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

Episode Date: November 16, 2020

Paul Offit is a pediatrician specializing in infectious diseases and an expert in virology and vaccine development. He currently serves on the FDA committee overseeing and evaluating COVID-19 vaccines. In this episode, Paul discusses the strategies and major companies pursuing a vaccine against the SARS-CoV-2 virus. He gets into the nuances of the vaccine approval process and its implications for COVID-19 vaccine outlook. Paul also explains potential risks, reveals his own confidence level in safety, and gives insight into protection against reinfection with vaccination. Please note that this episode was recorded 11/05/2020, prior to the 11/09/2020 news release of the Pfizer vaccine update.   We discuss: How Paul’s experience as a child in a chronic care hospital as child informed his path in pediatrics and vaccine development (3:30); Addressing the anti-vaccination sentiment and explaining the fraudulent origins of the anti-vaccination movement (8:00); Lessons and insights from 26 years studying rotavirus and creating a successful rotavirus vaccine (17:00); Developing a new vaccine: the different phases of clinical trials, overall timeline, and financial costs (27:15); Operation Warp Speed: the expedited process of creating a coronavirus vaccine (32:30); Various vaccine strategies—RNA, DNA, virus vector—and the challenges associated (35:00); The Moderna and Pfizer mRNA vaccines: strategy, timeline, and Emergency Use Authorization (41:15); Paul’s confidence level in the safety of the first coronavirus vaccines (48:30); The risks associated with different types of vaccines, and updates on the Johnson & Johnson and Astrazeneca coronavirus vaccines (52:15); What we know about the coronavirus vaccines approved in Russia and China (55:45); The latest on the Merck coronavirus vaccine (57:15); The recombinant/purified protein vaccine approach for coronavirus—big players, risks, and the best vaccine for the elderly (57:45); Attenuated and inactivated vaccine strategies for coronavirus (1:02:00); The genetic drift of SARS-CoV-2: Impacts for protection and vaccine development (1:02:30); Paul’s take on the hypothesis that a previous coronavirus infection offers protection against the novel COVID-19 (1:06:45); Addressing the concern that antibodies fade over time (1:09:15); Blood type and protective against coronavirus (1:13:00); Distribution: the challenge of prioritizing the limited doses of vaccines after approval (1:13:15); Paul’s perspective on COVID-19 vaccine safety (1:16:15); Considerations regarding vaccinating children for coronavirus and the role of a fever immune response (1:21:45); Why vaccine development can be challenging and risks of current COVID-19 strategies (1:29:45); and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/pauloffit  Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

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Now, without further delay, here's today's episode. I guess this week is Dr. Paul Offett. 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. It's also a professor of vaccinology at the Prolimin 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 the ROTA virus vaccine as if all of the above were not enough. I 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 good and what was good. And I wanted to talk about the virus vaccine as if all of the above were not enough.

I 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 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 Boffe. 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 club feet, which means that my feet turn sort of inward and down. Typically that's treated with casting. So I was casted when the first few hours of life really. And then so for months I was casted, but it seemed to work. I mean, my feet seems 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 club foot surgery. He was able to find a guy who was a son of a friend of his who would just finish his residency in orthopedics and thought, great, I get to do this surgery, which went badly. My father was a shirt manufacturer.

Benison wasn't really his strength, but he didn't like the way that he'll hit. Interesting, his 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 with an OV. And when the guy, this physician saw me, he said, if you do nothing, don't operate on this foot. Nonetheless, my father insisted to 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 Crenance Children's Hospital. Although I think then it may have been called Crenance Hospital for crippled children when you could use words like crippled in feeble mind. I was there

for about six weeks. And this was the 1950s that Polio was king. And I remember just a lot of children in that word with polio. I was probably about 20 kids in the world, some in our long, some in traction. And there was one visiting hour week. That was it. Sunday's 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. Plus, it 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 and one of the fact they seeing myself the same way. And I remember looking, there was 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 two to three. It was like they had therapy dogs, or iPads, or televisions, or anything. You just pretty much lay 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 The hospital never happened When I was a Medical student at the University of Maryland we rotated through a cronant's children's hospital and that room was still there That wasn't a poly award anymore. It was a group of secretaries But that window was still there that fest wasn't a poly-award anymore. It was a group of secretaries, but that window was still there. That facility is still there, isn't it? Yeah, Chronant's in Children's Hospital 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. So I was a member member of the student then,

walk out of Neural Medical, but I remember walking up to that window and looking out of it and seeing that front door. And I cried. So I think that's it. I mean, I think that we are motivated by the scars of our youth. For me, a choice to go into pediatric, a choice to go into pediatric infectious diseases, a choice to write a book about polio, specifically about a sort of a tragic event associated with the making of the polio vaccine, a choice to make vaccines, I think,

enter the world of science and stuff. Probably all is motivated by the scars. Pretty much every book I've written at its hard child advocacy, at its hard 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 a fraud that was catapulted upon them in the late 90s and 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 wake field 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's story that started at that time. And frankly, on some levels, there's a solid number of people who continue to believe this, despite the efforts of people like Brian Deere 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

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 etc. Yeah, I guess I thought come out on the angry side I think Andrew wake was a fraud I think it's some level he was a knowing fraud. I mean he misrepresented clinical data he misrepresented biological data that paper should have never been published it was basically a story of 12 children, eight of whom had autism, presumably within a month of receiving MMR vaccine. When in fact, at least a couple of the children had developed signs and symptoms of autism before ever having received that vaccine, which he knew. He also, he had biopsies on all those children and presumably measles vaccine virus was supposed to be destroying intestinal epithelial cells. He had biopsies on those children. He never did 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 Deere has actually done a very good job uncovering. Those biopsies were done in process and the amount of virus that was found in them was identical to that which was found in basically the formal in itself, demonstrating that it was a pure contaminant. So actually, there was no mesol virus whatsoever in any of the colonns or distal iliums of any of those children. And I talked to a person who did some of the serology with Ander Wakefield for a meeting I had in England. And he refused

to be on the paper because he felt that Ander Wakefield had basically misrepresented sort of IGMI-G-Response, immunoglobulin responses to measles. That was Ander Wakefield. Brian Deere just wrote a book called The Doctor Who Fulled 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 totology 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 percent? 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, 100 legal claims to 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's great. So at some level, he helped us marginalize, to some extent, the voices that were the anti-vaccine voices, Barbara Lofischer, Jeff Schwartz, JB 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. I'm obviously their platform of social media, but so I think Wakefield in some ways helped decide me. We did the studies to answer the question whether you were more likely to develop autism through got the MMR vaccine or not. It'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 have children with autism no longer believe that vaccines were the cause. So I do think that that good science did win out to some extent. And I think Andrew Wakefield has lost that. He's now, you know, he goes on Alex Jones show. We're 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 than the MMR vaccine does not cause autism. If you really stop to think about it, Paul, do statins cause Alzheimer's disease. I think the data 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 Cahood's 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 nose bleed on Wednesday, had a fever on Thursday, and started banging their head 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 Suzy 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. He tried to really make the case that measles contained your vaccine also was a cause of

inflammatory bowel disease. It 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 double down and that's where really the frog got out of control. Let's take a step back to give people a bit of a sense of your work. What were you doing? What was a day in the life of Paul Offit a year ago, basically before SARS-CoV-2 was a

known entity? What were you working on? I spent 26 years of my life working on creating the strains of virus that became the bovine human re-assorting vaccine rotobacter. That was my 26-year effort. Before that was done, about 2000, we created the vaccine education center children's hospital, Philadelphia, which sort of creates and distributes educational materials to educate the press, educate the public, educate doctors about vaccines. So we can sort of meet this anti-vaccine movement, or at least the anti-vaccine sentiment that people have so that we can answer their questions.

What we're trying to avoid is are those children who suffer needlessly by not getting vaccines that would protect them? So that's been the passion. I mean, I think the passion for me came because I think I saw how hard it was to make a vaccine, how hard it was to prove that a vaccine was safe and effective, and how easy it was to damn them. That paper was awful. It 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. Let's talk a little bit about road virus. 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 H5. All children would be infected by H5. 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 two 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 subform and perhaps even parental nutrition if necessary. Is that the fundamental distinction? The story that I tell is that there was a friend of mine who was a PhD in chemistry, she actually worked for a pharmaceutical company. Her baby got some road-of-art 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 in a major traffic jam, which is why you get an ambulance. And so she was stuck and she was much longer to get to the hospital than she would have others. By the time she got to the hospital, the child was out of it. So they whisked a child back into the treatment room. They were able to do a cut-down essentially 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 a double-stranded segment at 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 the least moderate to severe disease. Then you know that you should be able to admit that part of the immune response is associated with that protection. Those studies were done in the 70s, actually, with Bishop published a paper showing that if you got a rotavirus infection in your first year of life, when you were then subsequently challenged with the virus, again, just naturally, you could get mild infection or you could get asymptomatic infection, but you wouldn't get moderate to severe infection.

The minute that paper was published, we thought, okay, we can make a vaccine. We just have to mimic that part of the immune responses associated with protection. And was that protection life long, Paul? No, like many of you coastal viruses, rotavirus, influenza virus, power flow, respiratory sensitive virus, those viruses, which have generally short incubation periods, meaning time from your first viruses, rotavirus, influenza virus, power flow, respiratory cinchal virus,

those viruses which have generally short incubation periods, meaning time from your first and effect that to when you get sick, which generally don't have varimia as part of pathogenesis. They're natural infection and immunization and do this protection that is short lived and incomplete, meaning decades and meaning protection against moderate to severe disease

but not mild disease. These are the mucocell viruses, which I think brings us to SARS-CoV-2. 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 mucusal service. We had to induce an antibody response that was active at the intestinal mucusal service,

which made us think it was gonna have to be an oral vaccine, which stimulated then immunity at the intestinal mucusal service and not a parental 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 in 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 rotovirus is our ubiquitous. Every mammal that walks the face of this earth has its own unique strength as a rotovirus. And species barriers are pretty high, meaning that a cow rotavirus or calf rotavirus would cause disease and calves, but not people. And vice versa, human rotavirus

is would cause disease and babies, but not calves. So we basically took advantage of that. It was a generic approach, if you will, an Edward-Gener-like approach. I mean, Edward-Gener basically used a cow virus to protect against human smallpox virus. So cow smallpox, essentially cowpox, would protect against human smallpox. So calp smallpox, essentially calpox would protect against human smallpox because they were

energinically related enough that immunization with one could protect you from a disease caused by it. Other, that was our approach. So, and that was our initial approach was just to take a calvirus, a calf virus, that it caused diarrhea, adapted 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 coated for the proteins that evoked what we found were neutralizing antibodies or two surface proteins of the virus. And we thought both independently evoked neutralizing antibodies. That's what we proved. So then it was a matter of just constructing these combination virus, so called reassorting viruses between calf and animal strains that became the vaccine. Thus summarizing 10 years worth of work in about 35 seconds, still 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, it's the calf viruses. Will they behave differently and people? Will they cause something that's on tour 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 that was made by National Institutes of Health

and Collaboration with Wyeth called Rotasheal, which was a simian rotavirus, that was also a recombinant virus, simian human reassort and rotavirus that was found to be a rare cause of interception, which is intestinal blockage. It occurred in depending on who you read between one in 10,000 and one in 30,000 recipients. It wasn't picked up pre-licensure because the studies would 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, road of ours had been studied for 50 years by that time. I mean, it was known to be an animal pathogen in the 40s, veterinarian study that we knew as 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 the side effect in a deception that would have never been predicted by all those studies. Yeah, let me tell people what that is. So an inesception 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 an assumption 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 into sepsion, could be a side effect here. And if it only occurs one 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 the surprise was that vaccine, which was sort of a semi-rhodivirus-based vaccine, that virus reproduced itself far less efficiently at the intestinal buccal surface than did

wild-type virus, natural virus. There was no evidence that natural rotivirus caused an exception. So why would this be true? And the reason is that an exception really appeared to be around phenomenon. It wasn't a winter phenomenon in the United States, which was what rotivirus was. You would expect't a winter phenomenon in the United States, which was what road virus 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 clinical and pathological surprises, which we are now about to counter with a series of vaccine strategies, 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 started so called preclinical studies. I mean, 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're unacculated 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 that part of the immune responses to associated with protection against child. 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 pre-clinical where you've now filed an IND and you now would be applying to, you know, institutional review board to do a phase one. In the normal world that takes how long? Usually. I think probably it's fair to say 10 years, 15 years. Okay, we'll make sure everybody keeps that in mind when we pivot to coronavirus. The other thing I want to highlight that you just said there is 20 to 40 people ish.

The 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, etc. Right? They're dose range and trials. Exactly right. You go slow and you work your way up to see

what seems to consistently induce immune response that is, and that is safe. The third thing I want to highlight there is we're not actually able to assess whether or not the people have legitimate immunity, we're using a proxy presumably, which is some form of serology. In other words, we're not actually testing their ability to resist an infection. We're measuring an antibody. Is that correct? 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 chancers. As 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 inducing an immune response that you think is protective and that it's at least safe and that it doesn't cause a relatively common, serious side effect. That's face to. 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, 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

thousand 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 zero on all those children, meaning we looked at the antibodies on all those children. Hopefully that would provide a clear immunological correlated protection, which it didn't. We knew that the vaccine worked, we knew there was safe,

and so we could submit it for licensure to the FDA. But as you go along, things are much more expensive. You go from sort of millions to tens of millions to hundreds and hundreds of millions, and then you mass produce the vaccine after you've found 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. 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-CoV-2 shows up, and by March, I guess it becomes pretty clear this is not going to be contained, which means any strategy

towards containment is going to fail. It became readily apparent that a vaccine was going to be 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 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 mind set 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 to how long will it take? What would you have said then? I would have said it was 10 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 the pharmaceutical companies. What the government said is both Varda, which is part of health and human services, the

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, it's a year and a quarter 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 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 and 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 in another way, infecting you.

That protein is the spike protein. It's the protein that emanates from the surface of the virus and gives it its crown-like appearance hence coronavirus. You also know the gene that codes for that protein. It's an mRNA virus, meaning messenger RNA virus, single stranded messenger RNA virus like rubel 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 and the cell side of plasma, outside the nucleus. It enters the so-called ribosomal system and is translated to a protein, which is excreted. So that says, your body makes the system and is translated to a protein, which is excreted. So, your body makes the spike, the coronavirus spike protein, then your body makes antibodies to the spike protein.

That's very similar strategies, the so-called DNA vaccines, and then these so-called replication defective, simine or human adenovirus vaccines, or replication competent vector vaccines, all have the same strategy in mind, which is introduce the gene that codes for the coronavirus spoke 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 gonna be the last best vaccines, but that's why they're gonna be the first 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 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 degree centigrade or in liquid nitrogen because as you say, it's an incredibly low 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 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. You're right. I think the liability of Messer-Darrin A will be a challenger. And just one sort of nerdy, verologist thing that I'd like to say as a nerdy verologist is that when you're infected with this virus, you'll shed infectious virus for a week, roughly. You'll shed infectious virus for a week. You'll be PCR positive, polymerase chain reaction 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 going to 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 transcribe 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. We'll be inoculated in your arm. It will be the muscle cells. And then to some extent also, antigen presenting cells like macrophages, dendritic cells. We'll be inoculated in your arm. It will be the muscle cells. And then to some extent also, antigen presenting cells like macrophases, 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-CoV-2, that virus then reproduces itself over and over again, part in the back of your throat. And it makes infectious virus particles. It enters your cells, it 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 any more.

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 it's 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 front runners in this, and I think that's in no small part to the fact that one of their partners is NIH.

That's, you know, national institutes of health here in the United States has bankrolled to the tune of about a billion dollars as you said. Has N.I.H. 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, the 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 T-Leaves on this. They're strong. 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 2-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, compared to Moderna's shipping and storing at minus just at minus 20. They are different constructs, so they're given a different amounts. 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 skipped through phase two, right to phase three, really. They all did that. Do you think that that distinction, Paul, from a logistic 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 we'll 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 is doing and the Dernist doing, you can be comfortable that the companies are very good at overseeing

this shipment and storage of that product. 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 stalled 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, the United States under natural conditions, how is it going to be distributed? Probably at least in part in large chain pharmacies. Are the pharmaciesists gonna be as good at doing what was done during the trial? Because certainly, as you said at the beginning, I mean, these are mRNA as labile,

and if it degrades and it certainly has the capacity to degrade, will we get less efficacy affecting this 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, me and the CEO, for example, doesn't know who's gotten vaccine, who's gotten placebo, doesn't know who's gotten sick and who hasn't gotten sick, doesn't know how many cases of disease of a current placebo group or vaccine group, doesn't know that. The data safety monitoring board doesn't 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 drawn, this person in 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 age, the inclusion criteria probably says we want people between ages X and Y of a certain, this many of them to be of this health, this many of them to not be of that health, we think the exposure risk at this stage of the virus is meaning at this life cycle of the virus, we think there's this many more people that can be exposed. The R not 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 vaccines for everyone, placebo or subciburn 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 they're 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 a fortifical vaccine which is not this vaccine? You can submit it for licensure with a biological license application. That's not these vaccines. These vaccines are all going to be permitted for use under emergency use authorization. It's different. And that I think is what scares people at some level because they saw what happened with, for example, hydroxychloroquine, which didn't work, now it's been shown clearly not to work to treat or prevent disease. Yet it was approved under a UA, or convalescent plasma, which is't work, now it's been clearly not to work to treat or prevent disease, yet it was approved under the U.A. Or a 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 assault authorization also, with no evidence that it worked. Which weird about this is that people

are doing the same kinds of trials they would do for any vaccine. The large placebo control 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 period of time. So 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 a UA, this PCR test just got a UA. 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 safer, a factor for that is a diagnostic it clearly works well. We're going to allow it under this condition because we're under duress with this COVID-19 pandemic. So we are 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 inquiry yesterday that I just heard before this show that it's going to be published, I think, on Sunday on the Philadelphia inquiry. But the point I'm trying to make in that piece is that how big of a risk are we take 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 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 say, 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 a, how long the FDA is vaccine advisory Committee, we had our meeting on October 22nd, and that dominated the meeting. That nine-hour meeting was dominated by the FDA's basically asking us, are you comfortable as a committee, allowing you 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 oropolio vaccine, which occurred in one in 2.4 million doses,

where narcolepsy, a disorder of wakefulness that was caused by the squaly and adjuvanted flu vaccine that was given in Europe, not in the United States, which occurred in roughly one in 55,000 doses. Thrombocytopenia, lowering the platelet count, that occurs with measles containing vaccine, which occurs in one 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 the yellow fever caused by the yellow fever vaccine, which occurs in about one in a million doses or a geombracenrom, which is this ascending paralysis,

which can affect your ability to breathe, that occurs in about one and a million doses of the influenza vaccine. How soon did you know that? I mean, how soon did you know about those serious problems? Did you know about them within two months? And the answer is yes. I was on a CDC conference call yesterday with a group of folks that are associated with the advisory committee for immunization practices and we collectively could not think of a serious side

effect. It 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 exam to talk about the companies. Are there any of those classes you worry about more than others from a risk standpoint? For example, some of the live attenuated viruses have been the ones that go on to cause. It isn't polio's live attenuated, correct?

Your polio vaccine was a live attenuated viral vaccine. 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 semi-natal viruses 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 hole with Johnson & Johnson's product, which was

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 adenovirus is the cause of 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 when you're inoculated with that vaccine, the cell takes up that particle, which does not amplify itself. It enters the nucleus, it then transcribe, it transcribe the messenger RNA, the messenger RNA is translated to a protein, and that protein is x-queated. So it's good news,

bad news. The good news is it's replication defective. Therefore it can't cause disease because the virus is reproducing itself. The bad news is it's replication defective, meaning you have to give a lot of virus to get enough of those virus particles into the cell to make the protein you're interested in. About 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 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 adenovirus is 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 defect of Adnovirus type five that coated the gene that coated for one of the liver enzymes that he was missing.

He was missing a gene that allowed him to take the ammonia that is a consequence of protein metabolism and excrete it from his body. So the ammonia would build up in his body and then he would get very sick and go into a coma occasionally. So, but he died. I mean, he died because he had a massive, so-called cytokine response with something called interleukin six, that at a time before we had antibodies directed against interleukin six, that would have saved his life. And we all lived through that. And it really set gene therapy back. If it's any consolation, the amount of

replication effect of thatenovirus, he got was log-rhythmically greater, exponentially greater than the amount that we're currently giving here, even though 10 billion sounds like a lot. It's still about 1,300 to what he got. But again, you're going into an out-red population. When you put it something into millions of people, you may find something out that's on-torrage. So yeah, that worries me. The clinical holds word me a little bit. The two clinical holds that were for 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 sheating of your nerves, and particularly one protein on the sheating of your nervous mind, basically protein. Multiple sclerosis is relatively common, but transverse myelitis isn't. That occurs maybe one in two hundred thousand in the general population. That travel was about 18,000 people big at the time, which is, 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 bizarreity. And you'd like to know what the problem was with Johnson and Johnson's vaccine, which you've done. This is the problem with the same. And they're both in the same class, right? They're both replication effect lednivirus. 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 that had five ad-nivirus type 5, which they actually had approved for use in the military, I'm not sure what extent they've done it, because it seems they've gone in the other direction now, and are looking just at an activated viral vaccine. That seems to be their focus now. Yeah, I was gonna say, do we have any data?

I mean, I'm 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 a result of the face retross. So I'd like to see whether or not it actually works would be nice to see. And then the Russian, the Gamalaya Research Institute in Moscow has also

replication defective adenovirus vaccines and also is a two dose vaccine. But the first dose is replication defective ad five. the second dose is replication defective ad 26, that's their vaccine. Gladden repudent 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 you. 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. It's 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 component for sickle or stompatitis 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 adenovirus slash viral vector front. Does that fare? Yes. As the leaders. Okay, so then the next 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 going to be threatened by them. I mean, it's going to be threatened appropriately to make an immune response, but obviously the protein by itself can't hurt you because it has no genetic material with which to take over your cells. As a general rule, how does that strategy work when you think of other non-coronavirus applications? Right. So, it's the strategy we used 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 2000s, around 2006. It's a strategy we used to make one of the influenza vaccines, so called flu block, 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 papilloma virus vaccine, you take a yeast plasma, which is 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, the codes for the coronavirus spike protein, you then sort of transfect that into yeast cells, actually just common bakergees. And as the bakergees reproduce itself, it also makes that protein, which you purify. In the case of flu block, which looks like it's closer to the strategy that's being used

by Sonofi GSK collaboration. There what you do is you take basically an insect virus, so-called baccala virus. You clone into it again, the gene that you're interested in, the coronavirus spike protein gene, and then you infect insects cells, and then that protein actually forms rosettes as it's excreted from the cell. That's why you make flu block, which I actually got this year as my influenza vaccine. And I'm still alive.

That's quadrivalent. It's quadrivalent. So you mentioned obviously, synovi GSK, that's one of the big guns. They're not in phase three yet, are they? They're gonna start that next month. Novavax is the other one that does purified protein in prozoostum. And Novavax

is in phase three. That's why I heard. Yeah, but GSK, Sonofi is next month for phase three. Novavax was enrolling in November. They've started and Sonofi 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 fork as we've already alluded to what the fourth strategy is, which is a live attenuated virus. The protein-based delivery seems the most benign. Is that necessarily true? 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 the shingricks, which is again a purified protein, it's just one of the proteins from phyroselosostrivirus, that vaccine actually works better than the live attenuated viral vaccine, zystevax. Essentially it's replaced zysteovax. We basically two years ago said we're done. It's 100% switched to Schengrevax now. Schengrevax, rather, yeah. Which is amazing.

I mean, typically, historically, live attaining IVA vaccines always work better than a single protein. The difference was the adjuvant. Schengrevax has two powerful adjuvantes. 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 monophasia, but A, the other is the so-called QS-21. That's all part of the varicela zoster virus, glycoprotein E, has these two adjuvants that are all part of the vaccine. Oh, I see. But we give shingricks in two. Is this second one just a booster?

You give two dose, right? The same thing. It's well contained the same. Understood. Okay. The adjuvant that's being used in the Novavax product is actually similar to the adjuvant in the Shringrich 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 Shringrich stuff. 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 that is commercially available, if you will. The first one, Tava, clear phase 3 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. We, I think, I have to be honest, I'm very surprised. I think in March of this year, I did not think it was plausible that there would be a vaccine on the market within a year. In fact, I probably

would have used the words impossible if you said to me in March, can there be a vaccine in a year? And by the way, that wasn't just based on the financial thing. I mean, when I asked you that question earlier, Paul, you alluded to how the government financially completely de-risked the operation. And I won't diminish that in any way, shape or form. I just didn't think it was going to be from a manufacturing standpoint possible enough

to make enough GMP stuff at volume and actually put it into clinical trials. I was like, there's no way. 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 strain in RNA virus. And like all single strain in RNA viruses, its replication isn't terribly faithful or said another way. It probably mutates to some extent

every time it reproduces its own. 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. The measles is a single stranded RNA virus too, so is mums. 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 zero type. So the vaccine that worked in 1963 still works today. And so the question is, which of those, is it going to be, 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-seerotype disease. In other words, it a vaccine that works now could well work next year in 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 mildly a little sloppy. That means every time this guy reproduces itself, it makes a little bit of a mistake. Sometimes those mistakes don't mean anything. Sometimes they do. It's yet to be determined. There's two things at least that matter with respect to the fidelity with which it can reproduce. One is, does it change the properties of how the virus responds, either making it less

toxic to us as humans or more toxic or pathogenic to us as humans? I think it's definitely too early to say if that's happening one way or the other. But the second property about its ability or inability to replicate itself perfectly is if it makes so many changes in its replication cycle, it might look so different year after year after year that our immune system, even if able to maintain robust immune cells that recognize the virus, may functionally be duped by it because it looks so different each year. That's why we get flu shots every year and we get MMR once, even though they're both single-randed mRNA viruses. You're 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 like that it's not going to drift and in a matter that is 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 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-CoV-2, is essentially a bat coronavirus that just reared its head in Wuhan in the middle of November of last year and now has swept across the world and made its debut in the human population. We are infected with human coronaviruses all the time. I mean, there are four strains of human coronaviruses

that circulate, they were first identified in the early 1960s or no that circulating well before that. They cause respiratory infections, meaning congestion, cough, running 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 what's called helper T cells,

does your previous experience with human coronaviruses, which we pretty much all had, it means something to us in terms of protecting us against this virus? I don't think so. This is my sense of it. In terms of what works, I mean, I guess I'm very simplistic on this based on my experiences with rotavirus, I think the trick is keeping the virus from binding to cells. It's really the way the measles vaccine works, the months vaccine works, the gallivac thing works, the virus cell, the trick-and-packs vaccine works. If you can prevent the virus from binding the cells, you can prevent the virus from entering cells. So when you make antibodies, or those antibodies directed against the so-called part of the spike protein that 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 the cells. And that's the business end of the SARS-CoV-2 spike protein is that so-called receptor-binding domain. So that's the question. And the other question I think the people are worried about is that antibodies can fade over time, even after natural infection. So what does that mean for a vaccine if antibodies fade?

And this is a little complicated, but when you're inoculated with a vaccine, or when you're naturally infected with a virus, it's not just that you make antibiotics. You induce immunological memory. So you have memory B cells, the kind of cells that make antibiotics or memory T cells. And so they're sort of like the base of the iceberg with the antibodies being the tip of the iceberg.

Do they matter? They do matter, especially for longer incubation period diseases. So for really short incubation period diseases like rotavirus, meaning the time when you're infected, when you get sick, rotavirus, influenza, respiratory symptoms, or virus, those have short incubation groups. This is sort of a medium length incubation period. It's around six, seven days. Measals 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 screening cells. So it still

would work. I think that's what we're going to be. So I think memory is important. So when people talk to me about how nervous they are that antibodies are fading, I'm not sure you should be nervous about it yet. Let's wait to see what happens as we move forward with these vaccines. 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. 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 probably get sicker because you wouldn't have any of that memory response, but at least it would have been contained. We sort of have the opposite problem. That's a glass half full way to look at this, I suppose.

Let me offer one thing just as hopeful because I usually get older, you get sort of grimmer, but I'm gonna try and offer some hopeful thing. But it appears that, especially in men, there were two papers in science that showed that when you're infected with this virus, SARS-CoV-2, that you can actually make antibodies directed against interferon, which is a protein that your body's immune system makes

to help fight viruses. That's where the name comes from. It interferes with the ability of virus to infect cells. And the thinking is that that may be one reason why men are more likely to suffer and die from this disease than others. This offers hope for the fact that a vaccine may be better than natural infection, because it's unlikely that a vaccine would do that. There are certainly examples of vaccines that are better than natural infection.

This may be one of them. There are 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 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. What's the minute? 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.

It's so that having type O blood would be some level protective, because you can make antibodies say, or be, 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 role 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 Humanization Practices at the CDC have come up with their first-year group. But it's huge. And the first-year group includes healthcare workers.

It also includes other essential personnel like people who work in mass transportation or grocery stores or pharmacies or work in law enforcement or sort of water purification. That includes people over 65, who when they get infected or 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 one 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. We're vaccines, where the hero that's doing. 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. I don't know. It's really complicated, right? So Moderna is basically the NIH, Pfizer, J&J, AstraZeneca, and Oxford. These companies have presumably never been in a situation to have to say, here's where

this shipment goes to this pharmacy versus that pharmacy or this city versus that city. I mean, not to dwell too long on a seemingly strange question, but we're not that far from when this is going to happen. We're only a couple months away from that potentially. So it's a 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 portion it, 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 where it's a vaccine. So they may have a different distribution strategy, but I think you're right. It's gonna be a real chance plus the two dose vaccine. So they may have a different distribution strategy. But I think you're right. It's going to be a real challenge plus the two dose vaccine plus you mean 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, one 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 gonna be plenty of people

who are gonna be perfectly willing to take these vaccines. And then we'll have a few million doses out there and we'll have a better sense of things. Marie Silliman, 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 read this I relief

until the first three 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 FCA vaccine advisory board. So I will see the data. And if I feel confident that the safety issues were good issues were good for people my age. I mean, I'm over 65. With 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 gonna point something else out to the listener who can't see you. You at least look to my eye as a very healthy 65 year old. You look like you're about 55, you're not overweight, I assume you don't have diabetes, you look like a model of health. So are you really that high risk aside from your age and if so, why are you taking it? 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. You're 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 taking a vaccine and wearing a mask in 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-assistant inflammatory disease of children, and it can affect, it causes heart attacks, it can cause strokes, it can cause liver or kidney disease,

because it causes vasculitis. So why does it cause vasculitis? It doesn't really enter the blood stream fewer than 1% of people infected with this virus have so-called varemia. So it induces your immune response to damage and ethereal cells that line blood vessels and because every organ in your body has a blood supply, every organ can be affected. I mean, that's so called long haulers at least in part are probably determined by a vas I just 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 this kind of notion

that the virus would eliminate itself by population-inducing unity, which has never happened for a virus before. I think they sort of ignore the fact that the long-term measures of this particular virus have happened. This isn't flu. I think of all the 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 tradeoff 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 risk? 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 going to have a pretty good sense of it. And most of us listening to this podcast are not going to be the guys getting it on day one. Just due to the simple sense of it. And most of us listening to this podcast are not gonna be the guys getting it on day one. Just due to the simple logistics of it,

like I'm not gonna be in the first million doses of this vaccine, you aren't gonna be in the first million doses of this vaccine. There are people, frankly, who are at much higher risk that deserve to be there, and I guess we'll have a better sense of it. But I think that this discussion for me, Paul,

is also interesting 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 Sonofi product ultimately might end up being safer than say a J&J product. The devil's in the details and the thing that's gonna 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, 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 and mortality week, the 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. That's what it usually is around anywhere 140, 150, 160 in that area. So it's no more less fatal than influenza for children. Two, can cause long-term problems in children with a so-called MISC disease of children. So I think there isn't a compelling desire to make a vaccine 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've dropped the age to 12. So they're starting to look at younger people. So the question is then, what happens, and this is applied to Broly?

What happens if a vaccine is approved through EUA? Pfizer has 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 the 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 control trial, it's the same way we do adults. Where it could be done as immunobridging studies, meaning that you actually find out there is an immunological correlate of protection to adults, that it is a certain level of neutralizing antibodies that it's about. And then 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 right to respectively, because not all

children will be inoculated at the moment that you start not relating children. You can see whether or not it's practically the same way that it worked with the Ebola vaccine. I mean, that wasn't a prospect of placebo control trial unless people just started getting vaccine and because not everybody got it at once, you could get a sense of the fact that this by knowing who got the vaccine and who didn't. So that may be it. When we had the FDA vaccine advised for committee meeting October 22nd, the FDA was very clear about this that when you approved something under emergency use authorization, which is the same sort of permission you would give to an investigation or a new drug, you were really under no ethical obligation to vaccinate a placebo group. You aren't. And nor are you under an ethical obligation

to no longer do placebo control trials. Now, I'm not sure how that's going to play out. I mean, you can see, for example, if somebody's 70 years old, they see that this vaccine works, and they win 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 we used to be called compassionate use access, but do it that way. And I think that may be the way this plays out. I don't think I'm making a bold prediction by saying, I think the first vaccines may not be the last best vaccines, but you have to know that you have the last best vaccines. You have to know that down the line or maybe a vaccine that's 90% effective. You can't know that unless you do it as a placebo trial.

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, how 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 ya, it's kinda changing the way I think about how much Tylenol I kick around the house. You wanna talk a little bit about what that paper showed while we're on the topic of kids?

Right, you actually wrote a book called Overkill when Modern Medicine Goes Too Far, and that's the first chapter, sort of, in defensive fever, that treating fever can prolong our worst illnesses. And then 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 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.

Nutrophils 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 the 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. 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 gonna let a child have a fever again. What's the risk of that? And at what temperature is that something that a parent needs to be aware of? So it's what called febrile seizures, or benign.

I mean, my daughter actually had a febrile seizure. They're generally short. Live, they don't have long list of sequelae. And it's not the height of the temperature seizures or benign. I mean, my daughter actually had a febrile seizure. They're generally short-lived. They don't have long-listing sequelae. And it's not the height of the temperature. It's the rapid rising temperature that causes that. So it's not the height of the most part. I'm just saying, most of, I think physiological fevers

don't cause harm. Your body is not interested in hurting you in that way. Now environmental fevers can heat stroke. I mean, if you labor the athlete or the soldier who's out there on heavy gear and on a hot day and is not able to Dispair heat through sweating. They can suffer strokes. I mean, it's, you know, you can die from heat strokes in back some about 600 people die from heat strokes every year. So environmental fevers can do that, but not physiological fevers. So again, I think you jump with an edge. It's very hard to watch this. A case accident at hospital, the boy, the soccer player was hit on the hip. He had a clot in a vein, so called thrombosis and then had that got infected, so called thrombophilitis

with staph, the mercer, sort of a hard to treat staph. Travel to his brain and cause absesia, travel to his lungs and cause absesia, travel to his bone and joint and cause abses. We were treating with antibiotic, Bank of America might have sort of treated that, but he was continually positive, had blood cultures that continued to sow

he was shedding bacteria. And every day, every two hours, we were rotating, you know, either Tom or I be proven, finally, I met with a boy, I met with a 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 consequences. So It's not a proof in any sense. But you couldn't convince the parents of that. They thought we were geniuses by doing that that way. Give us immune system of chance to work as good as it can. Why cripple his neutrophilus ability to adjust 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 of that, I mean, because you increase your basal metabolic rate at a certain percentage wherever degree centigrade, increasing 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 like a teenager, a young teenager, and he, 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 he 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 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?

The more technical issue of creating a vaccine, there were two events that occurred in the 1960s. One was with RSV. We're Bob Chanuk, head of the laboratory in infectious disease at NIH. Wanted to make an RSV vaccine. This isuk headed the laboratory in 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. We took the virus, grew it up, and activated it with formaldehyde, the same way that Jonas Salk made his polio vaccine, and then gave it to babies. And what he found was that 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 on the menu, 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 1963. Take the virus, grow it up, kill it with purify, kill it with formal high. That too caused children to have an ab-barren immune response directed against that measles virus that caused us a typical pneumonia. So they were more likely to get pneumonia than children who were never vaccinated. That was ultimately taken off the market. The reason that may be relevant to today, to SARS-CoV-2

today is that both of those viruses, or viruses respiratory sensitive virus, and measles have a fusion protein. That's how it attaches to cells of f refuses to cells, so does SARS-CoV-2. It has a fusion protein. So, people are always a little nervous about an inactivative vaccine. And it's because you sort of change the confirmation of that protein, that SARS-CoV-2 protein, so it didn't really look like it looked on the natural virus. So that's always in the back of people's minds with fusion proteins. So, you asked me earlier what sort of safety things I'm worried about. That actually is one of the safety things.

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're worried that the confirmation as it made in under these conditions, mRNA or DNA or replication defective virus or a whole kill virus, but we're 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. 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. I don't think I've ever done a podcast this long, but it was definitely fine. And in fact, I thought you said to Aaron, I thought, oh my God, to Aaron, somebody to live through this, it really flew. I am just surprising.

Well, I appreciate your time and your willingness to sit down for so long, Paul. My pleasure, thanks for having me. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the

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