the virus in hand [chuckles] in January, that's remarkably fast. It's unimaginably fast. But it's the government that did that, so give credit to them.

8. 35:00 – 41:15

   Various vaccine strategies—RNA, DNA, virus vector—and the challenges associated

   1. PAPeter Attia35:00

      Let's talk a little bit about some of the different ways in which vaccines are made. Again, there's so many different ways to skin this, but one way is you actually deliver the RNA of the coronavirus in a vehicle that then gets taken up by our DNA, and it creates enough of an immune response that we create an immune response to it. How do you think of that overall strategy?

   2. POPaul Offit35:24

      So if there's any good news about this virus, it's that we know the part of the virus, the protein in the virus that attaches the virus to cells. If you can prevent the virus from attaching to cells, in theory, you should be able to prevent the virus from infecting cells, or said another way, infecting you. That protein is the spike protein. It's the protein that emanates from the surface of the virus and gives it its crown-like appearance, hence coronavirus. You also know the gene that codes for that protein. It's an mRNA virus, meaning messenger RNA virus, single-stranded messenger RNA virus like rubella or German measles. So the initial strategies to make this vaccine are all based on that knowledge. We know the gene that codes for that protein. Take the mRNA strategy, which is the most naked and obvious, which is that you basically take the messenger RNA, which codes for that protein. You inject it into people. It's taken up by the cell in the cell cytoplasm outside the nucleus. It enters the so-called ribosomal system, and it's translated to a protein, which is excreted. So that's as though your body makes the pro-- the spike, the coronavirus spike protein, then your body makes antibodies to the spike protein This very similar strategy is the so-called DNA vaccines, and then these so-called replication defective simian or human adenovirus vaccines or replication competent, uh, vectored vaccines all have the same strategy in mind, which is introduce the gene that codes for the coronavirus spo- spike protein, induce your body to make that spike protein, and then your body will make antibodies. These are so-called genetic plug and play vaccines. The reason that they're the first ones to come out is because they're the easiest to construct and the easiest to mass produce. It doesn't mean they're gonna be the last best vaccines, but that's why they're gonna be the first vaccines.

   3. PAPeter Attia37:08

      One question I have for you on that, Paul, is given the instability of RNA, I've always been kinda surprised that they work. I can understand why DNA could work, but given how unstable RNA could be, when you take a single strand of messenger RNA and deliver it, what allows it... I mean, this might sound like a silly sort of technical question. What allows it to make its way into our cells, into the cytoplasm, head over to the ribosome, and then get translated ultimately into protein?

   4. POPaul Offit37:40

      So anybody who works with messenger RNA in a laboratory stores messenger RNA at minus 70 degrees centigrade or in liquid nitrogen because, as you say, it's an incredibly labile molecule. It breaks down within moments, frankly.

   5. PAPeter Attia37:54

      I've burned myself on said vats of liquid nitrogen many a time [laughs] in the lab, yeah.

   6. POPaul Offit38:01

      So to get around that problem, these vaccines, the messenger RNA vaccines, have to be encapsulated in a complex lipid delivering system which stabilizes them to some extent. The Moderna has been able to figure out a way to both store and ship and store at minus 20 degrees, which is just freezer temperature. But Pfizer, no, they're gonna ship and store at minus 70, minus 80, this sort of ultra cold chain which we've never done in this country, which I think will be a challenge. So you have to constantly maintain that product on dry ice. Once you thaw it out and put it in the refrigerator, it can't be there for more than a day before you give it. You're right, I think the lability of messenger RNA will be, uh, challenging. And just one sort of nerdy virologist thing that I'd like to say as a nerdy virologist is that when you're infected with this virus, you'll shed infectious virus for a week roughly. You'll shed infectious virus for a week. You'll be PCR positive, polymerase chain react positive. You could be PCR positive for three months. What you're detecting in the back of the throat is not infectious virus, it's messenger RNA. That's what you're detecting, which means because it's so quickly degraded, why would it be around so much longer? And the answer is the virus is continuing to make messenger RNA, but not making whole virus particles. Why would it do that? I mean, this virus continues to surprise, I think.

   7. PAPeter Attia39:17

      Let me make sure I understand what you just said because I never actually thought about it that way. You're saying that let's say I take the Moderna vaccine. I'm getting a bolus of mRNA. My body is gonna just take that and incorporate it and start kicking off protein. But it does two things. It doesn't just take it like one single transcribed piece of mRNA and translate it into protein and be done with it. It actually incorporates it back into the DNA, and that cell of mine continues to transcribe and translate it. Is that what you're saying, for months?

   8. POPaul Offit39:53

      The mRNA will amplify itself in the cell, true.

   9. PAPeter Attia39:57

      Which cell? Epithelial cells? Like, which of my cells?

   10. POPaul Offit40:00

       Muscle cells. You'll be inoculated in your arm. It'll be the muscle cells and then to some extent also antigen presenting cells like macrophages, dendritic cells.

   11. PAPeter Attia40:09

       Okay, that's kind of interesting to think about because why would it show up in a throat swab? How is it making it all the way to the epithelial cells in my throat or in my nose or wherever?

   12. POPaul Offit40:19

       I guess I'm saying two different things. When you're naturally infected with SARS-CoV-2, that virus then reproduces itself over and over again, part in the back of your throat, and it makes infectious virus particles. It enters your cells, it re- it's transcribed, it's translated, and then it makes new virus particles. But what happens is it's only making new virus particles for about a week, and then it stops making infectious particles anymore. But you still have messenger RNA in the back of your throat. You can for months, which means the virus is still there. It's still in the cell. It's still making messenger RNA, but it's not making a whole virus particle anymore. That's weird. I don't know of any virus that does that. I'm not sure it says anything about the messenger RNA approach. I mean, messenger RNA does amplify itself in, in your body, but then it's quickly broken down, as is all messenger RNA in your body. It'll be curious to see what happens with this. I mean, we're gonna learn a lot with this strategy. We'll see whether it applies to other vaccines, possibilities, and we'll see whether or not we run into a problem.

   13. PAPeter Attia41:14

       Moderna that you mentioned

9. 41:15 – 48:30

   The Moderna and Pfizer mRNA vaccines: strategy, timeline, and Emergency Use Authorization

   1. PAPeter Attia41:15

      is obviously one of the front runners in this, and I think that's in no small part to the fact that one of their partners is NIH. That's, you know, National Institutes of Health here in the United States has bankrolled to the tune of about a billion dollars, as you said. Has NIH partnered with anyone else besides Moderna?

   2. POPaul Offit41:30

      No, just Moderna. It's their construct that Moderna uses. The nucleoside analogs that are used in that vaccine, that was all developed by a couple researchers at the National Institutes of Health. Actually, National Institutes of Health, as far as I know, holds the patent on that vaccine.

   3. PAPeter Attia41:43

      And they basically entered phase three this summer, correct? I mean, I think they're fully enrolled, aren't they?

   4. POPaul Offit41:49

      They entered the end of July. As far as I know, they're fully enrolled, but it's hard to know. I mean, it's always trying to read the tea leaves on this, these trials.

   5. PAPeter Attia41:56

      Okay. Anyone else on the mRNA strategy that you think is... I mean, Moderna is probably the leader, correct?

   6. POPaul Offit42:03

      Moderna and Pfizer, both.

   7. PAPeter Attia42:05

      Let's talk a little bit about the Pfizer platform. How does it differ?

   8. POPaul Offit42:09

      Whereas Moderna gives 100 micrograms per dose in a two-dose series, Pfizer gives 30 micrograms. So it's not the same nucleoside analogs. And I'm curious to know, I'd love to hear a scientific presentation on why Pfizer needs to ship and store at minus 70, which is gonna be a challenge as compared to Moderna's shipping and storing at minus, just at minus 20. They are different constructs, so they're given at different amounts, and we'll see to what extent any of them work or are safe.

   9. PAPeter Attia42:35

      Now, Pfizer is doing a phase two, phase three combined. Is that correct?

   10. POPaul Offit42:39

       They sort of all are. I mean, you sort of went right, sort of skipped through phase two right to phase three really. They all did that.

   11. PAPeter Attia42:47

       Do you think that that distinction, Paul, from a logistics standpoint is going to matter? In other words, when we start to think, let's just assume for a moment that the Moderna vaccine and the Pfizer vaccine have equal efficacy in the real world. So in a phase three trial, we see, call it a 70% reduction severity of infection in those receiving the vaccine over the placebo. Would we agree that that's a win?

   12. POPaul Offit43:11

       Yes.

   13. PAPeter Attia43:12

       Okay. All other things being equal, is the need to transport tens of millions of doses of something basically in liquid nitrogen going to pose a challenge?

   14. POPaul Offit43:24

       So it won't be in liquid nitrogen, but it will be on dry ice. Is that gonna pose a challenge? Yes. I think what worries me in this a little bit is that when you do the studies, which Pfizer's doing and Moderna's doing, you can be comfortable that the companies are very good at overseeing the shipment and storage of that product, and they're making sure that the investigators, they've got the special package in which this vaccine is stored. They're constantly maintaining dry ice. That doesn't worry me. And when it's thawed out and put in the refrigerator, it can only be there for a day. When the vaccine then gets distributed to the, the world under natural conditions or the United States under natural conditions, how is it going to be distributed? Probably at least in part in like large chain pharmacies. Are the pharmacists gonna be as good at doing what was done during the trial? Because certainly, as you said at the beginning, I mean, these are, mRNA is labile, and if it degrades, and it certainly has the capacity to degrade, will we get less efficacy, effectiveness of the vaccine in a real world situation than we did in a, uh, experimental situation?

   15. PAPeter Attia44:21

       Yeah. I guess TBD. Your best guess of how those companies are signaling when we're gonna see data? I mean, it depends in large part on how active the third wave of this is because this is one of those things where the more people that get exposed, the more quickly we see the difference between the placebo and the vaccine.

   16. POPaul Offit44:46

       The company technically doesn't know what's going on [laughs] in the trial. I mean, technically the company, meaning the CEO, for example, doesn't know who's gotten vaccine, who's gotten placebo, doesn't know who's gotten sick and who hasn't gotten sick, doesn't know how many cases of disease have occurred in placebo group or vaccine group, doesn't know that. The Data Safety Monitoring Board does knows that, which is composed of a group of academics and researchers who are not affiliated with the company and not affiliated with the government.

   17. PAPeter Attia45:10

       These are being run through large CROs, I assume?

   18. POPaul Offit45:13

       Yes. Depends on who's doing it, but yes.

   19. PAPeter Attia45:16

       For the listener, clinical research organizations, when large companies or even academics do clinical trials, they usually contract out with companies that are exceptional at all the stuff that Paul's talking about, which is the logistics of how do you actually ship this thing from A to B and make sure it goes perfectly? How do you get the blood draw on this person and measure this and all these things? And so that's not an expertise that a company wants to build in-house. They typically outsource that, and it's those companies that are-- it's a part of that is the monitoring. But presumably, there's a power analysis that's gone into this that said, "Look, we're gonna enroll 30,000 people. We know half of them are gonna get a placebo, half of them are gonna get an active agent. We've stratified on some level by age." The inclusion criteria probably says, "We want people between ages X and Y of a certain... This many of them to be of this health, this many of them to not be of that health. We think the exposure risk at this stage of the virus is, meaning at this life cycle of the virus, we think there's this many more people that can be exposed. The R nought is something." Do you think that they can at least back into a, an answer which says, "Hey, by February, we should know this, good or bad"? Or is that simply something that just can't be known a priori?

   20. POPaul Offit46:27

       My hope is that these companies do what was recommended actually by the NIH active group that was put together by Francis Collins, which is it depends on whether it's a one-to-one or two-to-one trial, meaning two vaccine recipients for every one placebo recipient or one-to-one. But if that's true, you need at least around between 147 and 160 people to get sick in the trial in order to be able to say you can so-called reject the null hypothesis. The null hypothesis is this vaccine doesn't work. To reject the null hypothesis is to say, "I have statistically significant, robust evidence that says it does." You need 90% confidence interval [laughs] to be able to say that. You need about 150 people. Now, their Data Safety Monitoring Board, they're looking all the time, in real time, so they know when they feel you've met a safety or efficacy standard, and then they call the company, and they say, "Okay, now you can submit this vaccine." What would be for a typical vaccine, which is not this vaccine, you can submit it for licensure with a biological license application. That's not these vaccines. These vaccines are all going to be permitted for use under emergency use authorization. It's different, and that, I think, is what scares people at some level because they saw what happened with, for example, hydroxychloroquine, which didn't work, now has been shown clearly not to work to treat or prevent disease, yet it was approved under EUA, or convalescent plasma, which is to say antibodies taken from people who've survived the infection, which again, was heartily approved by the [laughs] FDA through this emergency use authorization also with no evidence that it worked. What's weird about this is that people are doing the same kinds of trials they would do for any vaccine, large placebo controlled trials, yet it's still not gonna go through a biological license application mechanism. It's going through EUA.

   21. PAPeter Attia48:09

       Just because of time?

   22. POPaul Offit48:10

       I think it's because the FDA would not typically license a product that was studied for this short a period of time. So yeah, because of time.

   23. PAPeter Attia48:16

       Can you just explain to people what the EUA is? I guess by now most people have heard the term Emergency Use Authorization. It's been granted to not just medications, but frankly to even testing modalities. "Oh, this serology test just got EUA. This PCR test just got EUA."

10. 48:30 – 52:15

    Paul’s confidence level in the safety of the first coronavirus vaccines

    1. PAPeter Attia48:30

       What does it actually mean?

    2. POPaul Offit48:32

       It's a permission to use something, which is to say that even though there aren't clear data showing that something is safe or effective or that it's a diagnostic, it clearly works well, we're going to allow it under this condition because we're under duress with this COVID-19 pandemic, so we're going to put it out there with the hopes that it works. I actually wrote an op-ed piece that I submitted to The Philadelphia Inquirer yesterday that I just heard before this show that is gonna be published, I think, on Sunday. On the Philadelphia Inquirer. But the point I'm trying to make in that piece is that how big of a risk are we taking? If we're gonna be studying these vaccines for four months, five months, six months, and we're gonna be putting them out there into millions and arguably tens of millions and hundreds of millions of people, are we taking a risk? And I think in terms of effectiveness, you're only gonna know that a vaccine is effective for a few months. You don't know whether it's effective for nine months or a year or two years. You don't know that. I don't think that's a huge risk. I think it's likely that it's effective in the short term. It's probably effective in the somewhat longer term. I don't think it's gonna be effective for decades, but I think it's likely to be effective at least for a year or two or three, I think. I mean, we'll see. And worst case scenario, you could give a booster dose. That would be the worst case scenario. But then safety, which is what everybody worries about. I mean, have you really studied it enough to say whether it's safe? I'm on the FDA's Vaccine Advisory Committee. We had our meeting on October twenty-second, and that dominated the meeting. That nine-hour meeting was dominated by the FDA's basically asking us, "Are you comfortable as a committee allowing use through EUA, knowing we're not gonna have a certain amount of data?" What you'll have basically is you'll have two-month follow-up after the last dose for safety issues. Is that enough time? Personally, I think the answer is yes. I do. I mean, if you look at the serious side effects that vaccines occasionally cause, like polio caused by the oral polio vaccine, which occurred in one in two point four million doses, or narcolepsy, a disorder of wakefulness that was caused by the squalene adjuvanted flu vaccine that was given in Europe, not in the United States, which occurred in roughly one in fifty-five thousand doses. Thrombocytopenia, lowering the platelet count that occurs with measles-containing vaccine, which occurs in one in twenty-five thousand doses, or something called viscerotropic disease, which is basically a sort of multi-system disease caused by the yellow fever vaccine. It's basically yellow fever caused by the yellow fever vaccine, which occurs in about one in a million doses, or Guillain-Barré syndrome, which is this ascending paralysis which can affect your ability to breathe, that occurs in about one in a million doses of the influenza vaccine. How soon did you know that? I mean, how soon did you know about those serious problems? Did you know about them within two months? And the answer is yes. I was on a CDC conference call yesterday with a group of folks that are associated with the Advisory Committee for Immunization Practices, and we collectively could not think of a serious side effect that was not picked up after two months. So I'm optimistic that that would happen here as well.

    3. PAPeter Attia51:16

       When you think of all of the different types of vaccines, we just talked about the mRNA vaccine, we'll get to sort of the viral vectors, the inactivated or attenuated variants, and then obviously just the proteins that are delivered. I wanna go through these in some detail and use it as an exam to talk about the companies. Are there any of those classes you worry about more than others from a risk standpoint? For example, some of the live attenuated viruses have been the ones that go on to cause... Isn't polio's live attenuated, correct?

    4. POPaul Offit51:43

       The oral polio vaccine was a live attenuated viral vaccine, yes.

    5. PAPeter Attia51:46

       Right, and so that's presumably why you had, even though it was a minuscule risk, you still had some risk of getting polio. So do you look at those four categories of vaccines equally from a safety question?

    6. POPaul Offit51:58

       I'm not sure we know enough about mRNA, DNA, replication defective human or simian adenoviruses to say. Here are the things that I worry about, though. I worry that you've had three clinical holds for these vaccines. You have one clinical hold with Johnson & Johnson's product, which was, is a replication defective

11. 52:15 – 55:45

    The risks associated with different types of vaccines, and updates on the Johnson & Johnson and Astrazeneca coronavirus vaccines

    1. POPaul Offit52:15

       adenovirus twenty-six. So adenovirus is a virus, human virus that causes a variety of clinical diseases. Type twenty-six just means it's one of the many types of adenovirus, human adenoviruses that cause disease. Replication defective means that the virus has been genetically engineered so it can't reproduce itself, but it has also been genetically engineered so it contains the gene that codes for the coronavirus spike protein, so that when you're inoculated with that vaccine, the cell takes up that particle, which does not amplify itself. It enters the nucleus, it then, uh, is transcribed, it's transcribed to messenger RNA, the messenger RNA is translated to a protein, and that protein is excreted. So it's good news, bad news. The good news is it's replication defective, therefore it can't cause disease because the virus is reproducing itself. The bad news is it's replication defective, meaning you have to give a lot of virus to get enough of those virus particles into the cell to make the protein you're interested in. About ten billion virus particles per dose. That's a lot of virus. That's why it is that side effect profile can be a little rough, meaning fever, including high fever, and then symptoms associated with fever, chills, headache, muscle ache. And that was seen fairly commonly, especially after the second dose, with these vaccines.

    2. PAPeter Attia53:23

       Which is also part of the issue with some of the genetic engineering stuff. This is a little off topic, but the use of adenoviruses for genetic engineering even twenty years ago at, at CHOP, right? I mean, that's a big part of what kinda got into some of the trouble there, isn't it?

    3. POPaul Offit53:35

       Yes. [chuckles] That's it. I mean, I'm at Penn, so we're all thinking the same thing, which is Jesse Gelsinger.

    4. PAPeter Attia53:41

       Gelsinger, yeah. God, I still remember that story like it was yesterday. It's gotta be at least twenty years.

    5. POPaul Offit53:46

       He was inoculated with a replication defective adenovirus type five that included the gene that coded for one of the liver enzymes that he was missing. He was missing a gene that allowed him to take the ammonia that is a consequence of protein metabolism and excrete it from his body. So the ammonia would build up in his body, and then he would get very sick and go into a coma occasionally. So but he died. I mean, he died because he had a massive cy- so-called cytokine response with something called interleukin six at a time before we had antibodies directed against interleukin six that would have saved his life, and we all lived through that, and it really set gene therapy back. If it's any consolation, the amount of replication defective adenovirus that he got was logarithmically greater, exponentially greater than the amount that we're currently giving here. Even though ten billion sounds like a lot, it's still about one three-hundredth of what he got. But again, you're going into an outbred population with, when you put something into millions of people, you may find something out that's untoward. So yeah, that worries me. The clinical holds worried me a little bit. The two clinical holds that were for the replication defective simian adenovirus, which was the UK AstraZeneca vaccine, were both because of neurological issues. The first was so-called undiagnosed multiple sclerosis The second was transverse myelitis, which is an inflammation of a segment of the spinal cord. The mechanism by which both of those diseases happen is the same, which is that you make an immune response really to the sheathing of your nerves, and particularly one protein of the sheathing of your nerves, myelin basic protein. Multiple sclerosis is relatively common, but transverse myelitis isn't. That occurs in maybe one in 200,000 in the general population. That trial was about 18,000 people big at the time, which is to say 9,000 people got vaccine, and they saw that case. It was adjudicated to be likely to be coincidental and not causal, but it does worry you a little bit that... 'cause it certainly was a statistical bizarrety, and you'd like to know what the problem was with Johnson & Johnson's vaccine, which you don't. This is the problem with these things.

    6. PAPeter Attia55:42

       And they're both in the same class, right?

    7. POPaul Offit55:44

       They're both

12. 55:45 – 57:15

    What we know about the coronavirus vaccines approved in Russia and China

    1. POPaul Offit55:45

       replication defective adenovirus.

    2. PAPeter Attia55:46

       Yeah, exactly. While we're on that topic, aren't these the same classes that were actually approved in Russia and China? Doesn't Russia and China each have something that they've approved for limited use already in this category?

    3. POPaul Offit56:01

       Yeah. So China had a replication defective Ad5, adenovirus type 5, which they actually had approved for use in the military. I'm not sure to what extent they've done it, 'cause it seems they've gone in the other direction now and are looking just at a inactivated viral vaccine. That seems to be their focus now.

    4. PAPeter Attia56:15

       Yeah, I was gonna say, do we have any data? I mean, not that we would have any data from China necessarily, but we don't know how many people received that outside of, I mean, in actual clinical use and if there's been any other safety defects noted, I mean.

    5. POPaul Offit56:27

       I have heard they have given it to tens of thousands of people, but what I haven't heard is the results of the phase three [laughs] trial, so I, I'd like to see whether or not it actually works, would be nice to see. And then the Russian, the Gamaleya Research Institute in Moscow, has also replication defective adenovirus vaccines, and also is a two-dose vaccine, but the first dose is replication defective Ad5, the second dose is replication defective Ad26. That's their vaccine. Vladimir Putin came out in the end of August and said, "We are going to now start giving this to our public, the Russian public. We have checked all the boxes," which near as I could tell [laughs] at the time was doing a small phase one trial. They hadn't even started doing phase three trials yet. So I'm not sure what's going on in Russia. It's hard to know what's going on. I know that I got a call from a Venezuelan reporter who said that that Russian vaccine had been shipped to Venezuela for use, so I don't know what's going on out there.

13. 57:15 – 57:45

    The latest on the Merck coronavirus vaccine

    1. POPaul Offit57:15

       But you really would like to wait for phase three trials to at least prove safety and efficacy at some level before you start giving it to the general population.

    2. PAPeter Attia57:22

       The other big player here is Merck, although they're a step behind, right? They're mostly phase one at this point. Do they have a candidate that has made it through phase one yet?

    3. POPaul Offit57:30

       I've heard of two candidates. One is the replication competent vesicular stomatitis virus, which although reproduces itself in your body, doesn't really cause disease. That's what they used for their Ebola vaccine. That was Merck's Ebola vaccine. Um, but they also apparently are, are interested in using their measles vaccine virus as a

14. 57:45 – 1:02:00

    The recombinant/purified protein vaccine approach for coronavirus—big players, risks, and the best vaccine for the elderly

    1. POPaul Offit57:45

       vector for this as well. So I haven't seen any data yet.

    2. PAPeter Attia57:48

       But again, just summarizing where we are, we've got Moderna and Pfizer as the big guns on the mRNA front. We've got Johnson & Johnson and then AstraZeneca with Oxford as the big guns on the adenovirus/viral vector front. Is that fair?

    3. POPaul Offit58:04

       Yes.

    4. PAPeter Attia58:04

       As the leaders. Okay. So then the next sorta category is, let's just give you the protein off the virus itself. Let's just rip off a spike protein, give you a whole bunch of them, and when your body sees those, it's not gonna be threatened by them. I mean, it's gonna be threatened appropriately to make an immune response, but obviously the protein by itself can't hurt you because it has no genetic material with which to take over your cells. As a general rule, how does that strategy work when you think of other non-coronavirus applications?

    5. POPaul Offit58:33

       Right. So it's the strategy we use to make the hepatitis B vaccine, with which we have had experience since the '90s, early '90s. It's the strategy we use to make the human papillomavirus vaccine, which has been on the market since mid-2000s, around 2006. It's the strategy we use to make one of the influenza vaccines, so-called Flublok, which has also been around for years. You have the comfort at least of having a lot of commercial experience with that strategy. They're made using recombinant DNA technology, so in the case, for example, of the hepatitis B vaccine or the human papillomavirus vaccine, you take a yeast plasmid, which is just a small circular piece of DNA. You clone into that the gene you're interested in, which as we've said now a million times [laughs] on this show, the coronavirus gene, the codes for the coronavirus spike protein. You then sort of transfect that into yeast cells, actually just common baker's yeast, and as the baker's yeast reproduces itself, it also makes that protein, which you purify. In the case of Flublok, which looks like it's closer to the strategy that's being used by Sanofi, a GSK collaboration, there what you do is you take, uh, basically an insect virus, so-called baculovirus. You clone into it again the gene that you're interested in, the coronavirus spike protein gene, and then you infect insect cells, and then that protein actually forms rosettes as it's excreted from the, the cell. That's the way you make Flublok, which I actually got this year as my influenza vaccine, and I'm still alive.

    6. PAPeter Attia59:50

       That's quadrivalent?

    7. POPaul Offit59:51

       It's quadrivalent, yeah.

    8. PAPeter Attia59:53

       So you mentioned obviously Sanofi, GSK. That's one of the big guns. They're not in phase three yet, are they? They're gonna start that next month?

    9. POPaul Offit1:00:01

       Novavax is the other one that does purified protein approach, those two.

    10. PAPeter Attia1:00:05

        And Novavax is in phase three.

    11. POPaul Offit1:00:07

        That's what I, I heard, yeah.

    12. PAPeter Attia1:00:09

        Yeah, but GSK, Sanofi is next month for phase three.

    13. POPaul Offit1:00:13

        Novavax was enrolling in November. They've started, and Sanofi was starting to roll in December, so should be soon.

    14. PAPeter Attia1:00:20

        Is there anything about this approach that tends to go really wrong? Me not being a virologist and not knowing much about vaccines, of the three approaches we've discussed so far, I guess the four, 'cause we've already alluded to what the fourth strategy is, which is a live attenuated virus, the protein-based delivery seems the most benign. Is that necessarily true?

    15. POPaul Offit1:00:43

        I think that's fair. It's just a purified protein. Certainly we have a lot of history, decades' worth of history doing that approach successfully. If you look at Shingrix, which is, again, a purified protein, it's just one of the proteins from varicella zoster virus, that vaccine actually works better than the live attenuated viral vaccine, Zostavax. And it, essentially it's replaced Zostavax

    16. PAPeter Attia1:01:04

        We basically two years ago said we're done. It's 100% switched to Shingrix now. Shingrix rather, yeah

    17. POPaul Offit1:01:10

        Which is amazing. I mean, you know, typically, historically, live attenuated viral vaccines always work better than a single protein. The difference was the adjuvant. Shingrix has two powerful adjuvants

    18. PAPeter Attia1:01:21

        Which we sort of separate, I think, by like six months or something?

    19. POPaul Offit1:01:24

        No, no, they're all part of that vaccine. So one is monophosphoryl lipid A, the other is the so-called QS twenty-one. That's all part of the varicella zoster virus glycoprotein E has these two adjuvants that are all part of the vaccine.

    20. PAPeter Attia1:01:35

        Oh, I see. But we give Shingrix in two... Is the second one just a booster?

    21. POPaul Offit1:01:40

        You give two dose, right? It's the same thing. It's the same. It's both contain the same.

    22. PAPeter Attia1:01:44

        Understood. Okay.

    23. POPaul Offit1:01:45

        The adjuvant that's being used in the Novavax product is actually similar to the adjuvant in the Shingrix product. So you wonder if you had to take a guess, maybe this would be the vaccine that would be best for older people because that vaccine works remarkably well in older people, Shingrix does.

    24. PAPeter Attia1:01:57

        So this brings us to our fourth category then, which

15. 1:02:00 – 1:02:30

    Attenuated and inactivated vaccine strategies for coronavirus

    1. PAPeter Attia1:02:00

       again, we've talked about, which is these attenuated or live attenuated vaccines or inactivated vaccines. Now, this is something where I think China has a number of products in the pipeline. I don't believe that there... Is there a European or American counterpart in this space?

    2. POPaul Offit1:02:16

       Not that I know of. It looks like all the inactivated vaccines are coming out of China, and they've done a lot with it. You could argue that could be the first vaccine that is commercially available, if you will. The first one to have a clear phase three trial, at least you should for

16. 1:02:30 – 1:06:45

    The genetic drift of SARS-CoV-2: Impacts for protection and vaccine development

    1. POPaul Offit1:02:30

       my understanding for how much many people have been immunized in China already.

    2. PAPeter Attia1:02:35

       So let's talk a little bit about some of the other things that are going on here. We, I think, I have to be honest, I'm very surprised. I think in March of this year, I did not think it was plausible that there would be a vaccine on the market within a year. In fact, I probably would have used the words impossible if you said to me in March, "Can there be a vaccine in a year?" And by the way, that wasn't just based on the financial thing. I mean, when I asked you that question earlier, Paul, you alluded to how the government financially completely de-risked the operation, and I won't diminish that in any way, shape, or form. I just didn't think it was going to be, from a manufacturing standpoint, possible enough to make enough GMP stuff at volume and actually put it into clinical trials. I was like, "There's no way. Like, there's no way in 12 months we can get there." Well, it turns out I was wrong. We're probably going to have vaccines on the market by January. So let's start with a question about genetic drift. What do we know about how much the genome of this thing is moving?

    3. POPaul Offit1:03:43

       So it's a single-stranded RNA virus, and like all single-stranded RNA viruses, its replication isn't terribly faithful. Or said another way, it probably mutates to some extent every time it reproduces itself. The critical question is, does it mutate in a manner that causes a functional change? And by functional change, I mean more or less contagious or more or less virulent, or from the standpoint of the vaccine, does it mutate away from the vaccine so that immunization or natural infection one year doesn't protect you the following year, which is the influenza story. Influenza is also a single-stranded RNA virus, segmented RNA virus. But measles is a single-stranded RNA virus too, so is mumps, and they have different genotypes, meaning that there is drift, as you say, to cause there to be different strains, but never has measles really changed its serotype. So the vaccine that worked in 1963 still works today. And so the question is, which of those is it gonna be? This virus gonna be influenza-like or is it going to be measles-like? I'm gonna predict, I'm happy to make a series of predictions as long as you don't hold me to them. I would say that I'd be surprised, although the virus continues to surprise, it is going to be more than a single serotype disease. In other words, that a vaccine that works now could well work next year and the year after that.

    4. PAPeter Attia1:04:55

       Let's just make sure everyone understands what you said, 'cause you said a lot of interesting and important stuff there. Single-stranded RNA is, to put it mildly, a little sloppy. That means every time this guy reproduces itself, it makes a little bit of a mistake. Sometimes those mistakes don't mean anything. Sometimes they do. It's yet to be determined. There's two things at least that matter with respect to the fidelity with which it can reproduce. One is, does it change the properties of how the virus responds, either making it less toxic to us as humans or more toxic or pathogenic to us as humans? I think it's definitely too early to say if that's happening one way or the other. But the second property about its ability or inability to replicate itself perfectly is if it makes so many changes in its replication cycle, it might look so different year after year after year that our immune system, even if able to maintain robust immune cells that recognize the virus, may functionally be duped by it because it looks so different each year. That's why we get flu shots every year and we get MMR once, even though they're both single-stranded mRNA viruses. You're basically saying if you had to guess, this is going to be between them, so it's not gonna be changing so dramatically every year that we would need to go through this exercise annually. Is that what you're saying?

    5. POPaul Offit1:06:19

       Yeah, I'm gonna predict actually it's gonna be more measles-like, that it's not going to drift in, in a manner that is, means that the vaccine no longer works. That'll be my prediction, but I have been wrong about this virus before.

    6. PAPeter Attia1:06:31

       The good news is, I mean, I think we're getting to about a year on this thing, and I think the virus we're seeing today does not look meaningfully different from that which was identified in January, so hopefully that speaks in your favor. Do we have a sense of

17. 1:06:45 – 1:13:00

    Paul’s take on the hypothesis that a previous coronavirus infection offers protection against the novel COVID-19

    1. PAPeter Attia1:06:45

       how these vaccines are working at the real molecular level? Obviously, we love to look at immunoglobulins as a proxy for immune response, so, hey, this generated IgG and IgM. But there's been a lot of talk about the solubility of those things, and are those immunoglobulins actually active? Just because they're present, do they actually have the binding capacity to the virus to actually eradicate it? Of course, there's been a lot of talk about T cells and how some people might be getting A less aggressive version of COVID because perhaps they had some T cells that recognized a separate virus, a separate coronavirus that they may have had six months sooner. What's your thinking or what's the latest thinking on those hypotheses and ideas?

    2. POPaul Offit1:07:32

       This virus, SARS-CoV-2, is essentially a bat coronavirus that just reared its head in Wuhan in the middle of November of last year and now has swept across the world and made its debut in the human population. We are infected with human coronaviruses all the time. I mean, there are four strains of human coronaviruses that circulate. They were first identified in the early 1960s. They were no doubt circulating well before that. They cause respiratory infections, meaning congestion, cough, runny nose, occasionally more severe disease, pneumonia. They account for probably about fifteen to twenty percent of the diseases that we see in our emergency department or in our hospital every year, and that's pretty much invariant. The question is because the human coronaviruses do share some similarity to this bat coronavirus, which is recognized by so-called helper T cells, does your previous experience with human coronavirus, which we pretty much all had, mean something to us in terms of protecting us against this virus? I don't think so is my sense of it. In terms of what works, I mean, I guess I'm very simplistic on this based on my experiences with rotavirus. I think the trick is keeping the virus from binding to cells. It's really the way the measles vaccine works, the way the mumps vaccine works, the way the rubella vaccine works, the way the varicella chickenpox vaccine works. If you can prevent the virus from binding to cells, you can prevent the virus from entering cells. So when you make antibodies, are those antibodies directed against the so-called part of the spike protein, the receptor binding domain of the spike protein that is neutralizing the virus? We wanna neutralize the virus. You don't wanna just bind to the virus. You wanna neutralize it so it can't attach to cells, and that's the business end of the SARS-CoV-2 spike protein is that so-called receptor binding domain. So that's the question. And the other question I think that people are worried about is that antibodies can fade over time, even after a natural infection. So what does that mean for a vaccine if antibodies fade? And this is a little complicated, but when you're inoculated with a vaccine or when you're naturally infected with a virus, it's not just that you make antibodies. You induce immunological memory. So you have memory B cells, the kind of cells that make antibodies, or memory T cells. And so they're sort of like the base of the iceberg with the antibodies being the tip of the iceberg. Do they matter? They do matter, especially for longer incubation period diseases. So for really short incubation period diseases like rotavirus, meaning the time from when you're infected to when you get sick, rotavirus, influenza, respiratory syncytial virus, those have short incubation periods. This is sort of a medium length incubation period, around six, seven days. Measles is much longer, sort of ten to fourteen days. For longer incubation period diseases, there's enough time then for activation and differentiation of memory cells to become, in the case of B cells, antibody secreting cells. So it still would work. I think that's where we're gonna be. So I think memory is important. So when people talk to me about how nervous they are that antibodies are fading, I'm not sure you should be nervous about it yet. Let's wait to see what happens as we move forward with these vaccines.

    3. PAPeter Attia1:10:23

       Yeah, I think that's a great point, Paul, and I think there's really two points you made there that speak to that. The first is it's not antibodies that probably matter, it's neutralizing antibodies, and frankly, we don't have commercial tests for that. So I don't know how much it matters that your serology test that's measuring IgG and IgM levels over time is changing when that's not actually or certainly not necessarily the thing that we care about. We care about neutralizing antibodies, not antibodies. Your second point is just spot on, which is unless somebody is sampling bone marrow looking for B cells that have memory, again, maybe this doesn't matter, and we at least if there's one upside to having the long incubation period, which has allowed this silly virus to replicate like crazy and spread around the world, at least it's that the immune system gets some chance to rev up against it. I guess I always think of it that way. Like, biology usually takes something and gives something, right? [chuckles] It's like if this thing had no time between when you were infected and when you got sick, you'd probably get sicker because you wouldn't have any of that memory response, but at least it would have been contained. We sort of have the opposite problem. That's a glass half full way to look at this, I suppose.

    4. POPaul Offit1:11:34

       Let me offer one thing just as hopeful because, you know, as you get older, you get sort of grimmer, but I'm gonna try and offer some hopeful thing. But it appears that, especially in men, there were two papers in science that showed that when you're infected with this virus, SARS-CoV-2, that you can actually make antibodies directed against interferon, which is a protein that your body's immune system makes to help fight viruses. That's where the name comes from. It interferes with the ability of virus to infect cells. And the thinking is that that may be one reason why men are more likely to suffer and die from this disease than others. This offers hope for the fact that a vaccine may be better than natural infection because it's unlikely that the vaccine would do that. There certainly are examples of vaccines that are better than natural infection. This may be one of them. So there's some reasons for hope here.

    5. PAPeter Attia1:12:17

       Do you see any differences in male versus female in vaccine, or do you think no? I mean, there's nothing that has been published to date that has suggested a gender disparity between this.

    6. POPaul Offit1:12:27

       No. As a general, men tend to die and boys tend to die at a greater frequency than girls for most infectious disease. We are the weaker sex. Or as Murphy Brown used to say, "That silly little Y chromosome."

    7. PAPeter Attia1:12:40

       Do you think that's a response to a greater cytokine response, or what do you think accounts for that difference?

    8. POPaul Offit1:12:46

       I'm not sure.

    9. PAPeter Attia1:12:47

       Even when we age match and we match for morbidity, we don't know why?

    10. POPaul Offit1:12:52

        We're the weaker sex. Let's admit it.

    11. PAPeter Attia1:12:53

        [chuckles] Bit off topic, blood type. There was a lot of talk earlier about anti-A

18. 1:13:00 – 1:13:15

    Blood type and protective against coronavirus

    1. PAPeter Attia1:13:00

       antibodies potentially being a little bit protective. Do we have more data on that?

    2. POPaul Offit1:13:03

       Hadn't seen it. I-- So the, the, you know, the having type O blood would be some level protective 'cause you can make antibodies to A or B types. I think I would still put that in the hypothesis unproven category.

    3. PAPeter Attia1:13:14

       Okay.

19. 1:13:15 – 1:16:15

    Distribution: the challenge of prioritizing the limited doses of vaccines after approval

    1. PAPeter Attia1:13:15

       Do we have any data on the robustness of the immunologic response, at least based on phase two metrics in different demographics, starting with young versus old, obese versus non-obese, or some other metric where it's going to matter, because at some level there's going to need to be some rationing of this, right? It's not like vaccine gets approved on Wednesday and on Thursday three hundred million copies of the vaccine show up to everybody's doctor. So whether we like it or not, there's a slow roll and a partition to how this happens. What do we know about it in that sense, in terms of how people are responding to it, and who's most vulnerable and who should be getting it?

    2. POPaul Offit1:13:56

       Both the National Academy of Medicine and the Advisory Committee for Immunization Practices at the CDC have come up with their first tier group, but it's huge. I mean, the first tier group includes healthcare workers. It also includes other essential personnel, like people who work in mass transportation or grocery stores or pharmacies or work in law enforcement or sort of water purification. That includes people over 65, who when they get infected are more likely to die. That includes people with certain high-risk medical conditions like obesity, which is probably 30% of the American population, and diabetes and chronic obstructive pulmonary disease, et cetera. If you add that all up, it adds up to about 150 million adults, which is half the adult population in the United States, which who are gonna require a two-dose vaccine, which is already 300 million doses, and that's not gonna happen immediately. So how do you partition that? I don't know. I mean, I'm on this Commonwealth of Pennsylvania group that tries to make decisions like that. I'm on our hospital group to try and make decisions like that. I think it's gonna be a real learning curve that's associated with how this rolls out.

    3. PAPeter Attia1:14:59

       What are we prepared to do about that? Is this gonna produce social unrest? It sounds crazy, but have we ever experienced something like this from a healthcare delivery standpoint?

    4. POPaul Offit1:15:09

       No. I mean, this is a virus that's killed 230,000 people, so this may be sort of like the end of the movie Contagion, where people are, like, breaking down doors trying to get a vaccine, where vaccines were the hero of that story. I think there is going to have to, at some level, be a rationing in terms of who gets what and how it's gonna be done, and I don't know.

    5. PAPeter Attia1:15:28

       It's really complicated, right? So Moderna is basically the NIH, Pfizer, J&J, AstraZeneca, and Oxford, I mean, these companies have presumably never been in a situation to have to say, "Here's where this shipment goes to this pharmacy versus that pharmacy or this city versus that city." I mean, not to dwell too long on a seemingly strange question, but we're not that far from when this is going to happen. We're only a couple months away from that potentially.

    6. POPaul Offit1:15:56

       So it's the Department of Defense that's gonna take the lead at Operation Warp Speed for determining where these vaccines get distributed, but they'll be distributed to the states, and then the states, I think, will decide how to sort of apportion that, is my sense of it. The CDC initially had sort of four states and one city, which was Philadelphia actually, to try and do kind of this

20. 1:16:15 – 1:19:15

    Paul’s perspective on COVID-19 vaccine safety

    1. POPaul Offit1:16:15

       test program for how it would be distributed. Now, Pfizer is not an Operation Warp Speed vaccine, so they may have a different distribution strategy. But I think you're right. It's gonna be a real challenge. Plus it's a two-dose vaccine, plus you, it means you have to get people back for the second dose, and it's gonna, some of these vaccines are gonna be stored at minus 70. It's gonna be really a challenge to see how we get it out there. I mean, we had one issue in our hospital which was easily resolved, which was should we mandate the vaccine for hospital workers? No. One, for the practical reason that we probably won't have a lot of vaccine, and two, I think that with a novel vaccine strategy like messenger RNA or these replication-defective viruses, I don't think you really can fairly mandate that. I think you really should wait till it's out there a little more. There's gonna be plenty of people who are gonna be perfectly willing to take these vaccines, and then we'll have a few million doses out there and we'll have a better sense of things. Maurice Hilleman, who I consider the father of modern vaccines, having either done the primary research or development on 9 of the 14 that we use, said it best. He said, quote, "I never breathe a sigh of relief until the first three million doses are out there." So we'll see.

    2. PAPeter Attia1:17:18

       Personal question, would you take the vaccine right now?

    3. POPaul Offit1:17:21

       Not till I see the data. The good news, I'm on the FDA Vaccine Advisory Board, so I will see the data, and if I feel confident that the safety issues look good, issues look good for people my age, I mean, I'm over 65. I wanna feel I'm adequately represented in these trials.

    4. PAPeter Attia1:17:36

       At a sample size of 30,000, of which let's say a third of them are over 65, would 10,000 people over 65 having no adverse effects in three months make you feel comfortable enough to take it?

    5. POPaul Offit1:17:50

       I think it would, yes.

    6. PAPeter Attia1:17:52

       Okay, and I'm gonna point something else out to the listener who can't see you. You at least look to my eye as a very healthy 65-year-old. You look like you're about 55. You're not overweight. I assume you don't have diabetes. You look like a model of health. So are you really that high risk aside from your age, and if so, why are you taking it?

    7. POPaul Offit1:18:12

       Just my age.

    8. PAPeter Attia1:18:13

       Okay. So do you still believe that age by itself is enough of a predictor of morbidity beyond the obvious comorbidities that tend to track with age that presumably, at least, let's just assume you don't have them. Not that I'm asking you to disclose any medical things, but you're about as healthy a 65-year-old as there's gonna be out there.

    9. POPaul Offit1:18:32

       I would take it not because I necessarily think I'm gonna die from this virus. It's because I think that way I feel between taking a vaccine and wearing a mask and social distancing, I dramatically decrease having to suffer this virus. I mean, the virus, yes, it's a killer, and yes, it can cause pneumonia, which can kill you. What scares me the most about this virus is that it can cause vasculitis. I mean, who would've predicted that? It causes this multi-system inflammatory disease of children, and it can affect, it can cause heart attacks, it can cause strokes, it can cause liver or kidney disease because it causes vasculitis. So why does it cause vasculitis? It doesn't really enter the bloodstream. Fewer than 1% of people infected with this virus have so-called viremia. So it induces your immune response to damage endothelial cells

21. 1:19:15 – 1:21:45

    Addressing the concern that antibodies fade over time

    1. POPaul Offit1:19:15

       that line blood vessels, and because every organ in your body has a blood supply, every organ can be affected. I mean, the so-called long haulers, at least in part, are probably determined by a, a vasculitis maybe even at low level. That's what scares me about this. This is not a virus that just gets in, kills you, and, and gets out, or gets in, makes you sick, and gets out. There are longer term effects with this virus, and it should be taken seriously. I mean, I think when the administration occasionally says things like, "We need to embrace this virus," or live with kind of, you know, this kind of notion that the virus would eliminate itself by population induced immunity, which has never happened for a virus before, I think they sort of ignore the fact about the long-term measures of this particular virus. Like, this isn't flu.

    2. PAPeter Attia1:19:53

       I think of all the sort of lingering tail events of this virus, the one that probably concerns me the most is some of the cardiomyopathy that we're seeing persist in, especially in young people. On a personal level, I've just had to strike a balance between living my life but still trying not to be reckless. And to me, that's a really bad outcome, right? Is, is the probability that I'm going to die from this low? Yeah, it's staggeringly low, but there's some risk that I can't quantify of cardiomyopathy or some lingering respiratory thing that never fully resolves that impairs quality of life. I guess the real question is just the trade-off between how efficacious in the real world, and therefore, I guess effective is the better word, do I think this vaccine is relative to what other risks? I think what I'm hearing from you that I actually find heartening is at least using history as a guide within a few months of this vaccine coming out and entering the real world, which we can think of as phase four. We'll think of that as post-market surveillance phase four. We're gonna have a pretty good sense of it, and most of us listening to this podcast are not gonna be the guys getting it on day one just due to the simple logistics of it. Like, I'm not gonna be in the first million doses of this vaccine. You aren't gonna be in the first million doses of this vaccine. There are people, frankly, who are at much higher risk that deserve to be there, and I guess we'll have a better sense of it. But I think that this discussion for me, Paul, is also interesting 'cause it really frames the four different types of strategies that one can go about doing this, who the players are, and what the risks are potentially in each of them, and why maybe a Sanofi product ultimately might end up being safer than, say, a, a J&J product. The devil's in the details, and the only thing that's gonna matter [chuckles] is, "Hey, how do these things

22. 1:21:45 – 1:36:05

    Considerations regarding vaccinating children for coronavirus and the role of a fever immune response

    1. PAPeter Attia1:21:45

       look six months after they've been on the market?" The other thing I wanted to ask you about is, is there ever gonna be a time when we're gonna be immunizing children against this virus? I mean, what do we know today about kids getting infected by this?

    2. POPaul Offit1:22:00

       We know that children are less likely to be infected, and when they're infected, are less severely infected. I mean, of the people less than 21 years of age in the United States make up about 26% of the population, yet they account for 0.08% of the deaths. That said, about 120, at least the last morbidity mortality weekly report showed that about 120 children had died from COVID-19. That's not very different than the number of children that died from influenza last year, which was around 140. And that's what it usually is, around anywhere 140, 150, 160, in that area. So it's no more or less fatal than influenza for children. Two, can cause long-term problems in children with the so-called MISC disease of children. So I think there isn't a compelling desire to make a vaccine for children. So how to do that? Now, all the trials initially were done in people over 18, so we weren't studying children initially. Now recently, Pfizer sort of dropped the age to 16, and they've dropped the age to 12, so they're starting to look at younger people. So the question is then what happens, and this is applies broadly, what happens if a vaccine is approved through EUA? Pfizer's already said if that happens for them, they're gonna start to immunize their control group, which means now you lose information about safety and efficacy moving forward.

    3. PAPeter Attia1:23:13

       Why is that, Paul? Is that basically as a thank you to the control group and basically a crossover?

    4. POPaul Offit1:23:19

       Look at what that does.

    5. PAPeter Attia1:23:20

       From a scientific standpoint, you just lost your test case, but what is the rationale for doing that?

    6. POPaul Offit1:23:26

       I think it's a thank you for being the... And that may have been part of the deal when they signed up for the trial. I don't know.

    7. PAPeter Attia1:23:30

       Yeah. Got it. Okay.

    8. POPaul Offit1:23:32

       To get to the children, this could be done in one of two ways. It could be done as a placebo-controlled trial. It's the same way we do adults. Or it could be done as immuno-bridging studies, meaning that you actually find out there is an immunological correlative protection in adults, that it is a certain level of neutralizing antibodies that's, that's evoked, and that if you give to children a certain dose, that you find that you get that level of neutralizing antibodies, and so then you just move forward. And then you look retrospectively because not all children will be inoculated at the moment that you start inoculating children. You can see whether or not it's productive. It's basically the same way that it worked with the Ebola vaccine. I mean, that wasn't a prospective placebo-controlled trial unless I... People just started getting vaccine, and because not everybody got it at once, you could get a sense of effectiveness by knowing who got the vaccine and who didn't. So that may be it. When we had the FDA Vaccine Advisory Committee meeting October 22nd, the FDA was very clear about this, that when you approve something under emergency use authorization, which is the same sort of permission you would give to an investigational new drug, you are really under no ethical obligation to vaccinate a placebo group. You aren't. And nor are you under an ethical obligation to no longer do placebo-controlled trials. Now, I'm not sure how that's gonna play out. I mean, you can see, for example, if somebody's 70 years old, they see that this vaccine works, and they were in the placebo group, they can say, "I want this vaccine." So what the FDA has argued for is why not just make it an expanded access issue or extended access, which is what used to be called compassionate use access, but do it that way, and I think that may be the way this plays out. I don't think I'm making a bold prediction by saying I think the first vaccines may not be the last best vaccines, but you have to know that you have the last best vaccines. You have to know that down the line there may be a vaccine that's 90% effective, and you can't know that unless you do it as a placebo trial. And again, if you're gonna do it with the other vaccine as a trial, the thing, that would require a huge trial. I mean, really Or you'd be hard to prove it

    9. PAPeter Attia1:25:19

       You actually wrote an interesting paper this summer about the role of fever in fighting infection in children. I was really surprised at the results, and I gotta tell you, it's kinda changing the way I think about how much Tylenol I kick around the house. You wanna talk a little bit about what that paper showed while we're on the topic of kids?

    10. POPaul Offit1:25:41

        Right. I actually wrote a book called Overkill: When Modern Medicine Goes Too Far, and, and that's the first chapter, sort of in defense of fever, that treating fever can prolong or worsen illnesses. And, and the reason is, is that pretty much everything that walks, crawls, flies, or swims on the planet can make fever. Why do we do that? We do it because our immune system actually works better at a higher temperature. It's not because viruses or bacteria die more quickly at a higher temperature. It's because your immune system works better. B cells make antibodies more efficiently. Neutrophils or white blood cells that form pus can travel to areas where bacteria are and kill bacteria more efficiently. So if that's true, if your immune system works better at a higher temperature, then are there studies done showing that people who are given anti-fever medicines like Tylenol or ibuprofen, do they do worse? And the answer is redundantly yes. And in the world of vaccines, when people choose to treat fever with, uh, anti-fever medicines when they've gotten a vaccine, you have a lesser immune response. I mean, over and over again, this has been shown, yet we just can't help ourselves because we want people to feel better, or we want ourselves to feel better. But know this, that you are hurting one part of your immune system when you do that.

    11. PAPeter Attia1:26:49

        Is there a danger at some point, Paul, of kids having fevers when the temperatures get too high? I mean, I always feel like that's the one thing that scared the hell out of medical students or residents was you'd see those kids with febrile seizures, and so you have that image in the back of your mind of that kid in the ER that's seizing, and then God forbid they go on to have some neurologic consequence. And so you're sort of hardwired to think, "Well, God forbid I'm ever gonna let a child have a fever again." What's the risk of that, and at what temperature is that something that a parent needs to be aware of?

    12. POPaul Offit1:27:20

        So so-called febrile seizures are benign. I mean, my daughter actually had a febrile seizure. They're generally short-lived. They don't have long-lasting sequelae. And it's not the height of the temperature. It's the rapid rise in temperature that causes that, so it's not the height. And for the most part, I would say for the most part, I think physiological fevers don't cause harm. Your body's not interested in hurting you in that way. Now, environmental fevers can. Heatstroke. I mean, the laborer or the athlete or the soldier who's out there in heavy gear and on a hot day and is not able to dissipate heat through sweating, they can suffer strokes. I mean, it's, you know, you can die from heatstrokes. In fact, about six hundred people die from heatstrokes every year. So environmental fevers can do that, but not physiological fevers. So again, I think you jump with the net. It's just very hard to watch this. A case actually in our hospital, the boy, the soccer player was hit on the hip. He had a clot in a vein, so-called thrombosis, and then had that got infected, so-called thrombophlebitis with staph, the MRSA, the sort of hard to treat staph, traveled to his brain and caused abscesses. It traveled to his lungs and caused abscesses. It traveled to his bone and joint and caused abscesses. We were treating with an antibiotic, vancomycin, that should have treated that, but he was continually positive, had po- blood cultures that continued to show he was shedding bacteria. And every day, every two hours, we were rotating, you know, either Tylenol or ibuprofen. Finally, I met with the boy, I met with the parents, I met with the nurse, and I said, "Stop treating his fever. Just give his body a chance to have every part of his immune system working for him." And then within really about a day and a half, he was no longer shedding bacteria. That may have been a complete coincidence. It's not a proof in any sense. But you couldn't convince the parents of that. They thought we were geniuses by doing it that, that way. Give his immune system a chance to work as good as it can. Why cripple his neutrophils ability to ingest and kill bacteria by giving him anti-fever medicine? We think we're helping.

    13. PAPeter Attia1:29:01

        Is there any scenario then, Paul, in which... I mean, that's a pretty compelling case. Is there any scenario under which you would recommend taking something like Tylenol?

    14. POPaul Offit1:29:08

        I think if somebody cannot handle the metabolic strain of increased update, I mean, 'cause you increase your basal metabolic rate, a certain percentage for every degree centigrade increase in your fever. I think it's like twelve percent increase in BMI for every degree centigrade. But so if you have chronic lung disease, chronic heart disease, metabolic disease that makes you unable to handle that rise in temperature, sure, I think that's a reason. But otherwise, no.

    15. PAPeter Attia1:29:30

        Wow. So suffer it out, huh?

    16. POPaul Offit1:29:33

        Yeah, and that's that boy. I love this boy. He was, he's a teenager, a young teenager, and he, he was just brave. He was, "Okay, fine." Everybody was in. We were gonna do this thing, and nurses were in. We were gonna ride it out, and then he did better.

    17. PAPeter Attia1:29:46

        All right. Last thing I want to say on vaccines, just to kinda close the loop on this, are there viruses besides the obvious like HIV and even Hep C, I guess, where just vaccinating them is either impossible or outright dangerous? I mean, there was something about RSV, which we've talked a little bit about, that, I mean, RSV is really common, but there's no vaccine to RSV. Is that just that it's not cost effective, or was there sort of a, a more technical issue with it or a risk associated with creating vaccine towards it?

    18. POPaul Offit1:30:14

        B, more technical issue of creating a vaccine. There were two events that occurred in the nineteen sixties. One was with RSV, where, um, Bob Chanock, head of the Laboratory of Infectious Diseases at NIH, wanted to make an RSV vaccine. This is a virus that causes pneumonia. It causes about five thousand deaths every year in the United States, primarily in young children, especially premature children, babies. So let's make an RSV vaccine. He took the virus, grew it up, inactivated it with formaldehyde, the same way that Jonas Salk made his polio vaccine, and then gave it to babies. And what he found was the children who got that vaccine did worse. They were more likely, when they were then exposed to the natural virus, they were more likely to develop, uh, pneumonia, more likely to be hospitalized, in the case of two children, more likely to die than children who never got that vaccine. Same thing happened with the measles vaccine in nineteen sixty-three. Take the virus, grow it up, kill it with, purify it, kill it with formaldehyde. That too caused children to have an aberrant immune response directed against that measles virus that causes atypical pneumonia. So they were more likely to get pneumonia than children who were never vaccinated. That was ultimately taken off the market. The reason that may be relevant to today, to SARS-CoV-2 today, is that both of those virus, or viruses, respiratory syncytial virus and measles have a fusion protein. That's how it attaches to cells. It fuses to cells. So does SARS-CoV-2. It has a fusion protein. So people are always a little nervous about an inactivated vaccine And it's because you sort of change the conformation of that protein, that SARS-CoV-2 protein, so it didn't really look like it looked on the natural virus. So that's always in the back of people's minds with fusion proteins. So you asked me earlier what sort of safety things I'm worried about. That actually is one of the safety things.

    19. PAPeter Attia1:31:47

        And that would be more of a concern, I'm guessing, with the live attenuated virus as opposed to the other three classes? Or would you still worry about that in the mRNA and the viral vector viruses?

    20. POPaul Offit1:31:59

        I worry about it with all of them. You worry that the conformation as made in under these conditions, mRNA or DNA or replication-defective virus or whole killed virus or recombinant DNA-generated proteins, that it's different. It's critically different than the way it sits on the virus surface.

    21. PAPeter Attia1:32:14

        Paul, this is a unbelievably fascinating discussion. I'm glad I waited on this. You and I were gonna speak a couple of months ago. Obviously, for so long I've wanted to have a deep dive on the vaccine stuff, but I feel like this was the right time to do it, at least to be able to speak about it with more clarity and to really be able to say, "Look, by the time someone's hearing this, we're really on the cusp of these vaccines being out there in early '21," but it's not a switch. It's not a binary thing. It's not like we're going from no vaccines to everybody gets vaccines, and there's perfect information, and there's no risk. This is analog in delivery, analog in risk. [chuckles] I mean, it's analog in pretty much everything other than approval.

    22. POPaul Offit1:32:56

        Yeah. I think we're gonna learn a lot. Thanks for asking me. I enjoyed this, really. I, I don't think I've ever done a podcast this long, but it was definitely fun. And the fact that I thought when you said two hours, I thought, "Oh my God, two hours. Am I gonna live through this?" It really flew. Uh, you know, just surprising.

    23. PAPeter Attia1:33:10

        Well, I appreciate your time and your willingness to sit down for so long, Paul.

    24. POPaul Offit1:33:14

        My pleasure. Thanks for asking me.

    25. PAPeter Attia1:33:16

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Episode duration: 1:36:05