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

Hey everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in depth content. If you want to take your knowledge of this space to the next level, at the end of this episode, I'll explain what those benefits are. Or if you want to learn more now, head over to peterattiamd.com subscribe Now without further delay, here's today's episode. 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 of with 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 kind of defined 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 release releases and approvals of various vaccines. And so I'm really glad that actually we waited until this time because 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 basically what we go into. I mean, we certainly talk about Paul's background, which is fascinating, 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, 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 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. 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 want to 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 ultimately even being a pediatrician. Can you share a bit of that? Sure.

So I was born with clubbed feet, which means that my feet turn sort of inward and down. Typically, that's treated with casting. So I was casted in the first few hours of life, really. And then, so for months I was casted, but it seemed to work. I mean, my feet seem to straighten out. But at the age of five, my father decided that he didn't like the way that my heel didn't. Oh, 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 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 club foot 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, 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 Crnan Children's Hospital. Although I think then it may have been called 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. The 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 our lungs, some in traction. And there was one visiting hour week, that was it. Sundays from 2 to 3. 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. Thus was 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. Seeing myself the same way. And I remember looking. There was up. My bed was next to a window. This was when you had one visiting hour a week, polio day. So people were scared to death of having anybody else come into that hospital. Sundays from 2 to 3, it was 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 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.

That facility is still there, isn't it?

Yeah, Cornell. Anson Children's Hospital is still there.

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.

I remember as a student then walking. I was at Merrill Medical School, but I remember walking up to that window and looking out of it and seeing that front door and, you know, I. 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 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 this. 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.

We're going to 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 90s 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. 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? 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?

Yeah, I guess I felt come out on the angry side. I think Andrew Wake 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. 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.

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 was no measles virus whatsoever in any of the colons of or distal ileums of any of those children.

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 meas. That was Andrew Wakefield. Brian Dear just wrote a book called the Doctor who Fooled the World, which goes through all this.

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 95%?

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 going to 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. He was a darling of the anti vaccine. 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 where Cooper just destroyed him.

Yeah, yeah, it was great. So at some level he helped us. Marginalized to some extent the voices that were the anti vaccine voices, Barbara Fisher, Jeff Schwartz, J.B. hanley, et cetera, had a much bigger Voice I think 20 years ago, 15 years ago, than they do now. Because I think mainstream media anyway has chosen to set them aside. 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 18 times in seven different countries on three different continents. The question has been asked and answered. I do think, according to a study done by the Autism Science foundation, about 85% of parents who of 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.

Yeah, it's interesting. There aren't many things in medicine we can say with a higher degree of certainty. Actually then 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 is overwhelmingly convincing that it does not. But I think the data are more convincing than 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 18 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 because 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.

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 was a charlatan of the first order because he took advantage of parents desperate desire to do something for their children.

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.

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 containing vaccine also was a cause of inflammatory bowel disease. And he was wrong. And he admitted he was wrong and then he went on to the next thing where he was wrong but didn't admit he was wrong.

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 COV2 was a known entity. What were you working on?

I spent 26 years of my life working on creating the strains of virus that became the bovine human reassortant vaccine rototech. That was my 26 year effort. Before that was done, about 2000, we created the Vaccine Education center at Children's Hospital of 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 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. Virus.

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?

Rotavirus is a virus that affects the small intestine. It causes fever, vomiting and diarrhea, primarily in children between 6 and 24 months of age. In the United States. Before there was a vaccine, everybody would be infected by age 5. All children would be infected by age 5. It would cause about 75,000 children to be hospitalized in this country every year with severe dehydration or water loss. It would also cause about 60 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 500,000 babies a year. Typically children less than 2 years of age, about as many as 2,000 a day. So there was always a lot of interest in trying to make a vaccine to prevent it. That's where I came in.

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 going to 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 perhaps even parenteral nutrition if necessary. Is that the fundamental distinction?

The story that I tell is that there's a friend of mine who was a PhD in chemistry. She actually worked for a pharmaceutical company. Her baby got rotavirus infections. 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 an immune 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 whisked the child back into the treatment room. They were able to do a cut down a section 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 20 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.

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

It's double stranded segmented RNA virus.

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

The good news is when you're trying to make a vaccine, you want to 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 seventies. 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 charged 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.

And was that protection lifelong?

Paul no. Like many mucosal viruses, Rotavirus influenza virus, paraflu respiratory syncytial virus, those viruses which have generally short incubation periods, meaning time from your first infected to when you get sick, which generally don't have viremia as part of pathogenesis, their immunization or natural infection. Any immunization induces 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. COV2 I think that's going to be the same story here.

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

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

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 individual has when pursuing a vaccine? Or how did you guys problem solve around the different ways in which you could induce immunity?

The way we saw it was that rotaviruses are ubiquitous. Every mammal that walks the face of this earth has its own unique strain as a 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 generian approach, if you will, an Edward Jenner like approach. I mean, Edward Jenner basically used the cow virus to protect against human smallpox virus. So CALP 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 evoke neutralizing antibodies. That's what we proved. So then it was a matter of just constructing these combination viruses, 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.

What were the risks associated with the vaccine?

You don't know. Whenever you're dealing with something that's unknown is 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 1 and 10,000, and 1 and 30,000 recipients 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, it was known to be an animal pathogen in the forties. Veterinarian 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 in a ciception that would have never been predicted by all those studies.

Yeah, let me tell people what that is. So an inociception 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 Ana's sception 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 contraception could be a side effect here. And if it only occurs 1 in 10,000 cases, you're going to 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.

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 interception. So why would this be true? And the reason is, is that interception really appeared to be 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 interception, as was this vaccine. And I guess the COVID analogy is that here's a virus Covid for which we had at least 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 it's fair to say there's going to be a learning curve here. So there has to be real humility. I think as we move forward, 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 because 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?

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 babies, 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 20 to 100 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 20 to 100 people to see whether or not you can safely induce an immune response that you think is going to be protective based on your animal model work. Now you have a dose and a strategy.

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 institutional review board to do a phase one in the normal world, that takes how long usually?

I think probably it's fair to say 10 years, 15 years.

Okay, well, 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 20 to 40 people. Ish.

Yeah, 20 to 100.

We're not talking about 10,000 people.

No, no.

And these are often done with a little bit of a dose escalation built in. So maybe the first 10 people are going to get a really, really small dose. We make sure nothing catastrophic happens. We then escalate the next 10, et cetera. Right.

There are dose ranging trials. Exactly right. You go slow and you work your way up to see what seems to consistently induce an immune response and that is safe.

The third thing I want to highlight there is we are 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?

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 challenges. It was true in your animal models. You won't know that until you get to phase three.

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?

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 induced 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.

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, it's efficacy. We don't know if it's effective. And we don't really have any way of knowing what very minor, or I shouldn't say minor, infrequent negative consequences could look like because we're still dealing with a very small sample size.

That's exactly right.

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

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 70,000 babies, 35,000 got the vaccine, 35,000 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 stage 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 found out that it works.

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, but I generally say that's 20 years and $1 billion. And that's usually on the drug side. Is it about the same on the vaccine side?

Yes. 15 to 20 years with at least a billion dollars. That's right.

So let's now talk about coronavirus. And just understand that In January of 2020, when the sequence of the RNA identifying this as a novel pathogen, a Coronavirus named now SARS CoV2, 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 going to take 20 years and a billion dollars, that's not a very appealing strategy because it basically says it has to be hard 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?

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 Varda, 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 in January. That's remarkably fast. It's unimaginably fast. But it's the government that did that, so give credit to them.

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?

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 set it another way, infectious. That protein is the spike protein. It's the protein that emanates from the surface of the virus. It 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 your body makes the pro, the spike, the coronavirus spike protein. Then your body makes antibodies to the spike protein. This very similar strategies the so called DNA vaccines and then these so called replication defective sim, human adenovirus vaccines or replication competent vectored vaccines all have the same strategy in mind, which is introduce the gene that codes for the coronavirus 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 going to be the last best vaccines, but that's why they're going to be the first vaccines. Vaccines.

One question I have for you on that, Paul, is given the instability of rna, I've always been kind of 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?

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, I've burned myself on said vats of liquid nitrogen many a time in the lab. Yeah.

So to get around that problem, these vaccines, the messenger RNA vaccines, have to be in 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 going to 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. But you're right, I think the lability of messenger RNA will be 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 a week, you'll be PCR positive, polymerase chain react positive, you can 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.

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 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, the MRNA will amplify itself in the cell. True.

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

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.

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?

I guess I'm saying two different things. When you're naturally infected with SARS CoV2, that virus then reproduces itself over and over again hard in the back of your throat, and it makes infectious virus particles. It enters your cells, 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 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 going to 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.

Moderna that you mentioned is obviously one of the frontrunners in this, and I think that's in no small part to the fact that one of their parts 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?

No, just Moderna. It's their construct that Moderna uses, the nucleoside analogues 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.

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

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

Okay, anyone else on the MRNA strategy that you think is, I mean, Moderna is probably the leader, correct?

Moderna and Pfizer both.

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

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 going to 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.

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

They sort of all are. I mean, you sort of went right, sort of skip through phase two, right to phase three. Really? They all did that?

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?

Yes.

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?

So it won't be in liquid nitrogen, but it will be on dry ice. Is that going to 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 is 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 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 going to 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 experimental situation?

Yeah, I guess. Tbd. Your best guess of how those companies are signaling when we're going to 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.

The company technically doesn't know what's going on 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, of disease of occurrence. Placebo group or vaccine group doesn't know that. The Data Safety Monitoring Board 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.

These are being run through large CROs, I assume.

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

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 going to enroll 30,000 people. We know half of them are going to get a placebo, half of them are going to get an active agent. We've stratified on some level by 8. 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 naught is something do you think that they can at least back into 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?

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 to be able to say that. You need about 150 people. Now the 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 biologic license application. That's not these vaccines. These vaccines were 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 survived the infection, which again was heartily approved by the 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 going to go through a biological license application mechanism.

It's going through EUA just because of time.

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

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. What does it actually mean?

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 unless 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 going to be published. I think it's 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 going to be studying these vaccines for four months, five months, six months, and we're going to 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 going to 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 going to 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. I'm on the FDA's vaccine advisory committee. We had our meeting on October 22nd and that dominated the meeting. That nine hour meeting was dominated by the FDA is basically asking us are you comfortable as a committee allowing use through eua, knowing we're not going to 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 1 in 2.4 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 1 in 55,000 doses. Thrombocytopenia, lowering the platelet count that occurs with measles containing vaccine, which occurs in 1 in 25,000 doses. Or something called viscerotropic disease, which is basically 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 Barre 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? 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.

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 want to go through these in some detail and use it as an example 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 polio's live attenuated. Correct.

Your polio vaccine was a live attenuated viral vaccine. Yes.

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, 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 adenovirus 26. So adenovirus is a virus, human virus, that causes a variety of clinical diseases. Type 26 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 is transcribed. It's transcribed to messenger rna. The messenger RNA is translated to a protein, and that protein is then 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 effective, 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 10 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. Seen fairly commonly, especially after the second dose with these vaccines, 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 20 years ago at chop, right? I mean, that's a big part of what kind of got into some of the trouble there, isn't it?

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

Gelsinger, yeah. God, I still remember that story like it was yesterday. It's got to be at least 20 years.

He was inoculated with a replication defective adenovirus type 5 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. But he died. I mean he died because he had a massive so called cytokine response which with something called interleukin 6 at a time before we had antibodies directed against interleukin 6 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 10 billion sounds like a lot, it's still about 1/300th of what he got. But again, you're going into an outbread 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 of active 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, and particularly one protein on this evening of your neurosmyelin basic protein. Multiple sclerosis is relatively common, but transverse myelitis is that occurs maybe 1 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 because it certainly was a statistical. And you'd like to know what the problem was with Johnson and Johnson's vaccine, which you don't. This is the problem with these things.

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

They're both replication defect of adenovirus.

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?

Yeah. So China had a replication effect of 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 because 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.

Yeah, I was going to 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 an actual clinical use. And if there's been any other safety defects noted.

I mean, 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 trial. So I'd like to see whether or not it actually works. Would be nice to see. And then the Russian, the Gamaliel Research Institute in Moscow has also replication defective adenovirus vaccines and also as 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 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. 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.

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

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 use for their Ebola vaccine. That was Merck's Ebola vaccine. But they also apparently are interested in using their measles vaccine virus as a vector for this as well. So I haven't seen any data yet.

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 and Johnson and then AstraZeneca with Oxford as the big guns on the adenovirusviral vector front. Is that fair? Yes, as the leaders. Okay, so then the next sort of 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 system immune. 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?

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 used to make the human papillomavirus vaccine, which has been on the market since mid 2000, around 2006. It's a strategy we used to make one of the influenza vaccines, so called flubl, 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 on the show, the coronavirus gene that 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 Flubloc, which looks like it's closer to the strategy that's being used by Sanofi GSK collaboration there. What you do is you take basically an insect virus, so called bacalovirus, 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 cell. That's why you make Flubloc, which I actually got this year as my influenza vaccine, and I'm still alive.

That's quadrivalent.

It's quadrivalent, yeah.

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

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

And Novavax is in phase three.

That's what I heard, yeah.

But gsk, Sanofi is next month for phase three.

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

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, because we've already alluded to what the fourth strategy is, which is a live attenuated virus. Virus, the protein based delivery seems the most benign. Is that necessarily true?

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 Faricella Zostra virus, that vaccine actually works better than the live attenuated viral vaccine Zostavax. Essentially it's replaced that.

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

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

Sort of separate, I think by like six months or something?

No, no, they're all part of that vaccine. So one is monophosphorolipid A, the other is the so called QS21. That's all part of the varicella zoster virus. Glycoprotein E has these two adjuvants that are all part of the vaccine.

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

You give two dose. Right. It's the same thing. It's both contain the same thing.

Understood. Okay.

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 Shingrix does.

So this brings us to our fourth category then, which 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?

Not that I know 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, vaccine that is commercially available, if you will, the first one to have a clear phase three trial. At least you should. For my understanding for how much. Many people have been immunized in China already.

So let's talk a little bit about some of the other things that are going on here. 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?

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 going to, this virus going to be influenza like, or is it going to Be measles, Like I'm going to 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.

Let's just make sure everyone understands what you said, because you said a lot of interesting and important stuff there. Single stranded RNA is, to put it mild, 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, 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 are basically saying if you had to guess, this is going to be between them. So it's not going to be changing so dramatically every year that we would need to go through this exercise annually, Is that what you're saying?

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

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 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?

This virus, SARS CoV2, 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're 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 15 to 20% 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 bad 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 vaccinate vaccine works, where the mumps vaccine works, Bella vaccine works, where the varicella chickenpox vaccine works. If you can prevent the virus from binding your 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? You want to neutralize the virus. You don't want to just bind to the virus, you want to neutralize it so it can't attach to cells. And that's the business end of the SARS CoV2 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 natural infections. So what does that mean for a vaccine if antibodies fade, and this is a little complicated, but when you are 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 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 synthesis, virus, those have short incubation periods. This is sort of a medium length incubation period, around 6, 7 days. Measles is much longer, sort of 10 to 14 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 going to be here. 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.

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. 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 or sort of have the opposite problem. That's a glass half full way to look at this, I suppose.

Let me offer one thing just as hopeful because as you get older you get sort of grimmer. But I'm trying to 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 CoV2 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 a vaccine would do that. There certainly are examples of vaccines that are better than natural infection. This may be one the of. There's some reasons for hope here.

Do you see any differences in male versus female on 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.

No. As a general rule, 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.

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

I'm not sure.

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

We'Re the weaker sex.

Let's admit it bit off topic, blood type. There was a lot of talk earlier about anti A antibodies potentially being a little bit protective. Do we have more data on that?

I hadn't seen it. Having type O blood would be some level protective because you can make antibodies to A or B types. I think I would still put that in the hypothesis unproven category.

Okay. 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, 300 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.

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. 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 water purification. That includes people over 65 who when they get infected, are more likely to die. And it 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, etc. 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 going to require a two dose vaccine which is already 300 million doses. And that's not going to 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 going to be a real learning curve that's associated with how this rolls out.

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

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 going to be done.

And I don't know, 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 to going going to happen. We're only a couple months away from.

That potentially so it's the Department of Defense that's going to 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 in one city, which was Philadelphia actually, to try and do kind of this 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 going to be a real challenge. Plus it's a two dose vaccine, plus it means you have to get people back for the second dose. And it's going to. Some of these vaccines are going to be stored at minus 70. It's going to 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. 1, for the practical reason that we probably won't have a lot of vaccine. And two, I think that with the 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 going to be plenty of people who are going to 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 nine of the 14 that we use, said it best. He said, quote, I never breathe a sigh of relief until the first 3 million doses are out there. So we'll see.

Personal question. Would you take the vaccine right now?

Not until 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 want to feel I'm adequately represented in these trials.

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?

I think it would, yes.

Okay. And I'm going to 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 just my age?

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 going to be out there.

I would take it not because I necessarily think I'm going to die from this virus. It's because I think that way I feel between, 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 have predicted that it causes this multi system inflammatory disease of children and it can affect, it can cause heart attacks and 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 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 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 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 issues of this particular virus. But this isn't flu.

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 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. 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 because 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 JJ product. The devil's in the details. The only thing that's going to matter is, hey, how do these things look six months after they've been on the market? The other thing I wanted to ask you about is is there ever going to be a time when we're going to be immunizing children against this virus? I mean, what do we know today about kids getting infected by this?

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 MIS C disease of children. So I think there is 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 dropped the age to 12. So they're starting to look at younger people. So the question is then what happens? And this 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.

Why is that, Paul? Is that basically as a thank you to the control group and basically a crossover look at what that does from a scientific standpoint? You just lost your test case. But what is the rationale for doing that?

I think it's a thank you for being. And that may have been part of the deal when they signed up for the trial.

I don't know. Yeah, got it. Okay.

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 can 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 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 basically the same way that it worked with the Ebola vaccine. I mean, that wasn't a prospective placebo controlled trial in West Nap. 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 22, 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 investigation of new drugs. You were really under no ethical obligation to vaccinate a placebo group. You aren't. And nor are you under ethical obligation to no longer do placebo controlled trials. Now, I'm not sure how that's going to play out. I mean, you can see, for example, if somebody is 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, 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 going to do it with the other vaccine as a trial, the thing that would require a huge trial, I mean, really, you'd be hard to prove it.

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 kind of changing the way I think about how much Tylenol I kick around the house. You want to talk a little bit about what that paper showed while we're on the topic of kids?

Right. You 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 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 anti fever medicines, when they've gotten a vaccine, you have a lesser immune response 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.

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 going to 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?

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 height for the most part, honestly most. I think physiological fevers don't cause harm. Your body's not interested in hurting you in that way. Now environmental fevers can heat stroke. 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 heat strokes. In fact, about 600 people die from heat strokes every year. So environmental fact, fevers can do that, but not physiological fevers. So again, I think you jump with a note. It's very hard to watch. This a case actually in our hospital, the boy 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 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 nano antibiotic vancomycin that should have treated that, but he was continually positive, had 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 a boy, I met with the parents, I met with a 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, there's no longer shedding bacteria. That may have been 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 way. Give his immune system a chance to work as good as it can. Why cripple his neutrophil's ability to ingest and kill bacteria by giving him anti fever medicines? We think we're helping.

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?

I think if somebody cannot handle the metabolic strain of increased. I mean, because you increase your, your basal metabolic rate a certain percentage for every degree centigrade increase in your fever, it's like 12% 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 the reason. But otherwise, no. Wow.

So suffer it out, huh?

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

All right, last thing I want to say on vaccines, just to kind of 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. There's no vaccine to rsv. Is that just that it's not cost effective, or was there sort of a more technical issue with it or a risk associated with creating vaccine towards it?

B. More technical issue of creating a vaccine. There were two events that occurred in the 1960s. One was with RSV where 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 5,000 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 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 1970. 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 CoV2 today, is that both of those virus viruses, respiratory syncytial virus and measles, have a fusion protein. That's how it attaches to cells, it fuses to cells. So does SARS COV2. 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 confirmation of that protein, that SARS CoV2 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.

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?

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

Paul, this is an unbelievably fascinating discussion. I'm glad I waited on this. You and I were going to 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. Risk. I mean, it's analog in pretty much everything other than approval.

Yeah, I think we're going to learn a lot. Thanks for asking me. I enjoy this, really. I don't think I've ever done a podcast this long, but it was definitely fun. And in fact, I thought when you said two hours, I thought, oh my God, two hours. Am I going to live through this? It really flew. You know, it's just surprising.

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

My pleasure. Thanks for asking.

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Sam.