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

00:00:00.000 Hey, everyone. Welcome to the drive podcast. I'm your host, Peter Atiyah. This podcast,

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00:00:41.320 now, head over to peteratiyahmd.com forward slash subscribe. Now, without further delay,

00:00:47.740 here's today's episode. I guess this week is Dr. Paul Offit. Paul's a pediatrician specializing

00:00:55.140 in infectious diseases, and he's an expert on vaccines, immunology, and virology. He's the

00:01:00.420 director of the Vaccine Education Center and a professor of pediatrics in the Division of

00:01:05.100 Infectious Diseases at CHOP, the Children's Hospital of Philadelphia. He's also a professor

00:01:09.980 of vaccinology at the Perlman School of Medicine at the University of Pennsylvania. And he's on the

00:01:15.220 FDA Committee for Biologics Evaluation and Research Vaccines and Related Biological Products Advisory

00:01:21.240 Committee. In other words, he's on the FDA Committee that is overseeing the basically unprecedented scale

00:01:28.260 with which vaccines are being put into a pipeline to be evaluated for COVID. He's also the co-inventor

00:01:35.520 of the rotavirus vaccine, as if all of the above were not enough. I've wanted to talk with Paul for a

00:01:41.000 couple of months, but I wanted to wait until the time was right. And I kind of define that as a moment

00:01:46.340 when we had enough certainty in terms of what was going on with COVID vaccines that we could speak

00:01:53.560 about it in less abstractions and more straightforward terms with respect to likely releases and approvals

00:02:01.460 of various vaccines. And so I'm really glad that actually we waited until this time, because I do

00:02:05.100 think we're at that point where we have a pretty clear line of sight into the pipeline of a number of

00:02:13.540 companies and also a number of strategies that are being employed. And that's basically what we go

00:02:18.440 into. I mean, we certainly talk about Paul's background, which is fascinating and why he's

00:02:23.860 sort of the perfect guy to have this discussion. But the meat of this discussion really focuses on

00:02:28.540 delineating the four strategies with which one can pursue a vaccination against the virus that causes

00:02:34.820 COVID. And then we talk about basically who the major companies are in each of those categories,

00:02:41.120 where they are in their life cycle, what that actually means and what it implies as far as

00:02:47.100 vaccination approval. We talk a lot about what the potential risks are in each of the categories and

00:02:52.440 more broadly. And ultimately, we talk about what 2021 could look like and what the unknowns are.

00:02:58.560 So I learned a lot in this episode, actually, more than I expected. I was just completely riveted

00:03:04.400 by Paul's insights. And I think we all have a little bit of COVID fatigue at this point. That's

00:03:09.500 understandable. But I think anybody who's got questions about, will a vaccine change my life?

00:03:15.480 What should I expect next year? I think, and I hope at least most of your questions are going to be

00:03:20.160 answered here. And I don't suspect this is the last time that Paul and I will speak.

00:03:24.360 So without further delay, please enjoy my conversation with Paul Offit.

00:03:28.660 Paul, thank you so much for making time to sit down with me today. I know that you are someone

00:03:39.900 who a lot of people want to talk with, especially now that people are really starting to come to

00:03:44.360 grips with the fact that a vaccine for the coronavirus is going to be a very important

00:03:49.400 part of the story. I guess before we get that, though, I think it's important for people to

00:03:53.980 understand why your thoughts on the subject are important. In other words, you're not just someone

00:03:58.580 like me who's been thinking about the coronavirus for less than a year. You're someone who has spent

00:04:03.560 essentially a lifetime thinking about this type of a problem. There's a story about how you were

00:04:08.560 a very young boy, you were hospitalized, and that experience at such a young age kind of shaped the

00:04:15.280 way you thought about going into medicine and ultimately even being a pediatrician. Can you share a bit

00:04:20.300 of that? Sure. So I was born with clubbed feet, which means that my feet turned sort of inward and

00:04:26.740 down. Typically, that's treated with casting. So I was casted when the first few hours of life,

00:04:31.840 really. And then so for months, I was casted, but it seemed to work. I mean, my feet seemed to

00:04:36.400 straighten out. But at the age of five, my father decided that he didn't like the way that my heel

00:04:40.640 didn't, or my right foot didn't hit the ground as well as he would have liked. So he was able to find

00:04:46.080 a surgeon to do a surgery, frankly, that was perfected about 40 years later. We should have

00:04:51.580 never done that surgery. There was no clubfoot surgery. He was able to find a guy who was a son

00:04:56.080 of a friend of his who had just finished his residency in orthopedics and thought, great,

00:05:00.180 I get to do this surgery, which went badly. My father was a shirt manufacturer. Medicine wasn't

00:05:06.900 really his strength, but he didn't like the way that heel hit. Interesting as a side part of the story

00:05:11.540 is that my great uncle, my grandfather's brother was a bookie. He was really Baltimore's bookie.

00:05:16.900 He didn't print books. He made book. My mother initially had trouble getting me into the club

00:05:21.720 foot clinic at Johns Hopkins Hospital. But she just called my great uncle who called the guy who was

00:05:26.960 head of the foot clinic, who was a gambler, apparently. So we got in within a week. And when

00:05:30.860 the guy, this physician saw me, he said, if you do nothing, don't operate on this foot. Nonetheless,

00:05:36.380 my father insisted the foot be straighter. And so I had an operation that was a complete failure.

00:05:40.720 And as a consequence, I ended up in a chronic care facility called Kernan's Children's Hospital.

00:05:46.660 Although I think then it may have been called Kernan's Hospital for Crippled Children,

00:05:49.900 when you could use words like crippled and feeble-minded. I was there for about six weeks.

00:05:54.540 And this was the 1950s. The polio was king. And I remember just a lot of children in that ward

00:05:59.820 with polio. It was probably about 20 kids in the ward, some in our lungs, some in traction.

00:06:05.260 And there was one visiting hour week. That was it. Sundays from two to three,

00:06:08.820 my mother had a complication with pregnancy with my brother. So she never came. My father had tried

00:06:13.380 to sneak in once to see me. Thus was prohibited from seeing me again. So he traveled a lot. So

00:06:18.960 he couldn't do the hours that they had wanted him to do. So I just remember sort of seeing those

00:06:24.460 children as vulnerable and helpless. And in fact, seeing myself the same way. And I remember

00:06:28.660 looking, there was up, my bed was next to a window. This was when you had one visiting hour a week,

00:06:33.160 polio day. So people were scared to death of having anybody else come into that hospital.

00:06:36.820 Sundays from two to three. It wasn't like they had like therapy dogs or, you know, iPads or

00:06:42.780 televisions or anything. You just pretty much laid there. And in my case, looked out the window that

00:06:47.380 was right next to my bed, which looked out into the front door. And I kept waiting for my parents

00:06:51.720 to come rescue me to walk through that front door of the hospital. Never happened. When I was a medical

00:06:57.440 student at the University of Maryland, we rotated through Kernan's Children's Hospital. And that room

00:07:01.360 was still there. It wasn't a polio ward anymore. It was a group of secretaries, but that window was still

00:07:06.420 there. That festivity is still there, isn't it? Yeah. Kernan's Children's Hospital is still there.

00:07:10.800 I did my residency at Johns Hopkins. And I remember we would sometimes get transfers. I was in surgery.

00:07:16.920 So kids that would get infections that would need to be transferred to Hopkins for surgical care.

00:07:22.120 That's funny. I didn't think I'd hear that name again.

00:07:24.620 So I remember as a student then, I was at Merrill Medical School, but I remember walking up to

00:07:28.400 that window and looking out of it and seeing that front door. And, you know, I cried. So I think that's

00:07:33.980 it. I mean, I think that we are motivated by the scars of our youth. For me, a choice to go into

00:07:38.380 pediatrics, a choice to go into pediatric infectious diseases, a choice to write a book about

00:07:42.140 polio, specifically about a sort of a tragic event associated with the making of the polio

00:07:46.060 vaccine, a choice to make vaccines, I think, enter the world of science and stuff. Probably all is

00:07:50.740 motivated by the scars. Pretty much every book I've written, at its heart, child advocacy,

00:07:55.240 at its heart, sort of standing up for children who are vulnerable, who can't stand up for themselves.

00:07:58.960 We're going to talk about vaccines today. And I don't think a discussion of vaccines would be

00:08:03.760 complete without saying something about just the unbelievable disservice that has been done to so

00:08:11.380 many people, so many vulnerable people, specifically parents who are looking for answers when maybe there

00:08:18.500 are no answers by sort of the fraud that was catapulted upon them in the late nineties in the form of

00:08:25.040 that Lancet article that has been so thoroughly debunked as not just incorrect, but outright

00:08:32.620 fraud. Of course, I'm referring to that Wakefield paper of 12 completely fabricated case studies

00:08:38.820 that really on some level is kind of a big part of the anti-vaccine rhetoric and the vaccines cause

00:08:49.560 gastrointestinal disease, which causes autism story that started at that time. And frankly,

00:08:55.140 on some levels, there's a solid number of people who continue to believe this, despite the efforts

00:09:00.540 of people like Brian Deer, yourself, Peter Hotez, people who have so thoroughly debunked that type

00:09:07.340 of nonsense. How do you process that? Do you process it? There are some people who are very angry

00:09:14.160 about the anti-vaccine movement. There are others who I think speak to it more from a place of empathy.

00:09:20.200 How do you manage your own emotions around that, especially when you see the children themselves

00:09:25.920 are often the victims of parents who are themselves the victims, et cetera?

00:09:31.540 Yeah, I guess I come out on the angry side. I think Andrew Wake was a fraud. I think at some level,

00:09:36.780 he was a knowing fraud. I mean, he misrepresented clinical data. He misrepresented biological data.

00:09:42.100 That paper should have never been published. It was basically a story of 12 children,

00:09:45.820 eight of whom had autism, presumably within a month of receiving MMR vaccine, when in fact,

00:09:50.580 at least a couple of the children had developed signs and symptoms of autism before ever having

00:09:54.280 received that vaccine, which he knew. He also, he had biopsies on all those children and presumably

00:09:59.180 measles vaccine virus was supposed to be destroying intestinal epithelial cells. He had biopsies on those

00:10:04.580 children. He never did studies looking at, or at least never reported studies, looking at whether

00:10:08.600 there was measles virus genome or measles virus vaccine proteins in those cells, which is to say

00:10:13.360 he probably did do those studies and they didn't come out the way that he wanted them to.

00:10:17.760 Actually, we'll go one step further. I think Brian Deer has actually done a very good job uncovering

00:10:21.500 those biopsies were done and processed. And the amount of virus that was found in them was identical

00:10:31.080 to that, which was found in basically the formal in itself, demonstrating that it was a pure

00:10:38.080 contaminant. So actually there was no measles virus whatsoever in any of the colons of, or distal

00:10:46.300 ileums of any of those children. And I talked to a person who did some of the serology with

00:10:50.700 Andrew Wakefield for a meeting I had in England, and he refused to be on the paper because he felt that

00:10:55.660 Andrew Wakefield had basically misrepresented sort of IgM, IgG response, immunoglobulin responses to

00:11:00.980 measles. That was Andrew Wakefield. Brian Deer just wrote a book called The Doctor Who Fooled the World,

00:11:05.640 which goes through all this. I'll be interviewing Brian because I think it's such an important

00:11:10.180 discussion. Clearly there's no shortage of anger towards Wakefield because I agree with you.

00:11:16.280 And by the way, fraud and knowingly is a bit of a tautology. By definition, if it's fraud,

00:11:21.160 in my opinion, he was knowingly acting in bad behavior. And where are we today? Maybe just

00:11:27.740 talk about it through the geography that you understand best, which I assume is the United

00:11:31.260 States. Where are we at MMR vaccination levels? Are we above 95%? We were. I mean, I think what

00:11:38.080 happened with the COVID-19 pandemic is that we had a dramatic drop in the instance of vaccines in

00:11:42.460 general, including MMR vaccine. But I would say this, I think that this is going to probably surprise

00:11:46.900 you. I think in some way, Andrew Wakefield was good for science. Here's why. When he put that

00:11:53.220 out there, he became a darling of the anti-vaccine movement. He was attractive. He was well-spoken.

00:11:59.140 He had a British accent, which we all love. I think we're ready to give ourselves back to the

00:12:02.580 queen at this point. And he made the rounds in the United States. He was on everything,

00:12:06.500 morning, evening shows. He was on 60 Minutes with Ed Bradley. He was a darling of the anti-vaccine.

00:12:12.300 He was a physician, a scientist who now said all the right things. And I think the anti-vaccine

00:12:17.540 folks attached themselves to his star. When it was found out that he was not only wrong,

00:12:22.420 but fraudulent and wrong, that he not only had misrepresented clinical and biological data,

00:12:26.680 but in fact had basically laundered money, laundered legal claims through a medical journal,

00:12:32.340 his star fell. And I think the mainstream media rejected him. His last, I think,

00:12:37.580 appearance on mainstream media was on Anderson Cooper.

00:12:39.640 Where Cooper just destroyed him. Yeah.

00:12:42.400 Yeah. It was great. So at some level, he helped us marginalize to some extent the voices that were

00:12:49.780 the anti-vaccine voices, Barbara Lowe Fisher, Jeff Schwartz, J.B. Hanley, et cetera, had a much bigger

00:12:54.900 voice, I think, 20 years ago, 15 years ago than they do now, because I think mainstream media anyway

00:12:59.620 has chosen to set them aside. And obviously their platform is social media, but so I think Wakefield in

00:13:04.580 some ways helped us. I mean, we did the studies to answer the question, whether you were more likely

00:13:09.260 to develop autism, if you've got the MMR vaccine or not, that's been done 18 times in seven different

00:13:13.740 countries on three different continents. The question has been asked and answered. I do think,

00:13:18.300 according to a study done by the Autism Science Foundation, about 85% of parents who have children

00:13:22.480 with autism no longer believe that vaccines were the cause. So I do think that that good science did

00:13:27.360 win out to some extent. And I think Andrew Wakefield has lost that. He's now, you know,

00:13:30.500 he goes on Alex Jones' show, where all good conspiracy theorists go.

00:13:34.480 Paul? Yeah, it's interesting. There aren't many things in medicine we can say with a higher degree

00:13:39.840 of certainty, actually, than the MMR vaccine does not cause autism. If you really stop to think about

00:13:45.460 it, Paul, do statins cause Alzheimer's disease? I think the data is overwhelmingly convincing that

00:13:50.760 it does not. But I think the data are more convincing than MMR does not cause autism based on the extent to

00:13:57.500 which it's been studied. And maybe to some extent, the negative attention that Wakefield has brought

00:14:04.080 to this has actually forced so much scrutiny of those data, not just the 18 studies you refer to,

00:14:13.480 but also going back and really exposing the biological plausibility of the argument itself.

00:14:21.180 And frankly, exposing another issue that I think is very easy to understand. So I say this with a lot

00:14:30.160 of empathy, but is nevertheless an issue, which is any of us are capable of misremembering facts.

00:14:37.520 And so much of what I think gave Wakefield and his associate Barr, the lawyer with whom you referred

00:14:46.000 to earlier, that he was basically in cahoots, siphoning funds through his research organization,

00:14:52.280 the ability to carry on for so long, was effectively parents misremembering things.

00:14:58.340 I actually believe most of those parents were not nefarious. I think there are some that who clearly

00:15:03.780 were. I think there were some who consciously chose to sort of pursue legal action to get money,

00:15:11.120 knowing that what they were saying was false. But I don't think that that's the majority of them.

00:15:15.420 Because remember, all of those parents in that case said, little Susie got the vaccine on Tuesday,

00:15:21.720 had a nosebleed on Wednesday, had a fever on Thursday, and started banging their head against

00:15:26.800 the wall. And the rest is history. I actually think they believed that. Although the medical

00:15:31.960 records showed, no, actually, little Susie stopped talking six months before they ever got the vaccine.

00:15:38.060 And here are the medical records to demonstrate it. I mean, it was unambiguous what had happened.

00:15:42.560 But I just think that people, ourselves included, sometimes struggle when we go back to remember

00:15:48.680 things, especially things that are painful. I think we look for reasons for why things happen.

00:15:54.940 That gives us some level of control, even though the reason may not be the correct one. At least now we

00:15:59.940 feel like we have some handle on it. What Andrew Wakefield offered at some level is hope. If you don't

00:16:04.120 want your next child to get autism, separate the MMR into its three component vaccines. If you want to

00:16:08.980 treat this child, here's a variety of intestinal treatments that will work, that will be magical.

00:16:14.520 I mean, he was a charlatan of the first order because he took advantage of parents' desperate

00:16:20.120 desire to do something for their children. And not to get too far into Wakefield's psyche,

00:16:24.760 but I actually believe there was probably a day when he was honest. I believe there was a day when

00:16:30.680 he, like any scientist, had a hypothesis, set out to test it. The difference is he crossed a line.

00:16:37.160 The difference between a good scientist and a bad scientist and a charlatan

00:16:40.820 is that a good scientist can look at the data when they disagree with hypothesis and modify

00:16:46.620 hypothesis. He had done some early work on sort of vasculitis associated with

00:16:51.000 inflammatory bowel diseases. Yeah. He tried to really make the case that measles-containing

00:16:55.700 vaccine also was a cause of inflammatory bowel disease. He was wrong, and he admitted he was wrong.

00:16:59.840 And then he went on to the next thing where he was wrong, but didn't admit he was wrong.

00:17:03.480 Yeah. And doubled down. And that's where really the fraud got out of control.

00:17:06.500 So let's take a step back to give people a bit of a sense of your work. What were you doing? What

00:17:13.820 was a day in the life of Paul Offit a year ago, basically before SARS-CoV-2 was a known entity?

00:17:21.040 What were you working on? I spent 26 years of my life working on creating the strains of virus that

00:17:26.120 became the bovine human reassorting vaccine rototech. That was my 26-year effort. Before that was done,

00:17:31.820 about 2000, we created the Vaccine Education Center at Children's Hospital of Philadelphia,

00:17:35.440 which sort of creates and distributes educational materials to educate the press, educate the public,

00:17:40.840 educate doctors about vaccines so we can sort of meet this anti-vaccine movement, or at least the

00:17:46.460 anti-vaccine sentiment that people have so that we can answer their questions. What we're trying to

00:17:51.220 avoid is, are those children who suffer needlessly by not getting vaccines that would protect them?

00:17:56.560 So that's been the passion. I mean, I think the passion for me came because I think I saw how hard

00:18:01.220 it was to make a vaccine, how hard it was to prove that a vaccine was safe and effective, and how easy 0.98

00:18:05.420 it was to damn them. That paper was awful. It should have never been published. And yet it created a 0.99

00:18:10.440 movement, or at least supported a movement. So I think that was it. Seeing how hard vaccines were to

00:18:15.340 make, how easy it was to damn them got me interested in trying to fight with facts. 0.80

00:18:21.040 Let's talk a little bit about rotavirus. Can you tell folks a little bit about what that is and 0.84

00:18:24.740 how often it afflicts children?

00:18:27.300 Rotavirus is a virus that affects the small intestine. It causes fever, vomiting, and diarrhea,

00:18:31.900 primarily in children between six and 24 months of age. In the United States, before there was a

00:18:36.400 vaccine, everybody would be infected by age five. All children would be infected by age five.

00:18:40.640 And it would cause about 75,000 children to be hospitalized in this country every year with

00:18:45.720 severe dehydration or water loss. It would also cause about 60 children to die every year.

00:18:50.520 In the developing world, or in the rest of the world, it was a killer. I mean, it was really the 1.00

00:18:54.060 biggest killer of infants and young children, killing about 500,000 babies a year, typically

00:18:59.700 children less than two years of age, about as many as 2,000 a day. So there was always a lot of

00:19:05.040 interest in trying to make a vaccine to prevent it. That's where I came in.

00:19:08.600 And obviously, the difference between why so few kids would die in the United States

00:19:14.120 versus the rest of the world presumably had to do with supportive care. And these children in

00:19:19.520 the developing world were going to die of dehydration and or electrolyte imbalance. Whereas

00:19:23.620 in the United States, despite how many were hospitalized, at least they could receive

00:19:27.860 intravenous fluids in some form and perhaps even parenteral nutrition if necessary. Is that the

00:19:32.440 fundamental distinction?

00:19:33.480 The story that I tell is that there was a friend of mine who was a PhD in chemistry. She actually worked

00:19:37.740 for a pharmaceutical company. Her baby got rotavirus infections. So she took the baby to

00:19:42.880 the doctor and the child was severely dehydrated. The doctor said, let me call an ambulance and take

00:19:47.500 this child to a local hospital. The mother said, no, I can take her. I'll put her in the car and take 0.93

00:19:51.320 her. So she gets her in the car and then she's in a major traffic jam, which is why you get an

00:19:56.360 ambulance. And so she was stuck and she was much longer to get to the hospital than she would have

00:20:01.080 others. By the time she got to the hospital, the child was out of it. So they whisked the child back

00:20:05.020 into the treatment room. They were able to do a cut down essentially in the child's neck to thread

00:20:09.380 a catheter down because that was the only vein they could find. That child dies in the developing

00:20:13.860 world because you don't have the kind of equipment to do that cut down because you're walking 20 miles

00:20:18.840 to get to a clinic or hospital. So the difference between this country and other countries where

00:20:23.980 children die is not severity of disease. It's as severe here. It's just that we have the resources

00:20:28.040 here to keep children from dying.

00:20:30.020 So what type of a virus is a rotavirus? Is it an RNA or a DNA virus?

00:20:33.700 It's a double-stranded segmented RNA virus.

00:20:37.040 Does that pose any challenges for creating a vaccine against it?

00:20:41.260 The good news is when you're trying to make a vaccine, you want to see clear evidence that

00:20:45.100 natural infection can induce protection against at least moderate to severe disease.

00:20:49.400 Then you know that you should be able to mimic that part of the immune response that's associated

00:20:53.940 with that protection. Those studies were done in the 70s, actually. Ruth Bishop published a paper

00:20:58.460 showing that if you got a rotavirus infection in your first year of life, when you were then

00:21:01.800 subsequently challenged with the virus, again, just naturally, you could get mild infection

00:21:06.100 or you could get asymptomatic infection, but you wouldn't get moderate to severe infection.

00:21:09.340 The minute that paper was published, we thought, okay, we can make a vaccine. We just have to mimic

00:21:12.720 that part of the immune response that's associated with protection.

00:21:15.980 And was that protection lifelong, Paul?

00:21:17.660 No. No. Like many mucosal viruses, rotavirus, influenza virus, paraflu, respiratory syncytial

00:21:24.580 virus, those viruses, which have generally short incubation periods, meaning time from when you're

00:21:29.100 first infected to when you get sick, which generally don't have viremia as part of pathogenesis,

00:21:33.540 their natural infection and immunization induces protection that is short-lived and incomplete,

00:21:38.660 meaning decades and meaning protection against moderate to severe disease, but not mild disease.

00:21:44.000 These are the mucosal viruses, which I think brings us to SARS-CoV-2.

00:21:46.740 So I think that's going to be the same story here.

00:21:49.120 Did that paper in the 1970s offer an insight into whether the immunity was provided more by the

00:21:55.700 B cells or the T cells?

00:21:57.860 The thinking was that it was going to be an antibody response at the intestinal mucosal surface. We had

00:22:01.800 to induce an antibody response that was active at the intestinal mucosal surface, which made us think

00:22:06.680 it was going to have to be an oral vaccine, which stimulated then immunity at the intestinal

00:22:10.720 mucosal surface and not a parenteral vaccine, which would stimulate systemic immunity.

00:22:14.100 So what was the approach you took then to do that? In the spirit of that, at the time,

00:22:19.260 what were the options available? I mean, beginning with, say, a live attenuated virus,

00:22:23.600 is that generally the first thought an individual has when pursuing a vaccine? Or how did you guys

00:22:29.100 problem solve around the different ways in which you could induce immunity?

00:22:31.880 The way we saw it was that rotoviruses are ubiquitous. Every mammal that walks the face of this earth

00:22:39.360 has its own unique strain of the rotavirus. And species barriers are pretty high, meaning that a

00:22:44.740 cow rotavirus or calf rotavirus would cause disease in calves, but not people, and vice versa. Human

00:22:49.960 rotoviruses would cause disease in babies, but not calves. So we basically took advantage of that. It was

00:22:55.180 a generic approach, if you will, an Edward Jenner-like approach. I mean, Edward Jenner basically

00:22:59.380 used a cow virus to protect against human smallpox virus. So cow smallpox, essentially cowpox would 0.57

00:23:06.160 protect against human smallpox because they were antigenically related enough that immunization

00:23:10.960 with one could protect you from a disease caused by another. That was our approach. So that was our

00:23:14.860 initial approach, was just to take a cow virus, a calf virus that had caused diarrhea, adapted to growth

00:23:19.720 in cell culture, and then use that as our vaccine. And it did work, but it was inconsistent. So then we had

00:23:25.960 to modify that calf virus so that it included the genes that coded for the proteins that evoked what

00:23:32.680 we found were neutralizing antibodies. There were two surface proteins of the virus, and we thought

00:23:36.840 both independently evoked neutralizing antibodies. That's what we proved. So then it was a matter of

00:23:41.000 just constructing these combination virus, so-called reassortant viruses, between calf and animal strains

00:23:46.580 that became the vaccine, thus summarizing 10 years' worth of work in about 35 seconds. It's a little

00:23:53.020 depressing that you can do that, but that's what we did. What were the risks associated with the

00:23:58.400 vaccine? You don't know. Whenever you're dealing with something that's unknown, it's through calf

00:24:02.900 viruses. Will they behave differently in people? Will they cause something that's untoward that you

00:24:06.540 hadn't thought about? What we learned from other researchers was that surprisingly, actually, there was

00:24:12.260 a vaccine that was introduced in the late 1990s. It was made by National Institutes of Health in

00:24:16.300 collaboration with Wyeth called Rotashield, which was a simian rotavirus that was also a recombinant virus.

00:24:23.520 Simian human reassortant rotavirus that was found to be a rare cause of intussusception, which is

00:24:28.040 intestinal blockage. It occurred in, depending on who you read, between 1 in 10,000 and 1 in 30,000

00:24:33.060 recipients. It wasn't picked up pre-licensure because the studies wouldn't have been big enough

00:24:36.060 to pick it up pre-licensure. It was only picked up months after licensure, and then it was off the

00:24:40.720 market within 10 months. So that was a sobering experience. Just to relate it to today, if you don't mind,

00:24:46.000 that virus, rotavirus, had been studied for 50 years by that time. I mean, it was known to be an animal

00:24:52.500 pathogen in the 40s. Veterinarians studied it. We knew it was a human pathogen by the 70s. When

00:24:57.420 that vaccine came out in the late 1990s, we had 50 years worth of study. Nonetheless, it caused a

00:25:02.780 side effect, intussusception, that would have never been predicted by all those studies.

00:25:06.920 Yeah. Let me tell people what that is. So an intussusception is when usually a lymph node in the

00:25:11.980 small intestine acts as a foci and allows the small bowel to telescope on itself. So it gets tugged

00:25:19.700 probably through some sort of peristalsis action, and that can cause an obstruction. So if the piece

00:25:26.160 of the bowel telescopes into another and comes back out, easy peasy. But if it telescopes and gets

00:25:31.080 stuck, you now have a bowel obstruction. And I took care of many kids, as I'm sure you have,

00:25:36.360 who had intussusception from lymphoid hyperplasia or various other things. But obviously in this case,

00:25:41.040 it was a side effect of a vaccine and an understandable side effect, meaning there's a

00:25:44.720 biological plausibility of why giving a vaccine that has a GI mucosal effect could lead to lymphoid

00:25:52.020 hyperplasia that could act as the tugging point. But you're right. You would never in a million years

00:25:57.880 say, I think intussusception could be a side effect here. And if it only occurs one in 10,000 cases,

00:26:04.540 you're going to easily miss that in phase one, two, and phase three. Again, it speaks to

00:26:09.900 aftermarket surveillance and the absolute imperative of it. And it also speaks to the fact

00:26:14.640 that as we start to talk about coronavirus, which we're going to get to very shortly,

00:26:18.640 one has to be thoughtful about risk versus reward trade-off with small n, right?

00:26:23.920 Yeah, I think that the surprise was that vaccine, which was sort of a simian rotavirus-based vaccine,

00:26:29.120 that virus reproduced itself far less efficiently at the intestinal mucosal surface than did

00:26:33.620 wild-type virus, natural virus. There was no evidence that natural rotavirus caused

00:26:37.900 interception. So why would this be true? And the reason is, is that interception really

00:26:41.640 appeared to be a year-round phenomenon. It wasn't a winter phenomenon in the United States,

00:26:44.740 which was what rotavirus was. You would expect to see a bump in the winter, which you never saw.

00:26:48.400 So why would a vaccine do something that natural infection didn't do? I think what we know now is

00:26:52.160 that natural infection probably was a very rare cause of interception, as was this vaccine. And

00:26:57.480 I guess the COVID analogy is that here's a virus, COVID, for which we had at least the gene structure

00:27:02.780 in early January of this year, which has already had a number of sort of clinical and pathological

00:27:08.340 surprises, which we are now about to counter with a series of vaccine strategies with which we have

00:27:12.800 no commercial experience. I think it's fair to say there's going to be a learning curve here. So there

00:27:17.000 has to be real humility, I think, as we move forward. Let's help folks understand a little bit about

00:27:21.680 these different phases, because you can't turn on the news without hearing company X is in phase

00:27:27.100 one or two or three. And I just want people to understand what those mean specific to vaccines,

00:27:35.500 because they have slightly different meanings than, say, in drugs that treat blood pressure.

00:27:40.820 So can you explain to people what a phase one vaccine trial aims to accomplish and what a typical

00:27:47.640 size of that trial might look like? If you're trying to make a vaccine, you start in so-called

00:27:52.360 preclinical studies, meaning studies done before you get to humans. And hopefully you'll have an

00:27:57.060 animal model to study the disease. In the case of rotavirus, it was mice. If we inoculated baby's

00:28:01.160 mice with rotavirus, they got sick. Okay, great. So now we have a way to study this infection.

00:28:05.400 Then you have your idea for how you want to make your vaccine. You give your vaccine, you then

00:28:09.600 challenge the animal with the virus, and hopefully you can protect the animal from disease. And more

00:28:14.960 importantly, you can frankly literally dissect out that part of the immune response that's associated

00:28:18.820 with protection against challenge. So those preclinical studies are called proof of concept

00:28:22.560 studies. So now you have your way of making a vaccine. Then you go to phase one, which are usually

00:28:26.920 about 20 to 100 people. Now you have your idea for how you want to make it, but you don't really

00:28:31.300 know the dose. So you give a variety of different doses to these 20 to 100 people to see whether or

00:28:36.840 not you can safely induce an immune response that you think is going to be protective based on your

00:28:41.060 animal model work. Now you have a dose and a strategy. What's the typical length of time to go from

00:28:47.760 that preclinical where you've now filed an IND and you now would be applying to an institutional review

00:28:54.920 board to do a phase one. In the normal world, that takes how long usually?

00:28:58.940 I think probably it's fair to say 10 years, 15 years.

00:29:02.640 Okay. We'll make sure everybody keeps that in mind when we pivot to coronavirus. The other thing I want

00:29:07.200 to highlight that you just said there is 20 to 40 people-ish.

00:29:11.180 Yeah, 20 to 100.

00:29:12.180 We're not talking about 10,000 people.

00:29:14.520 No, no.

00:29:15.160 And these are often done with a little bit of a dose escalation built in. So maybe the first

00:29:19.400 10 people are going to get a really, really small dose. We make sure nothing catastrophic

00:29:24.000 happens. We then escalate the next 10, et cetera, right?

00:29:27.500 There are dose ranging trials. Exactly right. You go slow and you work your way up to see what

00:29:31.960 seems to consistently induce an immune response that is safe.

00:29:36.180 The third thing I want to highlight there is we're not actually able to assess whether or not

00:29:41.840 the people have legitimate immunity. We're using a proxy, presumably, which is some form of

00:29:48.360 serology. In other words, we're not actually testing their ability to resist an infection.

00:29:52.900 We're measuring an antibody. Is that correct?

00:29:55.500 That's right. You have a prediction based on your animal model studies that one aspect of the

00:29:59.840 immune response is going to be associated with protection against chance, as it was true in your

00:30:03.260 animal models. You won't know that until you get to phase three.

00:30:06.520 So now let's go to phase two. You've established a dose, potentially a frequency. What do you do in

00:30:12.680 phase two and roughly how many people do you do this with?

00:30:15.380 So phase two is typically hundreds of people. Now you've got your vaccine, you've got your dose,

00:30:19.580 and you just want to make sure that it's consistently induced an immune response that

00:30:22.680 you think is protective and that it's at least safe and that it doesn't cause a relatively common,

00:30:28.560 serious side effect. That's phase two.

00:30:31.840 And again, the two points worth making sure people understand, still a relatively small clinical trial,

00:30:38.420 hundreds of people, and you're still using surrogate markers. We don't actually know if this

00:30:43.680 vaccine is providing immunity in the real world. It's efficacy. We don't know if it's effective.

00:30:50.200 And we don't really have any way of knowing what very minor or I shouldn't say minor, infrequent

00:30:57.260 negative consequences could look like because we're still dealing with a very small sample size.

00:31:01.320 That's exactly right.

00:31:02.600 So now we go to phase three. And what does that look like?

00:31:06.760 This is the definitive trial. This is the trial that you're going to use to submit

00:31:10.500 information to the FDA, Food and Drug Administration, hopefully for licensure.

00:31:14.940 These are tens of thousands of people. In the case of our rotavirus vaccine, it was

00:31:19.000 70,000 babies. 35,000 got the vaccine. 35,000 got placebo, which is just essentially the vaccine

00:31:26.840 except no active ingredient, just the, frankly, sugar solution in which the vaccine virus was suspended.

00:31:32.940 And then you just send people out into the real world. I mean, rotavirus is a common infection.

00:31:36.680 It's the rare child who gets stage five without being infected. And then you just see whether or

00:31:40.940 not children who got the vaccine were less likely to get rotavirus, or if they got it,

00:31:44.960 that they were less likely to get it severely. And hopefully you'll have, we had zero on all those

00:31:49.880 children, meaning we looked at the antibodies on all those children. Hopefully that would provide

00:31:54.260 a clear immunological correlated protection, which it didn't. We knew that the vaccine worked. We knew

00:31:59.040 that it was safe. And so we could submit it for licensure to the FDA. But as you go along,

00:32:02.900 things are much more expensive. You go from sort of millions to tens of millions to hundreds and

00:32:07.500 hundreds of millions, and then you mass produce the vaccine after you found out that it works.

00:32:12.480 And as a general rule, the process we just described going from a preclinical model in animals

00:32:17.420 to the completion of a phase three trial with the FDA approval of an agent. Here's the rule of thumb

00:32:23.920 I use. Please correct me on the vaccine side. I generally say that's 20 years and $1 billion.

00:32:28.860 And that's usually on the drug side. Is it about the same on the vaccine side?

00:32:33.320 Yes. It's for 15 to 20 years with at least a billion dollars. That's right.

00:32:37.020 So let's now talk about coronavirus and just understand that in January of 2020, when the

00:32:47.700 sequence of the RNA identifying this as a novel pathogen, a coronavirus named now SARS-CoV-2 shows up.

00:32:55.780 And by March, I guess it becomes pretty clear, this is not going to be contained,

00:33:01.620 which means any strategy towards containment is going to fail. It became readily apparent that a

00:33:07.260 vaccine was going to be a very important piece of the strategy. Basically at that point, it was going

00:33:12.300 to be herd immunity without vaccine or herd immunity aided by vaccine. If you're staring down the barrel

00:33:18.760 of it's going to take 20 years and a billion dollars, that's not a very appealing strategy because

00:33:22.880 it basically says it has to be herd immunity without a vaccine, meaning this virus has to sort

00:33:27.520 of rip through a population without it. If I could ask you to put yourself back in your mindset in

00:33:33.540 February or March of last year, what would you have said if I asked you at the time, Paul,

00:33:39.320 how likely is it that a vaccine will be developed to at least thwart in some way this virus? And two,

00:33:45.720 how long will it take? What would you have said then?

00:33:48.040 I would have said it would take years. You do have to give credit to the administration for one

00:33:52.720 thing. Operation Warp Speed, what they did was they basically took the risk out of it for

00:33:58.820 pharmaceutical companies. What the government said is both BARDA, which is part of Health and Human

00:34:03.280 Services, the Wealth Health Organization, the Gates Foundation and others, but in this country,

00:34:06.780 the government said, here's what we'll do. We'll pay for phase three trials. We'll pay for mass

00:34:11.900 production at risk, meaning we'll mass produce this vaccine. We'll make millions of doses of vaccine

00:34:16.100 without knowing whether the vaccine works, without knowing whether it's safe, and showing a

00:34:20.400 willingness to, if it neither works or isn't safe, we'll throw out those tens of millions of doses.

00:34:24.620 No pharmaceutical company would ever do that. So now you basically had phase one trials. You

00:34:29.200 pretty much went right to phase three trials, which a company would never do. Went right to mass

00:34:33.760 producing, which a company would never do. And that's what meant having a vaccine in hand in

00:34:38.300 January. It is in all likelihood that we will have a vaccine that is rolling off the assembly line

00:34:43.460 into the arms of Americans by early next year. I mean, so a year and a quarter to make a vaccine

00:34:49.400 with only having the virus in hand in January. That's remarkably fast. It's unimaginably fast,

00:34:57.280 but it's the government that did that. So give credit to them. Let's talk a little bit about some

00:35:01.740 of the different ways in which vaccines are made. Again, there's so many different ways to skin this,

00:35:06.880 but one way is you actually deliver the RNA of the coronavirus in a vehicle that then gets taken up

00:35:15.160 by our DNA, and it creates enough of an immune response that we create an immune response to it.

00:35:21.920 How do you think of that overall strategy?

00:35:24.760 So if there's any good news about this virus, it's that we know the part of the virus, the protein in

00:35:30.700 the virus that attaches the virus to cells. If you can prevent the virus from attaching to cells,

00:35:35.480 in theory, you should be able to prevent the virus from infecting cells or, said another way,

00:35:39.080 infecting you. That protein is the spike protein. It's the protein that emanates from the surface of

00:35:43.700 the virus. It gives it its crown-like appearance, hence coronavirus. You also know the gene that codes

00:35:49.600 for that protein. It's an mRNA virus, meaning messenger RNA virus, single-stranded messenger RNA virus

00:35:56.320 like rubella or germane measles. So the initial strategies to make this vaccine are all based on that

00:36:02.620 knowledge. We know the gene that codes for that protein. Take the mRNA strategy, which is the most

00:36:08.640 naked and obvious, which is that you basically take the messenger RNA, which codes for that protein,

00:36:14.420 you inject it into people, it's taken up by the cell in the cell cytoplasm outside the nucleus,

00:36:20.140 it enters the so-called ribosomal system, and it's translated to a protein, which is excreted.

00:36:24.740 So that's your body makes the coronavirus spike protein, then your body makes antibodies to the

00:36:30.180 spike protein. This very similar strategy is the so-called DNA vaccines, and then these so-called

00:36:35.720 replication defective, simian or human adenovirus vaccines, or replication competent vector vaccines,

00:36:42.120 all have the same strategy in mind, which is introduce the gene that codes for the coronavirus

00:36:47.260 spike protein, induce your body to make that spike protein, and then your body will make antibodies.

00:36:52.900 These are so-called genetic plug and play vaccines. The reason that they're the first ones to come out

00:36:58.940 is because they're the easiest to construct and the easiest to mass produce. It doesn't mean they're

00:37:03.740 going to be the last best vaccines, but that's why they're going to be the first vaccines.

00:37:08.060 One question I have for you on that, Paul, is given the instability of RNA, I've always been kind of

00:37:12.720 surprised that they work. I can understand why DNA could work, but given how unstable RNA could be,

00:37:20.560 when you take a single strand of messenger RNA and deliver it, what allows it, I mean, this might

00:37:26.880 sound like a silly sort of technical question, what allows it to make its way into our cells,

00:37:33.060 into the cytoplasm, head over to the ribosome, and then get translated ultimately into protein?

00:37:40.400 So anybody who works with messenger RNA in a laboratory stores messenger RNA at minus 70 degrees

00:37:46.040 centigrade or in liquid nitrogen, because as you say, it's an incredibly labile molecule. It breaks

00:37:51.180 down within moments, frankly. I've burned myself on said vats of liquid nitrogen many a time in the lab.

00:38:00.440 Yeah. So to get around that problem, these vaccines, the messenger RNA vaccines have to be

00:38:06.280 encapsulated in a complex lipid delivering system, which stabilizes them to some extent.

00:38:11.740 And the Moderna has been able to figure out a way to both store and ship and store at minus 20

00:38:18.160 degrees, which is just freezer temperature. But Pfizer, no, they're going to ship and store at

00:38:22.320 minus 70, minus 80, this sort of ultra cold chain, which we've never done in this country, which I

00:38:26.380 think will be a challenge. So you have to constantly maintain that product on dry ice. Once you thaw it

00:38:31.540 out and put it in the refrigerator, it can't be there for more than a day before you give it.

00:38:35.180 You're right. I think the lability of messenger RNA will be a challenge here. And just one sort of

00:38:39.840 nerdy virologist thing that I'd like to say as a nerdy virologist is that when you're infected

00:38:45.560 with this virus, you'll shed infectious virus for a week, roughly. You'll shed infectious virus for

00:38:50.900 a week. You'll be PCR positive, polymerase chain react positive. You can be PCR positive for three

00:38:56.280 months. What you're detecting in the back of the throat is not infectious virus. It's messenger RNA.

00:39:01.900 That's what you're detecting, which means because it's so quickly degraded, why would it be around so

00:39:06.580 much longer? And the answer is the virus is continuing to make messenger RNA, but not making

00:39:11.500 whole virus particles. Why would it do that? I mean, this virus continues to surprise, I think.

00:39:17.280 Let me make sure I understand what you just said, because I never actually thought about it that way.

00:39:23.120 You're saying that, let's say I take the Moderna vaccine. I'm getting a bolus of mRNA. My body is going

00:39:30.820 to just take that and incorporate it and start kicking off protein, but it does two things. It

00:39:36.920 doesn't just take it like one single transcribed piece of mRNA and translate it into protein and be

00:39:42.480 done with it. It actually incorporates it back into the DNA and that cell of mine continues to

00:39:50.400 transcribe and translate it. Is that what you're saying for months? The mRNA will amplify itself in

00:39:55.700 the cell. True. Which cell? Epithelial cells? Like which of my cells? Muscle cells. You'll be

00:40:01.500 inoculated in your arm. It'll be the muscle cells. And then to some extent, also antigen presenting

00:40:05.480 cells like macrophages, dendritic cells. Okay. That's kind of interesting to think about because

00:40:11.700 why would it show up in a throat swap? How is it making it all the way to the epithelial cells in my

00:40:17.120 throat or in my nose or wherever? I guess I'm saying two different things. When you're naturally

00:40:21.100 infected with SARS-CoV-2, that virus then reproduces itself over and over again, part in the back of

00:40:27.480 your throat. And it makes infectious virus particles. It enters your cells. It's transcribed. It's

00:40:32.940 translated. And then it makes new virus particles. But what happens is it's only making new virus

00:40:37.740 particles for about a week. And then it stops making infectious particles anymore. But you still

00:40:42.400 have messenger RNA in the back of your throat. You can for months, which means the virus is still

00:40:46.560 there. It's still in the cell. It's still making messenger RNA, but it's not making a whole virus

00:40:50.680 particle anymore. That's weird. I don't know of any virus that does that. I'm not sure it says

00:40:55.820 anything about the messenger RNA approach. I mean, messenger RNA does amplify itself in your body,

00:41:00.180 but then it's quickly broken down as it's all messenger RNA in your body. It'll be curious to

00:41:05.160 see what happens with this. I mean, we're going to learn a lot with this strategy. We'll see whether

00:41:09.340 it applies to other vaccines possibilities, and we'll see whether or not we run into a problem.

00:41:14.140 Moderna that you mentioned is obviously one of the front runners in this. And I think that's in no 0.97

00:41:17.920 small part to the fact that one of their partners is NIH. That's, you know, National Institutes of

00:41:22.020 Health here in the United States has bankrolled to the tune of about a billion dollars, as you said.

00:41:27.260 Has NIH partnered with anyone else besides Moderna?

00:41:30.060 No, just Moderna. It's their construct that Moderna uses. The nucleoside analogs that are used in that

00:41:36.100 vaccine, that was all developed by a couple of researchers at the National Institutes of Health.

00:41:40.220 Actually, National Institutes of Health, as far as I know, holds the patent on that vaccine.

00:41:43.180 And they basically entered phase three this summer, correct? I mean, I think they're fully

00:41:48.480 enrolled, aren't they? They entered the end of July. As far as I know,

00:41:51.780 they're fully enrolled, but it's hard to know. I mean, it's always trying to read the tea leaves

00:41:54.420 on this. They're strong. Okay. Well, anyone else on the mRNA strategy that you think is,

00:42:00.780 I mean, Moderna is probably the leader, correct? Moderna and Pfizer, both.

00:42:05.600 Let's talk a little bit about the Pfizer platform. How does it differ?

00:42:08.900 Sure. Whereas Moderna gives 100 micrograms per dose in a two-dose series, Pfizer gives 30 micrograms.

00:42:14.940 So it's not the same nucleoside analogs. And I'm curious to know, I'd love to hear a scientific

00:42:19.280 presentation on why Pfizer needs to ship and store at minus 70, which is going to be a challenge as

00:42:24.340 compared to Moderna's shipping and storing at minus, just at minus 20. They are different

00:42:29.060 constructs. So they're given at different amounts and we'll see to what extent any of them work or

00:42:33.960 safe. Now, Pfizer is doing a phase two, phase three combined. Is that correct?

00:42:39.760 They sort of all are. I mean, you sort of went right, sort of skipped through phase two,

00:42:44.260 right to phase three, really. They all did that.

00:42:47.060 Do you think that that distinction, Paul, from a logistic standpoint is going to matter? In other

00:42:52.820 words, when we start to think, let's just assume for a moment that the Moderna vaccine and the Pfizer

00:42:56.980 vaccine have equal efficacy in the real world. So in a phase three trial, we see, call it a

00:43:03.900 70% reduction severity of infection in those receiving the vaccine over the placebo. Would

00:43:10.080 we agree that that's a win? Yes.

00:43:12.340 Okay. All other things being equal, is the need to transport tens of millions of doses of something

00:43:19.740 basically in liquid nitrogen going to pose a challenge?

00:43:23.700 So it won't be in liquid nitrogen, but it will be on dry ice. Is that going to pose a challenge? Yes.

00:43:28.960 I think what worries me in this a little bit is that when you do the studies, which Pfizer's doing

00:43:32.880 and Moderna's doing, you can be comfortable that the companies are very good at overseeing the

00:43:38.300 shipment and storage of that product. And they're making sure that the investigators, they've got the

00:43:42.940 special package in which this vaccine is stored. They're constantly maintaining dry ice. That

00:43:48.040 doesn't worry me. And when it's thawed out and put in the refrigerator, it can only be there for a

00:43:51.640 day. When the vaccine then gets distributed to the world under natural conditions or the United States

00:43:56.820 under natural conditions, how is it going to be distributed? Probably at least in part in like

00:44:01.180 large chain pharmacies. Are the pharmacists going to be as good at doing what was done during the

00:44:06.780 trial? Because certainly, as you said at the beginning, I mean, these are mRNA is labile. And

00:44:11.560 if it degrades and it certainly has the capacity to degrade, will we get less efficacy effect in this

00:44:17.040 of the vaccine in a real world situation than we did in a experimental situation?

00:44:21.280 Yeah. I guess TBD, your best guess of how those companies are signaling when we're going to see

00:44:30.640 data? I mean, it depends in large part on how active the third wave of this is, because this is one of

00:44:37.520 those things where the more people that get exposed, the more quickly we see the difference between the

00:44:44.340 placebo and the vaccine.

00:44:45.300 The company technically doesn't know what's going on in the trial. I mean, technically the company,

00:44:51.260 meaning the CEO, for example, doesn't know who's gotten vaccine, who's gotten placebo, doesn't know

00:44:56.040 who's gotten sick and who hasn't gotten sick, doesn't know how many cases of disease have occurred in

00:45:00.280 the placebo group or vaccine group, doesn't know that. The Data Safety Monitoring Board knows that,

00:45:04.400 which is composed of a group of academics and researchers who are not affiliated with the company

00:45:08.840 and not affiliated with the government.

00:45:10.720 These are being run through large CROs, I assume?

00:45:12.840 Yes. Depends on who's doing it, but yes.

00:45:16.300 For the listener, clinical research organizations, when large companies or even academics do

00:45:20.100 clinical trials, they usually contract out with companies that are exceptional at all the stuff

00:45:25.520 that Paul's talking about, which is the logistics of how do you actually ship this thing from A to B

00:45:30.460 and make sure it goes perfectly? How do you get the blood draw on this person and measure this and

00:45:34.600 all these things? And so that's not an expertise that a company wants to build in-house. They typically

00:45:39.360 outsource that. And it's those companies that are, it's a part of that is the monitoring.

00:45:43.900 But presumably there's a power analysis that's gone into this that said, look,

00:45:48.140 we're going to enroll 30,000 people. We know half of them are going to get a placebo. Half of them are

00:45:51.920 going to get an active agent. We've stratified on some level by age. The inclusion criteria probably

00:45:57.420 says we want people between ages X and Y of a certain, this many of them to be of this health,

00:46:03.320 this many of them to not be of that health. We think the exposure risk at this stage of the virus

00:46:09.680 is, meaning at this life cycle of the virus, we think there's this many more people that can be

00:46:14.360 exposed. The R not is something. Do you think that they can at least get back into an answer which 0.97

00:46:20.540 says, hey, by February, we should know this, good or bad? Or is that simply something that just can't

00:46:26.340 be known a priori? My hope is that these companies do what was recommended actually by the NIH active

00:46:32.680 group that was put together by Francis Collins, which is, it depends on whether it's a one-to-one

00:46:37.780 or two-to-one trial, meaning two vaccines recipients for everyone, placebo recipient or one-to-one.

00:46:43.180 But if that's true, you need at least around between 147 and 160 people to get sick in the trial

00:46:50.620 in order to be able to say you can so-called reject the null hypothesis. The null hypothesis is

00:46:55.760 this vaccine doesn't work. To reject the null hypothesis is to say I have statistically significant

00:47:00.680 robust evidence that says it does. You need 90% confidence interval to be able to say that

00:47:06.280 you need about 150 people. Now, their data safety monitoring board, they're looking all the time,

00:47:10.640 in real time. So they know when they feel you've met a safety or efficacy standard, and then they

00:47:16.500 call the company and they say, okay, now you can submit this vaccine. What would be for a typical

00:47:21.420 vaccine, which is not this vaccine, you can submit it for licensure with a biologic license application.

00:47:26.400 That's not these vaccines. These vaccines were all going to be permitted for use under emergency

00:47:32.220 use authorization. It's different. And that, I think, is what scares people at some level because

00:47:37.080 they saw what happened with, for example, hydroxychloroquine, which didn't work. Now it's

00:47:41.680 been shown clearly not to work to treat or prevent disease, yet it was approved under EUA. Or

00:47:46.400 convalescent plasma, which is to say antibodies taken from people who survived the infection,

00:47:50.820 which, again, was heartily approved by the FDA through this emergency use authorization, also

00:47:56.180 with no evidence that it worked. What's weird about this is that people are doing the same

00:48:00.700 kinds of trials they would do for any vaccine, large placebo-controlled trials, yet it's still

00:48:05.320 not going to go through a biological license application mechanism. It's going through EUA.

00:48:09.340 Just because of time?

00:48:10.440 I think it's because the FDA would not typically license a product that was studied for this

00:48:14.040 short a period of time. So yeah, because of time.

00:48:16.740 Can you just explain to people what the EUA is? I guess by now most people have heard the term,

00:48:20.620 emergency use authorization. It's been granted to not just medications, but frankly, to even

00:48:25.080 testing modalities. Oh, this serology test just got a EUA. This PCR test just got a EUA.

00:48:30.400 What does it actually mean?

00:48:31.920 It's a permission to use something, which is to say that even though there aren't clear data

00:48:35.680 showing that something is safe or effective, or that it's a diagnostic, it clearly works well.

00:48:39.840 We're going to allow it under this condition because we're under duress with this COVID-19 pandemic.

00:48:45.440 So we're going to put it out there in the hopes that it works. I actually wrote an op-ed

00:48:50.600 piece that I submitted to the Philadelphia Inquirer yesterday that I just heard before this show

00:48:54.440 that is going to be published, I think it's Sunday on the Philadelphia Inquirer. But the point I'm

00:48:59.160 trying to make in that piece is that how big of a risk are we taking? If we're going to be studying

00:49:02.880 these vaccines for four months, five months, six months, and we're going to be putting them out

00:49:07.300 there into millions and arguably tens of millions and hundreds of millions of people,

00:49:10.740 are we taking a risk? And I think in terms of effectiveness, you're only going to know

00:49:15.040 that a vaccine is effective for a few months. You don't know whether it's effective for nine months

00:49:19.020 or a year or two years. You don't know that. I don't think that's a huge risk. I think it's

00:49:22.560 likely that it's effective in the short term. It's probably effective in the somewhat longer

00:49:26.760 term. I don't think it's going to be effective for decades, but I think it's likely to be effective

00:49:30.740 at least for a year or two or three. I think. I mean, we'll see. And worst case scenario,

00:49:35.180 you could give a booster dose. That would be the worst case scenario. But then safety,

00:49:38.860 which is what everybody worries about. I mean, have you really studied it enough to say whether it's

00:49:42.560 safe? I'm on the FDA's Vaccine Advisory Committee. We had our meeting on October 22nd,

00:49:47.000 and that dominated the meeting. That nine-hour meeting was dominated by the FDA is basically

00:49:52.380 asking us, are you comfortable as a committee allowing use through EUA, knowing we're not

00:49:58.060 going to have a certain amount of data? What you'll have basically is you'll have two-month follow-up

00:50:02.980 after the last dose for safety issues. Is that enough time? Personally, I think the answer is yes,

00:50:08.620 I do. I mean, if you look at the serious side effects that vaccines occasionally cause, like

00:50:12.820 polio caused by the uropolio vaccine, which occurred in one in 2.4 million doses,

00:50:18.500 or narcolepsy, a disorder of wakefulness that was caused by the squalene adjuvanted flu vaccine that

00:50:23.380 was given in Europe, not in the United States, which occurred in roughly one in 55,000 doses.

00:50:28.780 Thrombocytopenia, lowering the platelet count that occurs with measles-containing vaccine,

00:50:32.280 which occurs in one in 25,000 doses, or something called viscerotropic disease,

00:50:36.780 which is basically a sort of multi-system disease caused by the yellow fever vaccine. It's basically

00:50:41.160 yellow fever caused by the yellow fever vaccine, which occurs in about one in a million doses,

00:50:45.360 or Guillain-Barre syndrome, which is this ascending paralysis, which can affect your ability to breathe,

00:50:50.700 that occurs in about one in a million doses of the influenza vaccine. How soon did you know that?

00:50:56.340 I mean, how soon did you know about those serious problems? Did you know about them within two months?

00:50:59.820 And the answer is yes. I was on a CDC conference call yesterday with a group of

00:51:03.140 folks that are associated with the Advisory Committee for Immunization Practices,

00:51:06.420 and we collectively could not think of a serious side effect that was not picked up after two months.

00:51:11.660 So I'm optimistic that that would happen here as well.

00:51:16.080 When you think of all of the different types of vaccines, we just talked about the mRNA vaccine.

00:51:20.660 We'll get to sort of the viral vectors, the inactivated or attenuated variants,

00:51:25.340 and then obviously just the proteins that are delivered. I want to go through these in some detail

00:51:29.040 and use it as an example to talk about the companies. Are there any of those classes

00:51:33.200 you worry about more than others from a risk standpoint? For example, some of the live

00:51:38.180 attenuated viruses have been the ones that go on to cause... It isn't polio is live attenuated,

00:51:43.140 correct? Your polio vaccine was a live attenuated viral vaccine, yes.

00:51:46.400 Right. And so that's presumably why you had, even though it was a minuscule risk,

00:51:50.800 you still had some risk of getting polio. So do you look at those four categories of vaccines

00:51:55.760 equally from a safety question?

00:51:57.680 I'm not sure we know enough about mRNA, DNA, replication defective, human or simian adenoviruses

00:52:03.840 to say. Here are the things that I worry about though. I worry that you've had three clinical

00:52:09.300 holds for these vaccines. You have one clinical hold with Johnson & Johnson's product, which was

00:52:13.960 a replication defective adenovirus 26. So adenovirus is a virus, human virus that causes a variety of

00:52:20.040 clinical diseases. Type 26 just means it's one of the many types of adenovirus, human adenoviruses

00:52:24.940 that cause disease. Replication defective means that the virus has been genetically engineered,

00:52:28.740 so it can't reproduce itself. But it has also been genetically engineered, so it contains the gene

00:52:33.780 that codes for the coronavirus spike protein. So that when you're inoculated with that vaccine,

00:52:38.460 the cell takes up that particle, which does not amplify itself. It enters the nucleus,

00:52:43.380 it then is transcribed, it's transcribed to messenger RNA, the messenger RNA is translated to a protein,

00:52:48.500 and that protein is excreted. So it's good news, bad news. The good news is it's replication defective.

00:52:53.480 Therefore, it can't cause disease because the virus is reproducing itself. The bad news is

00:52:57.620 it's replication defective, meaning you have to give a lot of virus to get enough of those virus

00:53:02.400 particles into the cell to make the protein you're interested in. About 10 billion virus particles per

00:53:08.500 dose. That's a lot of virus. That's why it is that side effect profile can be a little rough, meaning

00:53:13.900 fever, including high fever, and then symptoms associated with fever, chills, headache, muscle ache.

00:53:18.740 And that was seen fairly commonly, especially after the second dose with these vaccines.

00:53:23.960 Which is also part of the issue with some of the genetic engineering stuff. This is a little off

00:53:27.100 topic, but the use of adenoviruses for genetic engineering even 20 years ago at CHOP, right?

00:53:31.920 I mean, that's a big part of what kind of got into some of the trouble there, isn't it?

00:53:35.500 Yes. That's it. I mean, I'm at Penn. So we're all thinking the same thing, which is Jesse Gelsinger.

00:53:41.500 Gelsinger. Yeah. God, I still remember that story like it was yesterday. It's got to be at least 20 years.

00:53:45.820 He was inoculated with a replication defective adenovirus type 5 that included the gene that

00:53:51.820 coded for one of the liver enzymes that he was missing. He was missing a gene that allowed him to

00:53:56.400 take the ammonia that is a consequence of protein metabolism and excrete it from his body. So the

00:54:01.340 ammonia would build up in his body and then he would get very sick and go into a coma occasionally.

00:54:05.740 So, but he died. I mean, he died because he had a massive so-called cytokine response with

00:54:11.840 something called interleukin-6 at a time before we had antibodies directed against interleukin-6 that

00:54:17.120 would have saved his life. And we all lived through that. And it really set gene therapy back.

00:54:21.980 If it's any consolation, the amount of replication defective adenovirus he got was logarithmically

00:54:26.800 greater, exponentially greater than the amount that we're currently giving here. Even though 10

00:54:30.520 billion sounds like a lot, it's still about one 300th of what he got. But again, you're going into an

00:54:35.380 outbred population with, when you put something into millions of people, you may find something out 0.99

00:54:40.340 that's untoward. So yeah, that worries me. The clinical holds worried me a little bit.

00:54:45.200 The two clinical holds that were for replication defective simian adenovirus, which was the UK

00:54:49.620 AstraZeneca vaccine, were both because of neurological issues. The first was so-called

00:54:55.560 undiagnosed multiple sclerosis. The second was transverse myelitis, which is an inflammation of

00:55:01.460 a segment of the spinal cord. The mechanism by which both of those diseases happen is the same,

00:55:06.720 which is that you make an immune response really to the sheathing of your nerves, and particularly

00:55:11.000 one protein on the sheathing of your nerves, myelin basic protein. Multiple sclerosis is

00:55:15.220 relatively common, but transverse myelitis isn't. That occurs maybe one in 200,000 in the general

00:55:20.080 population. That trial was about 18,000 people big at the time, which is to say 9,000 people got

00:55:25.780 vaccine. And they saw that case. It was adjudicated to be likely to be coincidental and not

00:55:31.340 causal, but it does worry you a little bit because it certainly was a statistical bizarrety. And you'd

00:55:37.140 like to know what the problem was with Johnson & Johnson's vaccine, which you don't. This is the

00:55:41.040 problem with these things. And they're both in the same class, right?

00:55:44.560 They're both replication defective adenovirus. Yeah, exactly. While we're on that topic,

00:55:49.420 aren't these the same classes that were actually approved in Russia and China? Doesn't Russia and

00:55:55.340 China each have something that they've approved for limited use already in this category?

00:56:01.440 Yeah. So China had a replication defective adenovirus type 5, which they actually had

00:56:06.540 approved for use in the military. I'm not sure to what extent they've done it because it seems

00:56:09.100 they've gone in the other direction now and are looking just at an inactivated viral vaccine.

00:56:12.800 That seems to be their focus now. Yeah. I was going to say, do we have any data? I mean,

00:56:17.240 not that we would have any data from China necessarily, but we don't know how many people

00:56:20.840 received that outside of an actual clinical use and if there's been any other safety defects noted.

00:56:26.640 I mean, I have heard they have given it to tens of thousands of people, but what I haven't

00:56:29.840 heard is a result of the phase three trial. So I'd like to see whether or not it actually works

00:56:34.080 would be nice to see. And then the Russian, the Gamaleya Research Institute in Moscow

00:56:38.740 has also replication defective adenovirus vaccines and also is a two dose vaccine,

00:56:43.400 but the first dose is replication defective ad 5. The second dose is replication defective ad 26.

00:56:48.340 That's their vaccine. Vladimir Putin came out in the end of August and said,

00:56:52.100 we are going to now start giving this to our public, the Russian public. We have checked all the boxes,

00:56:57.620 which near as I could tell at the time was doing a small phase one trial. They hadn't even started

00:57:03.020 doing phase three trials yet. So I'm not sure what's going on in Russia. It's hard to know

00:57:06.580 what's going on. I know that I got a call from a Venezuelan reporter who said that that Russian

00:57:11.240 vaccine had been shipped to Venezuela for use. So I don't know what's going on out there,

00:57:14.920 but you really would like to wait for phase three trials to at least prove safety and efficacy at some

00:57:19.420 level before you start giving it to the general population.

00:57:22.120 The other big player here is Merck, although they're a step behind, right? They're mostly

00:57:26.680 phase one at this point. They have a candidate that has made it through phase one yet?

00:57:30.460 I've heard of two candidates. One is the replication competent vesicular stombatitis virus,

00:57:34.280 which although reproduces itself in your body, doesn't really cause disease. That's what they

00:57:37.640 use for their Ebola vaccine. That was Merck's Ebola vaccine. But they also apparently are interested

00:57:42.540 in using their measles vaccine virus as a vector for this as well. So I haven't seen any data yet.

00:57:48.140 But again, just summarizing where we are, we've got Moderna and Pfizer as the big guns on the mRNA

00:57:54.080 front. We've got Johnson and Johnson and then AstraZeneca with Oxford as the big guns on the

00:58:00.260 adenovirus slash viral vector front. Is that fair?

00:58:03.900 Yes.

00:58:04.580 As the leaders. Okay. So then the next sort of category is let's just give you the protein off

00:58:10.860 the virus itself. Let's just rip off a spike protein, give you a whole bunch of them.

00:58:16.600 And when your body sees those, it's not going to be threatened by them. I mean,

00:58:20.460 it's going to be threatened appropriately to make an immune response, but obviously the protein by

00:58:23.860 itself can't hurt you because it has no genetic material with which to take over your cells.

00:58:28.240 As a general rule, how does that strategy work when you think of other non-coronavirus

00:58:31.980 applications?

00:58:33.480 Right. So it's the strategy we use to make the hepatitis B vaccine with which we have had

00:58:37.240 experience since the 90s, early 90s. It's the strategy we use to make the human papillomavirus vaccine,

00:58:42.580 which has been on the market since mid 2000s, around 2006. It's a strategy we use to make one

00:58:47.720 of the influenza vaccines, so-called flu block, which has also been around for years. You have

00:58:52.080 the comfort at least of having a lot of commercial experience with that strategy. They're made using

00:58:56.840 recombinant DNA technology. So in the case, for example, of the hepatitis B vaccine or the human

00:59:01.840 papillomavirus vaccine, you take a yeast plasmid, which is just a small circular piece of DNA.

00:59:06.900 You clone into that the gene you're interested in, which as we've said now a million times on the

00:59:11.440 show, the coronavirus gene that codes for the coronavirus spike protein. You then sort of

00:59:15.760 transfect that into yeast cells, actually just common baker's yeast. And as the baker's yeast

00:59:20.180 reproduces itself, it also makes that protein, which you purify. In the case of flu block,

00:59:24.500 which looks like it's closer to the strategy that's being used by Sanofi GSK collaboration.

00:59:30.300 There, what you do is you take basically an insect virus, so-called bacalovirus. You clone into it again,

00:59:35.620 the gene that you're interested in, the coronavirus spike protein gene, and then you infect insect

00:59:39.640 cells. And then that protein actually forms rosettes as it's excreted from the cell. That's

00:59:44.780 where you make flu block, which I actually got this year as my influenza vaccine. And I'm still alive.

00:59:50.280 That's quadrivalent?

00:59:51.700 It's quadrivalent, yeah.

00:59:53.060 So you mentioned obviously Sanofi GSK. That's one of the big guns. They're not in phase three yet,

00:59:59.000 are they? They're going to start that next month?

01:00:01.620 Novavax is the other one that does purified protein, those two.

01:00:04.760 And Novavax is in phase three.

01:00:07.720 That's what I heard, yeah.

01:00:09.400 Yeah. But GSK Sanofi is next month for phase three.

01:00:13.600 Novavax was enrolling in November. They've started, and Sanofi was starting to roll in

01:00:18.060 December, so it should be soon.

01:00:20.280 Is there anything about this approach that tends to go really wrong? Me not being a virologist and

01:00:25.920 not knowing much about vaccines, of the three approaches we've discussed so far, I guess the

01:00:32.180 four, because we've already alluded to what the fourth strategy is, which is a live attenuated

01:00:36.380 virus. The protein-based delivery seems the most benign. Is that necessarily true?

01:00:42.840 I think that's fair. It's just a purified protein. Certainly we have a lot of history,

01:00:47.140 decades worth of history doing that approach successfully. If you look at Shingrix, which is, 0.99

01:00:52.700 again, a purified protein, it's just one of the proteins from varicella zoster virus,

01:00:56.600 that vaccine actually works better than the live attenuated viral vaccine, Zostavax.

01:01:01.960 And essentially it's replaced Zostavax.

01:01:04.260 We basically two years ago said, we're done. It's 100% switched to Shingrix now. Shingrix rather,

01:01:10.040 yeah.

01:01:10.380 Which is amazing. I mean, typically, historically, live attenuated viral vaccines always work better

01:01:15.600 than a single protein. The difference was the adjuvant. Shingrix has two powerful adjuvants.

01:01:20.940 Which we sort of separate, I think, by like six months or something?

01:01:23.320 No, no. They're all part of that vaccine. So one is monophosphorolipid A. The other is the

01:01:27.720 so-called QS21. That's all part of the varicella zoster virus. Glycoprotein E has these two

01:01:33.660 adjuvants that are all part of the vaccine. Oh, I see. But we give Shingrix in two... Is the

01:01:39.400 second one just a booster? You give two doses, right? It's the same thing. It's both contained

01:01:43.840 the same. Understood. Okay.

01:01:45.080 The adjuvant that's being used in the Novavax product is actually similar to the adjuvant in the

01:01:48.780 Shingrix product. So you wonder if you had to take a guess, maybe this would be the vaccine that

01:01:52.600 would be best for older people because that vaccine works remarkably well in older Shingrix 1.00

01:01:57.020 does. So this brings us to our fourth category then, which again, we've talked about, which is

01:02:01.000 these attenuated or live attenuated vaccines or inactivated vaccines. Now, this is something where

01:02:07.100 I think China has a number of products in the pipeline. I don't believe that there... Is there

01:02:12.380 a European or American counterpart in this space? Not that I know. It looks like all the inactivated

01:02:17.840 vaccines are coming out of China and they've done a lot with it. You could argue that could be the

01:02:21.920 first vaccine that is commercially available, if you will. The first one to have a clear phase three

01:02:28.140 trial. At least you should for my understanding for how much many people have been immunized in China

01:02:33.720 already. So let's talk a little bit about some of the other things that are going on here. We,

01:02:40.840 I think, I have to be honest, I'm very surprised. I think in March of this year, I did not think it was

01:02:47.580 plausible that there would be a vaccine on the market within a year. In fact, I probably would

01:02:52.980 have used the words impossible if you said to me in March, can there be a vaccine in a year? And by

01:02:59.480 the way, that wasn't just based on the financial thing. I mean, when I asked you that question

01:03:04.060 earlier, Paul, you alluded to how the government financially completely de-risked the operation.

01:03:10.300 And I won't diminish that in any way, shape or form. I just didn't think it was going to be from a 1.00

01:03:16.000 manufacturing standpoint possible enough to make enough GMP stuff at volume and actually put it

01:03:24.480 into clinical trials. I was like, there's no way. Like there's no way in 12 months we can get there.

01:03:29.180 Well, it turns out I was wrong. We're probably going to have vaccines on the market by January.

01:03:34.640 So let's start with a question about genetic drift. What do we know about how much the genome

01:03:41.120 of this thing is moving? So it's a single-stranded RNA virus. And like all single-stranded RNA viruses,

01:03:47.500 its replication isn't terribly faithful. Or said another way, it probably mutates to some extent

01:03:52.260 every time it reproduces itself. The critical question is, does it mutate in a manner that

01:03:57.080 causes a functional change? And by functional change, I mean more or less contagious or more

01:04:01.980 or less virulent. Or from the standpoint of the vaccine, does it mutate away from the vaccine so that

01:04:07.580 immunization or natural infection one year doesn't protect you the following year, which is the

01:04:11.560 influenza story. Influenza is also a single-stranded RNA virus, segmented RNA virus. But measles is a

01:04:17.320 single-stranded RNA virus too, so is mumps. And they have different genotypes, meaning that there is

01:04:21.880 drift, as you say, to cause there to be different strains, but never has measles really changed its

01:04:28.380 serotype. So the vaccine that worked in 1963 still works today. And so the question is, which of those,

01:04:34.580 is this virus going to be influenza-like, or is it going to be measles-like? I'm going to predict,

01:04:39.980 I'm happy to make a series of predictions, as long as you don't hold me to them. I would say that

01:04:44.640 I'd be surprised, although the virus continues to surprise, it is going to be more than a single

01:04:49.500 serotype disease. In other words, that a vaccine that works now could well work next year and the

01:04:53.840 year after that. Let's just make sure everyone understands what you said, because you said a lot

01:04:58.040 of interesting and important stuff there. Single-stranded RNA is, to put it mildly, a little sloppy.

01:05:04.580 That means every time this guy reproduces itself, it makes a little bit of a mistake. Sometimes those

01:05:11.140 mistakes don't mean anything. Sometimes they do. It's yet to be determined. There's two things,

01:05:16.260 at least, that matter with respect to the fidelity with which it can reproduce. One is, does it change

01:05:22.160 the properties of how the virus responds, either making it less toxic to us as humans or more toxic

01:05:28.400 or pathogenic to us as humans? I think it's definitely too early to say if that's happening one way or the

01:05:33.100 other. But the second property about its ability or inability to replicate itself perfectly is if it

01:05:40.540 makes so many changes in its replication cycle, it might look so different year after year after year

01:05:47.360 that our immune system, even if able to maintain robust immune cells that recognize the virus,

01:05:55.240 may functionally be duped by it because it looks so different each year. That's why we get flu shots

01:06:01.000 every year and we get MMR once, even though they're both single-stranded mRNA viruses.

01:06:06.300 You're basically saying if you had to guess, this is going to be between them. So it's not going to

01:06:12.640 be changing so dramatically every year that we would need to go through this exercise annually. Is that

01:06:18.360 what you're saying?

01:06:19.420 Yeah, I'm going to predict actually it's going to be more measles-like, that it's not going to drift

01:06:23.340 in a manner that means that the vaccine no longer works. That'll be my prediction,

01:06:27.860 but I have been wrong about this virus before. The good news is, I mean, I think we're getting

01:06:33.360 to about a year on this thing. And I think the virus we're seeing today does not look meaningfully

01:06:38.500 different from that, which was identified in January. So hopefully that speaks in your favor.

01:06:43.360 Do we have a sense of how these vaccines are working at the real molecular level? Obviously,

01:06:49.620 we love to look at immunoglobulins as a proxy for immune response. So, hey, this generated IgG and IgM,

01:06:57.080 but there's been a lot of talk about the solubility of those things. And are those immunoglobulins

01:07:03.540 actually active? Just because they're present, do they actually have the binding capacity to the

01:07:08.260 virus to actually eradicate it? Of course, there's been a lot of talk about T-cells and how some people

01:07:14.540 might be getting a less aggressive version of COVID because perhaps they had some T-cells that

01:07:22.140 recognized a separate coronavirus that they may have had six months sooner. What's your thinking,

01:07:29.200 or what's the latest thinking on those hypotheses and ideas?

01:07:32.600 This virus, SARS-CoV-2, is essentially a bat coronavirus that just reared its head in Wuhan

01:07:38.320 in the middle of November of last year, and now has swept across the world and made its debut in the

01:07:45.200 human population. We are infected with human coronaviruses all the time. I mean,

01:07:49.700 there are four strains of human coronaviruses that circulate. They were first identified in

01:07:53.260 the early 1960s. They're no doubt circulating well before that. They cause respiratory infections,

01:07:58.700 meaning congestion, cough, runny nose, occasionally more severe disease, pneumonia. They account for

01:08:03.740 probably about 15 to 20% of the diseases that we see in our emergency department or in our hospital

01:08:09.480 every year. And that's pretty much invariant. The question is, because the human coronaviruses do share

01:08:15.280 some similarity to this bat coronavirus, which is recognized by what's called helper T-cells,

01:08:20.680 does your previous experience with human coronavirus, which we pretty much all had,

01:08:24.540 mean something to us in terms of protecting us against this virus? I don't think so,

01:08:28.580 is my sense of it. In terms of what works, I mean, I guess I'm very simplistic on this based on my

01:08:33.860 experiences with rotavirus. I think the trick is keeping the virus from binding to cells. It's really

01:08:38.280 the way the measles vaccine works, the way the mumps vaccine works, the way the rubella vaccine works,

01:08:42.060 the way the varicella chickenpox vaccine works. If you can prevent the virus from binding to cells,

01:08:46.280 you can prevent the virus from entering cells. So when you make antibodies, are those antibodies

01:08:50.480 directed against the so-called part of the spike protein, the receptor binding domain of the spike

01:08:55.900 protein that is neutralizing the virus? You want to neutralize the virus. You don't want to just

01:09:00.000 bind to the virus. You want to neutralize it so it can't attach to cells. And that's the business end

01:09:05.760 of the SARS-CoV-2 spike protein is that so-called receptor binding domain. So that's the question.

01:09:11.060 And the other question I think that people are worried about is that antibodies can fade

01:09:14.340 over time, even if they're natural infection. So what does that mean for a vaccine, if antibodies

01:09:18.660 fade? And this is a little complicated, but when you're inoculated with a vaccine or when you're

01:09:23.020 naturally infected with a virus, it's not just that you make antibodies, you induce immunological

01:09:27.100 memory. So you have memory B cells, the kind of cells that make antibodies, or memory T cells.

01:09:32.780 And so they're sort of like the base of the iceberg with the antibodies being the tip of the iceberg.

01:09:36.640 Do they matter? They do matter, especially for longer incubation period diseases. So for

01:09:42.540 really short incubation period diseases like rotavirus, meaning the time from when you're

01:09:46.880 infected to when you get sick, rotavirus, influenza, respiratory system virus, those have short incubation

01:09:52.180 periods. This is sort of a medium length incubation period, around six, seven days. Measles is much

01:09:57.020 longer, sort of 10 to 14 days. For longer incubation period diseases, there's enough time then

01:10:03.280 for activation and differentiation of memory cells to become, in the case of B cells,

01:10:08.180 antibody secreting cells. So it still would work. I think that's where we're going to be. So I think

01:10:12.500 memory is important. So when people talk to me about how nervous they are that antibodies are fading,

01:10:17.380 I'm not sure you should be nervous about it yet. Let's wait to see what happens as we move forward

01:10:21.520 with these vaccines. Yeah, I think that's a great point, Paul. And I think there's really two points

01:10:25.840 you made there that speak to that. The first is, it's not antibodies that probably matter. It's

01:10:30.260 neutralizing antibodies. And frankly, we don't have commercial tests for that. So I don't know how

01:10:35.040 much it matters that your serology test that's measuring IgG and IgM levels over time is changing

01:10:41.280 when that's not actually, or certainly not necessarily the thing that we care about. We

01:10:46.920 care about neutralizing antibodies, not antibodies. Your second point is just spot on, which is unless

01:10:53.060 somebody is sampling bone marrow, looking for B cells that have memory, again, maybe this doesn't

01:10:59.140 matter. And we at least, if there's one upside to having the long incubation period, which has

01:11:05.300 allowed this silly virus to replicate like crazy and spread around the world, at least it's that the

01:11:10.920 immune system gets some chance to rev up against it. I guess I always think of it that way, like 0.96

01:11:16.260 biology usually takes something and gives something, right? It's like, if this thing had no time between

01:11:22.100 when you were infected and when you got sick, you'd probably get sicker because you wouldn't have any of

01:11:27.540 that memory response, but at least it would have been contained or sort of have the opposite

01:11:31.060 problem. That's a glass half full way to look at this, I suppose.

01:11:34.400 Let me offer one thing just as hopeful because as you get older, you get sort of grimmer, but I'm

01:11:38.620 trying to offer some hopeful thing. But it appears that, especially in men, there were two papers in

01:11:43.260 science that showed that when you're infected with this virus, SARS-CoV-2, that you can actually make

01:11:48.220 antibodies directed against interferon, which is a protein that your body's immune system makes to help

01:11:53.200 fight viruses. That's where the name comes from. It interferes with the ability of virus to infect

01:11:57.740 cells. And the thinking is that that may be one reason why men are more likely to suffer and die

01:12:02.320 from this disease than others. This offers hope for the fact that a vaccine may be better than natural

01:12:08.000 infection, because it's unlikely that a vaccine would do that. There certainly are examples of

01:12:12.360 vaccines that are better than natural infection. This may be one of them. There's some reasons for hope

01:12:16.280 here. Do you see any differences in male versus female on vaccine, or do you think no? I mean,

01:12:21.800 there's nothing that has been published to date that has suggested a gender disparity between this?

01:12:27.060 No. As a general, men tend to die and boys tend to die at a greater frequency than girls for most

01:12:33.700 infectious disease. We are the weaker sex, or as Murphy Brown used to say, that silly little Y chromosome. 0.97

01:12:39.960 Do you think that's a response to a greater cytokine response, or what do you think accounts for that 0.55

01:12:45.080 difference? I'm not sure. Even when we age match and we match for morbidity, we don't know why?

01:12:51.800 We're the weaker sex. Let's admit it.

01:12:54.980 A bit off topic, blood type. There was a lot of talk earlier about anti-A antibodies potentially

01:13:01.020 being a little bit protective. Do we have more data on that?

01:13:03.700 I hadn't seen it. Having type O blood would be some level protective, because you can make

01:13:08.960 antibodies to A or B types. I think I would still put that in the hypothesis unproven category.

01:13:13.860 Okay. Do we have any data on the robustness of the immunologic response, at least based on phase

01:13:23.740 two metrics in different demographics, starting with young versus old, obese versus non-obese,

01:13:30.660 or some other metric where it's going to matter? Because at some level, there's going to need to be

01:13:35.720 some rationing of this, right? It's not like vaccine gets approved on Wednesday, and on Thursday,

01:13:41.760 300 million copies of the vaccine show up to everybody's doctor. So whether we like it or not,

01:13:47.160 there's a slow roll and a partition to how this happens. What do we know about it in that sense,

01:13:52.200 in terms of how people are responding to it, and who's most vulnerable, and who should be getting it?

01:13:55.720 Both the National Academy of Medicine and the Advisory Committee for Immunization Practices at the CDC

01:13:59.940 have come up with their first-tier group. But it's huge. The first-tier group includes

01:14:04.580 healthcare workers. It also includes other essential personnel, like people who work in

01:14:09.320 mass transportation, or grocery stores, or pharmacies, or work in law enforcement, or sort

01:14:14.200 of water purification. That includes people over 65, who, when they get infected, are more likely to die.

01:14:20.100 And it includes people with certain high-risk medical conditions, like obesity, which is probably

01:14:25.140 30% of the American population, and diabetes, and chronic obstructive pulmonary disease, et cetera.

01:14:30.960 If you add that all up, it adds up to about 150 million adults, which is half the adult population

01:14:37.020 in the United States, who are going to require a two-dose vaccine, which is already 300 million

01:14:42.300 doses. And that's not going to happen immediately. So how do you partition that? I don't know. I mean,

01:14:47.880 I'm on this Commonwealth of Pennsylvania group that tries to make decisions like that. I'm on our

01:14:52.760 hospital group to try and make decisions like that. I think it's going to be a real learning curve

01:14:57.380 that's associated with how this rolls out. What are we prepared to do about that? Is this

01:15:01.500 going to produce social unrest? It sounds crazy, but have we ever experienced something like this

01:15:07.120 from a healthcare delivery standpoint? No. I mean, this is a virus that's killed 230,000

01:15:11.620 people. So this may be sort of like the end of the movie Contagion, where people are like breaking

01:15:15.560 down doors trying to get a vaccine, where vaccines were the hero of that story. I think there is going

01:15:20.580 to have to, at some level, be a rationing in terms of who gets what and how it's going to be done. And

01:15:26.840 I don't know. It's really complicated, right? So Moderna is basically the NIH, Pfizer, J&J,

01:15:34.080 AstraZeneca, and Oxford. I mean, these companies have presumably never been in a situation to have to

01:15:40.500 say, here's where this shipment goes to this pharmacy versus that pharmacy, or this city versus

01:15:46.300 that city. I mean, not to dwell too long on a seemingly strange question, but we're not that

01:15:51.400 far from when this is going to happen. We're only a couple months away from that, potentially.

01:15:56.520 So it's the Department of Defense that's going to take the lead at Operation Warp Speed for

01:16:00.520 determining where these vaccines get distributed, but they'll be distributed to the states. And then

01:16:05.720 the states, I think, will decide how to sort of apportion that, is my sense of it. The CDC initially

01:16:10.740 had sort of four states in one city, which was Philadelphia, actually, to try and do kind of this test

01:16:15.440 program for how it would be distributed. Now, Pfizer is not an Operation Warp Speed vaccine,

01:16:20.340 so they may have a different distribution strategy. But I think you're right. It's going to be a real

01:16:26.540 challenge, plus it's a two-dose vaccine, plus it means you have to get people back for the second

01:16:30.360 dose, and some of these vaccines are going to be stored at minus 70. It's going to be really a

01:16:34.920 challenge to see how we get it out there. I mean, we had one issue in our hospital, which was easily

01:16:38.820 resolved, which was, should we mandate the vaccine for hospital workers? No. One, for the practical

01:16:44.020 reason that we probably won't have a lot of vaccine. And two, I think that with a novel

01:16:47.280 vaccine strategy like messenger RNA or these replication-defective viruses, I don't think

01:16:52.220 you really can fairly mandate that. I think you really should wait till it's out there a little

01:16:56.400 more. There's going to be plenty of people who are going to be perfectly willing to take these

01:16:58.960 vaccines, and then we'll have a few million doses out there, and we'll have a better sense of

01:17:03.100 things. Maurice Hilleman, who I consider the father of modern vaccines, having either done the primary

01:17:07.680 research or development on nine of the 14 that we use, said it best. He said, quote,

01:17:12.300 I never breathe a sigh of relief until the first three million doses are out there.

01:17:16.420 So we'll see.

01:17:18.080 Personal question, would you take the vaccine right now?

01:17:21.360 Not till I see the data. The good news, I'm on the FDA vaccine advisory board, so I will see the

01:17:25.780 data. And if I feel confident that the safety issues look good, issues look good for people my age. I

01:17:31.740 mean, I'm over 65. I want to feel I'm adequately represented in these trials.

01:17:36.200 At a sample size of 30,000, of which, let's say, a third of them are over 65,

01:17:42.300 would 10,000 people over 65 having no adverse effects in three months make you feel comfortable

01:17:49.360 enough to take it? I think it would, yes.

01:17:52.040 Okay. And I'm going to point something else out to the listener who can't see you.

01:17:56.420 You at least look to my eye as a very healthy 65-year-old. You look like you're about 55.

01:18:02.300 You're not overweight. I assume you don't have diabetes. You look like a model of health.

01:18:06.880 So are you really that high risk aside from your age? And if so, why are you taking it?

01:18:12.060 Just my age.

01:18:12.960 Okay. So do you still believe that age by itself is enough of a predictor of morbidity beyond

01:18:20.480 the obvious comorbidities that tend to track with age that presumably, at least, let's just assume

01:18:26.280 you don't have them. Not that I'm asking you to disclose any medical things, but you're about as

01:18:29.860 healthy a 65-year-old as there's going to be out there.

01:18:32.200 I would take it not because I necessarily think I'm going to die from this virus. It's because I

01:18:36.040 think that way I feel between taking a vaccine and wearing a mask and social distancing, I

01:18:42.080 dramatically decrease having to suffer this virus. I mean, the virus, yes, it's a killer. And yes,

01:18:47.360 it can cause pneumonia, which can kill you. What scares me the most about this virus is that

01:18:51.400 it can cause vasculitis. I mean, who would have predicted that? It causes this multi-system

01:18:56.460 inflammatory disease of children. And it can affect, it can cause heart attacks, it can cause strokes,

01:19:01.420 it can cause liver or kidney disease because it causes vasculitis. So why does it cause vasculitis?

01:19:06.240 It doesn't really enter the bloodstream. Fewer than 1% of people infected with this virus have

01:19:10.200 so-called viremia. So it induces your immune response to damage endothelial cells that line

01:19:15.340 blood vessels. And because every organ in your body has a blood supply, every organ can be affected.

01:19:19.940 I mean, the so-called long haulers, at least in part, are probably determined by a vasculitis,

01:19:25.060 maybe even at low level. That's what scares me about this. This is not a virus that just gets in,

01:19:29.060 kills you and gets out, or gets in, makes you sick and gets out. There are longer term effects

01:19:33.480 with this virus and it should be taken seriously. I mean, I think when the administration occasionally

01:19:37.940 says things like, you need to embrace this virus or live with kind of, you know, this kind of notion

01:19:42.520 that the virus would eliminate itself by population-induced immunity, which has never happened

01:19:47.020 for a virus before. I think they sort of ignore the fact about the long-term issues of this particular

01:19:51.520 virus, but this isn't flu. I think of all the sort of lingering tail events of this virus,

01:19:57.220 the one that probably concerns me the most is some of the cardiomyopathy that we're seeing

01:20:02.000 persist in, especially in young people. On a personal level, I've just had to strike a balance

01:20:06.520 between living my life, but still trying not to be reckless. And to me, that's a really bad outcome,

01:20:13.480 right? Is the probability that I'm going to die from this low? Yeah, it's staggeringly low,

01:20:19.380 but there's some risk that I can't quantify of cardiomyopathy or some lingering respiratory

01:20:26.580 thing that never fully resolves that impairs quality of life. I guess the real question is just

01:20:31.960 the trade-off between how efficacious in the real world, and therefore I guess effective is the better

01:20:38.620 word, do I think this vaccine is relative to what other risks? I think what I'm hearing from you that

01:20:43.040 I actually find heartening is at least using history as a guide within a few months of this vaccine

01:20:51.300 coming out and entering the real world, which we can think of as phase four. We'll think of that as

01:20:56.860 post-market surveillance phase four. We're going to have a pretty good sense of it. And most of us

01:21:03.260 listening to this podcast are not going to be the guys getting it on day one, just due to the simple

01:21:08.060 logistics of it. Like I'm not going to be in the first million doses of this vaccine. You aren't

01:21:13.980 going to be in the first million doses of this vaccine. There are people, frankly, who are at much

01:21:18.400 higher risk that deserve to be there. And I guess we'll have a better sense of it. But I think that

01:21:23.440 this discussion for me, Paul, is also interesting because it really frames the four different types

01:21:28.740 of strategies that one can go about doing this, who the players are and what the risks are

01:21:34.020 potentially in each of them and why maybe a Sanofi product ultimately might end up being safer than,

01:21:39.940 say, a J&J product. The devil's in the details. The only thing that's going to matter is, hey,

01:21:44.380 how do these things look six months after they've been on the market? The other thing I wanted to ask

01:21:49.100 you about is, is there ever going to be a time when we're going to be immunizing children against this

01:21:55.540 virus? I mean, what do we know today about kids getting infected by this? We know that children

01:22:00.720 are less likely to be infected and when they're infected are less severely infected. I mean,

01:22:05.460 of the people less than 21 years of age in the United States, make up about 26% of the population,

01:22:11.280 yet they account for 0.08% of the deaths. That said, about 120, at least the last morbidity

01:22:18.020 mortality week, the report showed that about 120 children had died from COVID-19. That's not very

01:22:23.480 different than the number of children that died from influenza last year, which was around 140.

01:22:27.320 That's what it usually is, around anywhere 140, 150, 160 in that area. So it's no more or less fatal

01:22:34.900 than influenza for children. Two, it can cause long-term problems in children with the so-called

01:22:40.640 MISC disease of children. So I think there is a compelling desire to make a vaccine for children.

01:22:47.500 So how to do that? Now, all the trials initially were done in people over 18. So we weren't studying

01:22:52.160 children initially. Now, recently Pfizer sort of dropped the age to 16 and then they've dropped the age to 12.

01:22:56.320 So they're starting to look at younger people. So the question is then, what happens, and this applies

01:23:01.780 broadly, what happens if a vaccine is approved through EUA? Pfizer has already said, if that happens for

01:23:06.980 them, they're going to start to immunize their control group, which means now you lose information

01:23:11.220 about safety and efficacy moving forward. Why is that, Paul? Is that basically as a thank you to the

01:23:16.780 control group and basically a crossover? Look at what that does. From a scientific standpoint, you just

01:23:22.000 lost your test case, but what is the rationale for doing that?

01:23:25.940 I think it's a thank you for being, and that may have been part of the deal when they signed up for

01:23:29.340 the trial. I don't know. Yeah, got it. Okay. To get to the children, this could be done in one of

01:23:34.080 two ways. It could be done as a placebo-controlled trial, it's the same way we do adults, or it could

01:23:39.280 be done as immunobridging studies, meaning that you actually find out there is an immunological

01:23:42.960 correlate of protection in adults, that it is a certain level of neutralizing antibodies that's

01:23:47.440 evoked. And then if you give to children a certain dose, that you find that you get that level of

01:23:51.600 neutralizing antibodies, and so then you just move forward. And then you look retrospectively,

01:23:55.620 because not all children will be inoculated at the moment that you start inoculating children,

01:23:59.580 you can see whether or not it's... It's basically the same way that it worked with the Ebola vaccine.

01:24:04.200 I mean, that wasn't a prospective placebo-controlled trial in West Africa. People just started getting

01:24:08.560 vaccine, and because not everybody got it at once, you could get a sense of effectiveness

01:24:11.900 by knowing who got the vaccine and who didn't. So that may be it. When we had the FDA vaccine

01:24:16.900 advisory committee meeting on October 22nd, the FDA was very clear about this, that when you approve

01:24:21.660 something under emergency use authorization, which is the same sort of permission you would give to

01:24:25.940 an investigation of a new drug, you were really under no ethical obligation to vaccinate a placebo

01:24:30.420 group. You aren't. And nor are you under an ethical obligation to no longer do placebo-controlled

01:24:35.300 trials. Now, I'm not sure how that's going to play out. I mean, you can see, for example, if somebody's

01:24:39.840 70 years old, they see that this vaccine works, and they were in the placebo group, they can say,

01:24:44.380 I want this vaccine. So what the FDA has argued for is why not just make it an expanded access

01:24:49.780 issue or extended access, which is what used to be called compassionate use access, but do it that

01:24:55.440 way. And I think that may be the way this plays out. I don't think I'm making a bold prediction by

01:24:59.780 saying I think the first vaccines may not be the last best vaccines, but you have to know that you

01:25:03.940 have the last best vaccines. You have to know that down the line, there may be a vaccine that's 90%

01:25:07.520 effective. And you can't know that unless you do it as a placebo trial. And again, if you're going to do it

01:25:12.900 with the other vaccine as a trial, the thing that would require a huge trial, I mean, really,

01:25:18.220 you'd be hard to prove it. You actually wrote an interesting paper this summer about the role of

01:25:24.620 fever in fighting infection in children. I was really surprised at the results. And I got to tell

01:25:32.480 you, it's kind of changing the way I think about how much Tylenol I kick around the house. You want to

01:25:38.480 talk a little bit about what that paper showed while we're on the topic of kids?

01:25:41.260 Right. You actually wrote a book called Overkill When Modern Medicine Goes Too Far. And that's the

01:25:45.520 first chapter sort of in defense of fever, that treating fever can prolong or worsen illnesses. And

01:25:50.580 the reason is, is that pretty much everything that walks, crawls, flies, or swims on the planet can make

01:25:56.160 fever. Why do we do that? We do it because our immune system actually works better at a higher

01:26:01.640 temperature. It's not because viruses or bacteria die more quickly at a higher temperature. It's because

01:26:06.100 your immune system works better. B cells make antibodies more efficiently. Neutrophils are

01:26:10.860 white blood cells that form pus can travel to areas where bacteria are and kill bacteria more

01:26:15.560 efficiently. So if that's true, if your immune system works better at a higher temperature, then

01:26:19.560 are there studies done showing that people who are given anti-fever medicines like Tylenol or

01:26:25.360 ibuprofen, do they do worse? And the answer is redundantly, yes. And in the world of vaccines,

01:26:31.080 when people choose to treat fever with anti-fever medicines when they've gotten a vaccine, you have

01:26:36.280 a lesser immune response. I mean, over and over again, this has been shown, yet we just can't help

01:26:41.660 ourselves because we want people to feel better or we want ourselves to feel better. But know this,

01:26:45.780 that you are hurting one part of your immune system when you do that.

01:26:49.400 Is there a danger at some point, Paul, of kids having fevers when the temperatures get too high? I mean,

01:26:54.840 I always feel like that's the one thing that scared the hell out of medical students or residents,

01:27:00.060 was you'd see those kids with febrile seizures. And so you have that image in the back of your mind

01:27:04.840 of that kid in the ER that's seizing. And then God forbid, they go on to have some neurologic

01:27:09.840 consequence. And so you're sort of hardwired to think, well, God forbid, I'm ever going to let a

01:27:13.580 child have a fever again. What's the risk of that? And at what temperature is that something that a

01:27:18.380 parent needs to be aware of? So so-called febrile seizures are benign. I mean, my daughter actually

01:27:23.220 had a febrile seizure. They're generally short-lived. They don't have long-lasting sequelae. And it's not

01:27:27.200 the height of the temperature. It's the rapid rise in temperature that causes that. So it's not

01:27:31.100 height. And for the most part, I'm going to say for the most part, I think physiological fevers

01:27:34.740 don't cause harm. Your body is not interested in hurting you in that way. Now, environmental

01:27:39.060 fevers can. Heat stroke. I mean, the laborer or the athlete or the soldier who's out there in heavy

01:27:44.020 gear and on a hot day and is not able to dissipate heat through sweating, they can suffer strokes.

01:27:49.400 I mean, it's, you know, you can die from heat strokes. In fact, about 600 people die from heat

01:27:53.080 strokes every year. So environmental fevers can do that, but not physiological fevers.

01:27:57.200 So again, I think you jump with a net. It's just very hard to watch this. A case actually

01:28:01.640 near a hospital of a boy, a soccer player was hit on the hip. He had a clot in a vein,

01:28:06.720 so-called thrombosis. And then that got infected, so-called thrombophlebitis, with staph, the MRSA,

01:28:12.560 the sort of hard to treat staph. Traveled to his brain and caused abscesses. It traveled to his

01:28:16.540 lungs and caused abscesses. It traveled to his bone and joint and caused abscesses. We were

01:28:19.900 treating with an antibiotic vancomycin that should have treated that, but he was continually

01:28:23.260 positive, had blood cultures that continued to show he was shedding bacteria. And every day,

01:28:28.620 every two hours, we were rotating, you know, either Tylenol or ibuprofen. Finally, I met with a boy,

01:28:33.000 I met with the parents, I met with a nurse, and I said, stop treating his fever. Just give his body

01:28:37.640 a chance to have every part of his immune system working for him. And then within really about a

01:28:42.580 day and a half, there's no longer shedding bacteria. That may have been a complete coincidence. It's not a

01:28:46.880 proof in any sense, but you couldn't convince the parents of that. They thought we were geniuses by

01:28:50.800 doing it that way. Give his immune system a chance to work as good as it can. Why cripple his

01:28:55.220 neutrophils ability to ingest and kill bacteria by giving him anti-fever medicines? We think we're

01:29:00.180 helping. Is there any scenario then, Paul, in which, I mean, that's a pretty compelling case. Is there

01:29:04.440 any scenario under which you would recommend taking something like Tylenol? I think if somebody cannot

01:29:09.040 handle the metabolic strain of increase of, I mean, because you increase your basal metabolic rate

01:29:14.440 a certain percentage for every degree centigrade increase in your fever, I think it's like 12% increase in

01:29:19.340 BMI for every degree centigrade. But so if you have chronic lung disease, chronic heart disease,

01:29:24.100 metabolic disease that makes you unable to handle that rise in temperature, sure. I think that's

01:29:28.080 the reason. But otherwise, no. Wow. So suffer it out, huh? Yeah. And that's that boy. I love this

01:29:34.220 boy. He was a teenager, a young teenager. And he was just brave. He was, okay, fine. Everybody was in.

01:29:39.720 We were going to do this thing. And nurses were in. We were going to ride it out. And then

01:29:44.040 he did better. All right. Last thing I want to say on vaccines, just to kind of close the loop on this,

01:29:49.240 are there viruses besides the obvious, like HIV and even hep C, I guess, where just vaccinating

01:29:56.040 them is either impossible or outright dangerous? I mean, there was something about RSV, which we've

01:30:01.760 talked a little bit about that, I mean, RSV is really common, but there's no vaccine to RSV.

01:30:07.060 Is that just that it's not cost-effective or was there sort of a more technical issue with it or a

01:30:12.080 risk associated with creating vaccine towards it? The more technical issue of creating a vaccine,

01:30:17.440 there were two events that occurred in the 1960s. One was with RSV where Bob Chanik, head of the

01:30:22.920 Laboratory of Infectious Diseases at NIH, wanted to make an RSV vaccine. This is a virus that causes

01:30:28.100 pneumonia. It causes about 5,000 deaths every year in the United States, primarily in young children,

01:30:32.820 especially premature children, babies. So let's make an RSV vaccine. He took the virus, grew it up,

01:30:38.300 and activated it with formaldehyde, just the same way that Jonas Salk made his polio vaccine,

01:30:42.040 and then gave it to babies. And what he found was that children who got that vaccine did worse.

01:30:46.080 They were more likely, when they were then exposed to the natural virus, they were more likely to

01:30:50.020 develop pneumonia, more likely to be hospitalized. In the case of two children, more likely to die

01:30:54.300 than children who never got that vaccine. Same thing happened with the measles vaccine in 1963.

01:30:59.440 Take the virus, grow it up, purify it, kill it with formaldehyde. That too caused children to have

01:31:04.680 an aberrant immune response directed against that measles virus that causes atypical pneumonia. So they

01:31:10.700 were more likely to get pneumonia than children who were never vaccinated. That was ultimately taken

01:31:14.300 off the market. The reason that may be relevant to today, to SARS-CoV-2 today, is that both of those

01:31:19.940 viruses, respiratory syncytial virus and measles, have a fusion protein. That's how it attaches to

01:31:25.380 cells, it fuses to cells. So does SARS-CoV-2. It has a fusion protein. So people are always a little

01:31:29.920 nervous about an inactivated vaccine. And it's because you sort of change the confirmation of that

01:31:34.540 protein, that SARS-CoV-2 protein, so it didn't really look like it looked on the natural virus. So that's

01:31:39.600 always in the back of people's minds with fusion proteins. So you asked me earlier what sort of

01:31:43.840 safety things I'm worried about. That actually is one of the safety things. And that would be

01:31:47.940 more of a concern, I'm guessing, with the live attenuated virus as opposed to the other three

01:31:53.020 classes, or would you still worry about that in the mRNA and the viral vector viruses?

01:31:59.140 I worry about it with all of them. You worry that the confirmation as made under these conditions,

01:32:03.680 mRNA or DNA or replication defective virus, or a whole kill virus, or recombinant DNA generated,

01:32:09.600 proteins, that it's different. It's critically different than the way it sits on the virus

01:32:13.360 surface.

01:32:13.840 Paul, this is an unbelievably fascinating discussion. I'm glad I waited on this. You and I were going to

01:32:20.340 speak a couple of months ago. Obviously, for so long, I've wanted to have a deep dive on the vaccine

01:32:26.080 stuff. But I feel like this was the right time to do it, at least to be able to speak about it with

01:32:30.300 more clarity and to really be able to say, look, by the time someone's hearing this, we're really on

01:32:35.440 the cusp of these vaccines being out there in early 21. But it's not a switch. It's not a binary

01:32:40.820 thing. It's not like we're going from no vaccines to everybody gets vaccines, and there's perfect

01:32:45.860 information, and there's no risk. This is analog in delivery, analog in risk. I mean, it's analog in

01:32:54.060 pretty much everything other than approval. Yeah, I think we're going to learn a lot. Thanks for asking

01:32:58.740 me. I enjoy this, really. I don't think I've ever done a podcast this long, but it was definitely

01:33:02.840 fun. And in fact, I thought you said two hours. I thought, oh my God, two hours. I'm going to live

01:33:06.920 through this. It really flew. It was just surprising. Well, I appreciate your time and

01:33:12.360 your willingness to sit down for so long, Paul. My pleasure. Thanks for listening.

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The Peter Attia Drive - November 16, 2020

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

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