Hey everyone, welcome to the drive podcast. I'm your host Peter Atia this podcast my website and My Weekly Newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness. And we've assembled a great team of analysts to make this happen if you enjoyed
This podcast we've created a membership program that brings you far more in-depth content. If you want to take your knowledge of the space to the next level at the end of this episode. I'll explain what those benefits are or if you want to learn more now head over to Peter Atia m.com forward slash subscribe. Now without further delay. Here's today's episode. I guess this week is dr. Paul offit Paul's a pediatrician specializing in infectious diseases, and he's an expert on vaccines immunology and virology.
He's the director of the vaccine education center and a professor of Pediatrics in the division of infectious diseases at chop the Children's Hospital of Philadelphia. It's also a professor of vaccinology at the perelman school of medicine at the University of Pennsylvania. And he's on the FDA committee for biologics evaluation and research vaccines and related biological products advisory committee and other words. He's on the FDA committee that is overseeing. The basically unprecedented scale with which vaccines are
being put into a pipeline to be evaluated for covid is also the co-inventor of the rotavirus vaccine is if all of the above were not enough the wanted to talk with Paul for a couple of months, but I wanted to wait until the time was right and I kind of defined that as a moment when we had enough certainty in terms of what was going on with covid vaccines that we could speak about it in less abstractions and more straightforward terms with respect to likely
Releases and approvals of various vaccines and so I'm really glad that I should we wait until this time because I do think we're at that point where we have a pretty clear line of sight into the pipeline of a number of companies and also a number of strategies that are being employed and that's that's basically what we go into. I mean, we we certainly talk about Paul's background which is fascinating and why he's sort of the perfect guy to have this discussion, but the meat of this discussion really focuses on delineating the for
strategies with which one can pursue a vaccination against the virus that causes covid and then we talked about basically who the major companies are in each of those categories where they are in their life cycle what that actually means and what it implies as far as vaccination approval. We talked a lot about what the potential risks are in each of the categories and more broadly and ultimately we talk about what 20:21 could look like and what the unknowns are so I learned a lot in
Episode actually more than I expected. I was just completely riveted by Paul's insights. And I think we all have a little bit of covid fatigue at this point. That's understandable. But I think anybody who's got questions about Willa vaccine changed my life. What should I expect next year? I think and I hope at least most of your questions are going to be answered here. And I don't suspect this is the last time that Paul and I will speak so without further delay, please enjoy my conversation with Paul offit.
Thank you so much for making time to sit down with me today. I know that you are someone who a lot of people want to talk with especially now that people are really starting to come to grips with the fact that a vaccine for the coronavirus is going to be a very important part of the story, I guess before we get that though. I think it's important for people to understand why your thoughts on the subject are important in other words. You're not just someone like me who's been
About the coronavirus for less than a year. You're someone who has spent essentially a lifetime thinking about this type of a problem. There's a story about how you were a very young boy you were hospitalized and that experience at such a young age kind of shaped the way you thought about going into medicine and ultimately even being a pediatrician. Can you share a bit of that?
So I was born with club feet which means that my feet turn sort of Inward and down typically that's treated with casting so I was cast
Stood when the first few hours of Life freely and then so four months. I was casting but it seemed to work. I mean my feet seems to straighten out but at the age of five, my father decided that he didn't like the way that my heel didn't oh my right foot didn't hit the ground as well as he would have liked. So he was able to find a surgeon to do a surgery frankly that was perfected about 40 years later. We should have never done that surgery. There was no club foot surgery. He was able to find a guy who was a son of a friend of his who had just finished his residency in Orthopedics and thought
I get to do the surgery which went badly. My father was short manufacturer medicine wasn't really his strength, but he didn't like the way the he'll hit interesting is a side part of the story. Is that my great uncle my grandfather's brother was a bookie. He was really Baltimore's bookie. He didn't print books. He made book my mother initially had trouble getting me into the club Foot Clinic at Johns Hopkins Hospital, but she just called my great-uncle who called the guy who was head of the Foot Clinic who was a gambler apparently, so we
Got in with an awakened when the guy this physician saw me. He said I if you do nothing don't operate on this foot nonetheless, my father insisted at the foot be straighter. And so I had an operation that was a complete failure and as a consequence I ended up in a chronic Care Facility called kernan's Children's Hospital, although I think then it may have been called kernan's hospital for crippled children when you could use words, like crippled and feeble-minded I was there for about six weeks and this was the 1950s the polio was King and I remember just a lot of children in that word.
With Oli Olive is a private 20 kids in the word seminar long some traction and there was one visiting our week. That was it Sundays from two to three. My mother had a complication with pregnancy with my brother. So she never came my father had tried to sneak in once to see me that's was were prohibited from seeing me again. So he traveled a lot so he couldn't do the hours that they had wanted him to do. So, I just remember sort of seeing those children as vulnerable and helpless and alone and finally seeing myself the same way and I remember looking there was up my
My bed was next to a window. This was when you had one visiting our week polio day. So people were scared to death of having anybody else coming to that hospital Sundays from 2 to 3. Looks like they had like therapy dogs or you know iPads or televisions or anything. You just pretty much laid there and in my case looked out the window that was right next to my bed, which look out into the front door and I kept waiting for my parents to come rescue me to walk through that front door the hospital never happened when I was a medical student at the University of Maryland. We rotated through car.
Children's hospital and that room was still there and it wasn't a polio word anymore. It was a group of secretaries, but that window is still
there. That facility is still there, isn't it? Yeah
grants his films Hospital still there.
I did my residency at Johns Hopkins and I remember we would sometimes get transfers. I was in surgery so kids that would get infections that would need to be transferred to Hopkins for surgical care. That's funny. I didn't think I'd hear that name
again. That's my present student then walk out some aeromedical what I remember walking up to that window.
Endo and looking at it and seeing that front door and you know I cried so I think that's it. I mean, I think that we are motivated by the scars of our youth for me a choice to go into Pediatrics Choice. The only to Pediatric infectious disease is a choice to write a book about polio specifically about a sort of a tragic event associated with the making of the polio vaccine a choice to make vaccines. I think enter the world of science and stuff probably all is motivated by this cars pretty much every book. I've written at its heart child. Advocacy that it's hard to standing up for children who are vulnerable who can't stand up for themselves.
Going to talk about vaccines today and I don't think a discussion of vaccines would be complete without saying something about just the unbelievable disservice that has been done to so many people so many vulnerable people specifically parents who are looking for answers when maybe there are no answers by sort of the fraud that was catapulted upon them in the late 90s in the form of that Lancet article that has been so thoroughly debunked.
Punk'd as not just incorrect, but outright fraud, of course, I'm referring to that Wakefield paper of 12 completely fabricated case studies that really on some level is kind of a big part of the anti-vaccine rhetoric and the vaccines cause gastrointestinal disease which causes autism story that started at that time and frankly on some levels. There's a solid number of people who continue to believe this
The efforts of people like Brian deer yourself Peter hotez people who have so thoroughly debunked that type of nonsense. How do you process that do you process it or there are some people who are very angry about the anti-vaccine movement. There are others who I think speak to it more from a place of empathy. How do you manage your own emotions around that especially when you see the children themselves are often the victims of parents who are themselves the victims?
Items Etc.
Yeah, I guess I felt come out on the angry side. I think Andrew wake was a fraud. I think at some level he was in knowing for it. I mean, he misrepresented clinical data. He misrepresented biological data that paper should have never been published. It was basically a story of 12 children eight of whom had autism presumably within a month of receiving MMR vaccine when in fact at least a couple of the children had developed signs and symptoms of autism before ever having received that vaccine which he knew he also he had biopsies and all those children and presumably
Measles vaccine virus was supposed to be destroying intestinal epithelial cells. He had biopsies on those children. He never did studies looking at or at least never reported studies looking at whether there was musil's virus. Genome or measles virus vaccine proteins in those cells, which is to say he probably did do those studies and they didn't come out the way that he wanted them to
actually will go one step further. I think Brian deer has actually done a very good job uncovering those biopsies were done and processed and the amount of virus that was found in them.
It was identical to that which was found in basically the formal in itself demonstrating that it was a pure contaminant. So actually through there was no measles virus whatsoever in any of the colons of or distal ileum have any of those children?
I talked to a person who did some of the serology with Andrew Wakefield for a meeting I had in England and he refused to be on the paper because he felt that Andrew Wakefield had basically misrepresented sort of IGM igd.
You to grab them responses to measles that was Android with Brian deer just wrote a book called The Doctor Who fooled the world which goes through all
this I'll be interviewing Brian because I think it's such an important discussion. Clearly. There's no shortage of anger towards Wakefield because I agree with you and by the way fraud and knowingly is a bit of a tautology by definition if it's fraud in my opinion, he was knowingly acting in bad behavior. And where are we today? Maybe just talk about it through the geography that you
Understand best which I assume is the United States. Where are we at? MMR vaccination levels. Are we above 95%
we were I mean, I think what happened with the covid-19 pandemic as we had a dramatic drop in, you know, since of vaccines in general including MMR vaccine, but I would say this I think that this is going to probably surprise you I think in some way Andrew Wakefield was good for science. Here's why when he put that out there he became a darling of the anti-vaccine movement. He was attractive. He was well-spoken. He had a
Accent which we all love. I think we're ready to give ourselves back to the queen at this point and he made the rounds in the United States. He was on everything morning evening shows. It was on 60 Minutes with Ed Bradley. He was a darling of the anti-vaccine who's a physician a scientist who now said all the right things and I think the anti-vaccine folks attach themselves to his star when it was found out that he was not only wrong but fraudulent in wrong that he not only had misrepresented clinical and biological data, but in fact had basically laundered money,
800 legal claims to a medical journal his star fell and I think the mainstream media rejected him his last I think appearance will mainstream media was on
Anderson Cooper where Cooper just destroyed him.
Yeah, right. So at some level he helped us marginalized to some extent the voices that were the anti-vaccine voices bar below Fisher Jeff Schwartz, JB Hanley Etc had a much bigger voice. I think 20 years ago 15 years ago than they do now because I think mainstream media anyway,
Chosen to set them aside now obviously their platform and social media. But so I think Wakefield in some ways helping us. I mean, we did the studies to answer the question whether you were more likely to develop autism who got the MMR vaccine or not that's been done 18 times in seven different countries on three different continents. The questions been asked and answered I do think according to a study done by the autism Science Foundation about 85 percent of parents who have children with autism no longer believe that vaccines were the cause. So I do think that that good science did went out to some extent I think Andrew Wakefield has
Lost out. He's now, you know it goes on Alex Jones Show. We're all good conspiracy theorist go.
Yeah. It's interesting. There aren't many things in medicine. We can say with a higher degree of certainty. Actually then the MMR vaccine does not cause autism if you really stop to think about it Paul do statins cause Alzheimer's disease. I think the data is overwhelmingly convincing that it does not but I think the data are more convincing than MMR does not cause autism based on the extent to which it's been studied and
maybe to some extent the negative attention that Wakefield has brought to this has actually forced so much scrutiny of those data not just the 18 studies you refer to but also going back and really exposing the biological plausibility of the argument itself and frankly exposing another issue that I think is very easy to understand so I say,
This with a lot of empathy but is nevertheless an issue, which is any of us are capable of misremembering facts and so much of what I think gave Wakefield and his associate bar the lawyer with whom you referred to earlier that he was basically In Cahoots siphoning funds through his research organization the ability to carry on for so long was effectively parents misremembering things. I actually believe most
Those parents or not nefarious. I think there are some that who clearly were I think there were some who consciously chose to sort of pursue legal action to get money knowing that what they were saying was false, but I don't think that that's the majority of them because remember all of those parents in that case said little Susie got the vaccine on Tuesday had a nosebleed on Wednesday had a fever on Thursday and started banging their head against the wall and the rest is history. I actually
Really think they believed that although the medical records showed. No, actually Little Suzy stopped talking six months before they ever got the vaccine and here are the medical records to demonstrate it. I mean it was unambiguous what had happened, but I just think that people ourselves included sometimes struggle when we go back to remember things, especially things that are painful.
I think we look for reasons for why things happen that gives us some level of control even though the reason may not be the correct one at
Now we feel like we have some handle on it what Andrew Wakefield offered at some level is Hope. If you don't want your next child to get autism separate the MMR into its three component vaccines. If you want to treat this child, here's a variety of intestinal treatments that will work. That will be magical. I mean, he was a charlatan of the first order because he took advantage of parents desperate desire to do something for their children
and not to get too far into Wakefield psyche, but I actually believe there was probably a day when he was honest. I
Believe there was a day when he like any scientist had a hypothesis set out to test it the difference. Is he crossed a line the difference between a good scientist and a bad scientist and a charlatan is that a good scientist can look at the data when they disagree with hypothesis and modify
hypothesis. It doesn't really work on sort of vasculitis associated with inflammatory bowel disease is yeah. He tried to really make the case that measles continue accessing also was a cause of inflammatory bowel disease is wrong and he admitted he was wrong.
And then he went on to the next thing where he was wrong, but didn't admit he was wrong.
Yeah and double down and that's where really the Frog got out of control. Let's take a step back to give people a bit of a sense of your work. What were you doing? What was a day in the life of Paul offit a year ago. Basically before SARS Covey to was a known entity. What were you working
on? I spent 26 years of my life working on creating the strands of virus that became the bovine human reassortant vaccine world of tech. That was my
26-year effort before that was done about 2,000. We created the vaccine education center at Children's Hospital of Philadelphia which sort of creates and distributes educational materials to educate the Press educate the public educate doctors about vaccines so we can sort of meet this anti-vaccine movement or at least the anti-vaccine sentiment that people have so that we can answer their questions. What we're trying to avoid is or those children who suffer needlessly by not getting vaccines that would protect them. So that's been the passion. I mean, I think the passion for me came
Because I think I saw how hard it was to make a vaccine how hard it was to prove that a vaccine was safe and effective been how easy it was to damn them. That paper was awful should have never been published and yet it created a movement or at least supported a movement. So I think that was it seeing how hard vaccines were to make how easy it was to damn them got me interested in trying to fight with facts.
Let's talk a little bit about rotavirus. Can you tell folks a little bit about what that is and how often it afflicts children
Roto virus is a virus that affects the small intestine.
It causes fever vomiting and diarrhea primarily in children between 6 and 24 months of age in the United States before there was a vaccine everybody would be infected by age five. All children would be infected by H5. It would cause about 75,000 children to be hospitalized this country every year with severe dehydration or what our laws would also cause about 60 children who die every year in the developing world are in the rest of the world. It was a killer. I mean, it was really the biggest killer of infants and young children killing about 500,000 babies a year.
We traveling less than two years of age about this many as 2,000 a day. So there was always a lot of interest in trying to make a vaccine to prevent it. That's where I come in
and obviously the difference between why so few kids would die in the United States versus the rest of the world to presumably had to do with supportive care and these children in the developing World. We're going to die of dehydration and or electrolyte imbalance, whereas in the United States despite how many were hospitalized at least they could receive intravenous fluids and some
Foreman new perhaps even parenteral nutrition if necessary is that the fundamental distinction
the stories I tell is that there's a friend of mine who was a PhD in chemistry. She actually work for a pharmaceutical company her baby got rotavirus infection. So she took the baby to the doctor and the child was severely dehydrated doctor said, let me call an ambulance and take this child to a local hospital. The mother said no, I can take her. I'll put her in the car and take her so she gets her in the car and then she's an amazing your traffic jam which is why you get an ambulance and so she was stuck and she was much longer.
To get to the hospital that you would have others by the time she got to the hospital child was out of it. So they wish the child back into the treatment room. They were able to do a cut-down a session in the child's neck to thread a catheter down because that was the only thing they could find that child dies in the developing world because you don't have the kind of equipment to do that cut down because you're walking 20 miles to get to a clinic or hospital. So the difference between this country and other countries where children die is not severity of disease. It's as severe here. It's just that we have the resources here to keep children from dying.
So what type of virus is a rotaviruses at an RNA or DNA virus?
It's double-stranded segmented RNA virus.
Does that pose any challenges for creating a vaccine against
it the good news is when you're trying to make a vaccine you want to see clear evidence that natural infection can induce protection against the least moderate to severe disease then you know that you should be able to admit that part of the immune response associated with that protection. Those studies were done in the 70s actually with Bishop published a paper showing that if you got a row.
Virus infection in your first year of life when you were then subsequently chance with the virus again just naturally you could get mild infection or you could get a systemic infection, but you wouldn't get moderate to severe infection a minute. That paper was published. We thought okay, we can make a vaccine. We just have to mimic that part of the immune responses associated with production
and was that protection lifelong
Paul know like many mucosal viruses Roto virus influenza virus power flew respiratory syncytial virus those viruses which have generally short incubation periods meaning time from your phocion.
Affected to when you get sick, which generally don't have vairy me as part of pathogenesis their immunization or natural infection and immunization and Deuces protection that is short-lived and incomplete meaning that caves and meaning protection against moderate to severe diseases not model disease. These are the mucosal viruses which I think brings us our Discovery to I think that's going to be the same story
here did that paper in the 1970s offer an insight into whether the immunity was provided more by the B cells or the T-cells.
The thinking was it was going to be an antibody.
Spots at the intestinal mucosal surface. We had to induce an antibody response that was active in the intestinal mucosal surface, which made us think it was going to have to be an oral vaccine which stimulated then immunity at the intestine because service and not a parental vaccine which would stimulate systemic community.
So what was the approach you took then to do that in the spirit of that at the time what were the options available? I mean beginning with say a live attenuated virus is that generally the first thought in an individual has when pursuing a vaccine or how did you guys problem?
A solve around the different ways in which you could induce immunity
the way we saw it was that rotaviruses are ubiquitous every mammal that walks the face of this Earth has its own unique strain of the rotavirus and species barriers are pretty high meaning that a cow rotavirus or care for rotavirus would cause disease and calves but not people and vice versa human rotaviruses would cause disease and babies but not calves. So we basically took advantage of that. It was a generic and approach if you will and Edward Jenner like approach. I mean Edward Jenner basically
Use the Cal virus to protect against human small boxes are so calc smallpox essentially cowpox would protect against human smallpox because they were energetically related enough that immunization with one could protect you from a disease caused by other. That was our approach. So that was our initial approach was just to take a cal virus. I can't fire us that it causes diarrhea that the growth and cell culture and then use that as our vaccine and it did work but it was inconsistent. So then we had to modify that calf virus so that it in
included the genes that code for the proteins that evoked what we found were neutralizing antibodies or to surface proteins of the virus and we thought both independently evoke neutralizing antibodies. That's what we proved. So then it was a matter of just constructing these combination virus so-called reassortant viruses between KF and animal strange that became the vaccine the summarizing 10 years worth of work in about 35 seconds. So depressing that you can do that, but that's what we did.
What were the risks associated with the
vaccine you
Now when heading ever you're dealing with something that's unknown. Isn't you can't fire nurses. Will they behave differently in people? Will they cause something that's on tour that you hadn't thought about what we learned from other researchers was that surprisingly actually there was a vaccine was introduced in the late 1990s. It was made by National Institutes of Health in collaboration with Wyeth called Rhoda Shield, which was a simian rotavirus. That was also a recombinant virus Simeon human reassortant rotavirus that was found to be a rare cause of intussusception, which is intestinal blockage.
It occurred in depending on who you read between one and ten thousand one and thirty thousand resumes wasn't picked up pre-licensure because the studies wouldn't have been big enough to pick it up pre-licensure. It was only picked up months after licensure and then it was off the market within 10 months. So that was a sobering experience just to relate it to today. If you don't mind that virus had rotavirus had been studied for 50 years by that time. I mean, we it was known to be an animal pathogen in the 40s veterinarian study that we knew was a human pathogen by the 70s when That vaccine came out in the late 1990s we had
50 years worth of study nonetheless it cause the side effect and it's exception. That would have never been predicted by all those studies.
Yeah. Let me tell people what that is. So an innocent ception is when usually a lymph node in the small intestine acts as a Foci and allows the small bowel to telescope on itself. So it gets tugged probably through some sort of peristalsis action and that can cause an obstruction. So if the piece of the bowel telescopes into another and comes back out easy peasy
Yeah, but if it telescopes and get stuck you now have a bowel obstruction and took care of many kids as I'm sure you have who had in deception from lymphoid hyperplasia or various other things, but obviously in this case, it was a side effect of a vaccine and an understandable side effect. Meaning there's a biological plausibility of why giving a vaccine that has a GI mucosal effect could lead to lymphoid hyperplasia that could act as the tugging point, but you're right you would never in a million years say I think into
Option could be a side effect here. And if it only occurs one in 10,000 cases, you're going to easily miss that and Phase 1 2 and phase 3 again, it speaks to aftermarket surveillance and the absolute imperative of it and it also speaks to the fact that as we start to talk about coronavirus, which we're going to get to very shortly one has to be thoughtful about risk versus reward trade-off with small n right
now. You're gonna surprise was That vaccine which was sort of a simian rotavirus base. I think that
Virus reproduce itself far less efficiently at the intestinal mucosal surface and did Wild type virus natural virus. There was no evidence that natural rotavirus cause interception. So why would this be true? And the reason is is that interception really appear to be around phenomenon? It wasn't a winner phenomenon and United States welcomes. What rotavirus was you would expect to see a bump in the winter, which you never saw. So why would a vaccine do something that natural infection didn't do I think what we know now is that natural infection probably was a very rare cause of interception as was this vaccine and I guess the covid analogy is
Here's the virus covid for which we had at least in the gene structure and early January of this year, which has already had a number of sort of clinical and pathological surprises, which we are now about to counter with a series of vaccine strategies with which we have no commercial experience. I think it's fair to say there's going to be a learning curve here. So there has to be real humility. I think as we move forward, let's
help folks understand a little bit about these different phases because you can't turn on the news without hearing company X is in Phase 1 or 2 or 3.
And I just want people to understand what those mean specific to vaccines because I have slightly different meanings than say in drugs that treat blood pressure. So can you explain to people what a phase one vaccine trial aims to accomplish and what a typical size of that trial might look
like if you're trying to make a vaccine you start in so-called preclinical studies mean studies done before you got the humans and hopefully you'll have an animal model to study the Z as in the case of rotavirus.
It was my simply inoculated babies - with rotavirus. They got sick. Okay, great. So now we have a way to study this infection. Then you have your idea for how you want to make your vaccine. You give your vaccine you then change the animal with the virus and hopefully you can protect the animal from disease and more importantly you can find Li literally dissect out that part of the immune responses associated with protection against challenge for those preclinical studies are called proof of concept studies. So now you have your way of making a vaccine then you go to phase one which are usually about twenty to a hundred people now you
Have your idea for how you want to make it but you don't really know the dose. So you give a variety of different doses to these 2,200 people to see whether or not you can safely induce an immune response that you think is going to be protective based on your animal model work. Now, you have a dose and a
strategy. What's the typical length of time to go from that preclinical where you've now filed an IND and you now would be applying to an Institutional review board to do a phase 1 in the normal world that takes how long usually
I think
Wobbly, it's fair to say 10 years 15 years.
Okay, we'll make sure to keep that in mind when we pivot to coronavirus the other thing. I want to highlight that you just said there is 20 to 40 people ish
in 2100.
We're not talking about 10,000 people not a and these are often done with a little bit of a dose escalation built-in. So maybe the first 10 people are going to get a really really small dose. We make sure nothing catastrophic happens. We then escalate the next 10 etcetera right
there dose ranging trials exactly right you go.
Go slow and you work your way up to see what seems to consistently induce an immune response that is and that is safe.
The third thing I want to highlight there is we are not actually able to assess whether or not the people have legitimate immunity. We're using a proxy presumably which is some form of serology. In other words. We're not actually testing their ability to resist an infection. We're measuring an antibody. Is that correct?
That's right. You have a prediction based on your animal model studies that one.
But if the response is going to be associated with protection against channels as it was true in your animal models, you won't know that till you get to phase 3,
so now let's go to phase two you've established a dose potentially a frequency. What do you do in Phase 2 and roughly how many people do you do this with
phase two is typically hundreds of people now, you've got your vaccine you've got your dose and you just want to make sure that it's consistently induce an immune response that you think is protective and that it's at least safe and that it doesn't cause a relatively common serious
Side effect that's phase two. And
again, the two points worth making sure people understand still a relatively small clinical trial hundreds of people and you're still using surrogate markers. We don't actually know if this vaccine is providing immunity in the real world. It's efficacy. We don't know if it's effective and we don't really have any way of knowing what very minor or in or I shouldn't say minor infrequent negative consequences could look like because
Still dealing with a very small sample
size. That's exactly right.
So now we go to phase 3 and what does that look like?
This is the definitive trial. There's the trial that you're going to use to submit information to the FDA Food and Drug Administration. Hopefully for licensure. These are tens of thousands of people and the case of our Roto virus vaccine. It was seventy thousand babies. 35,000 got the vaccine 35,000 got Placebo, which is just essentially the vaccine except no active ingredient just the
at least sugar solution in which the vaccine virus was suspended and then you just send people out into the real world. I mean rotavirus is a common infection. It's the rare child who gets Stage 5 without being affected and then you just see whether or not children who got the vaccine were less likely to get rotavirus or if they got it that they were less likely to get it severely and hopefully you'll have we had Serie on all those children meaning we looked at the antibodies on all those children. Hopefully that would provide a clear immunological correlative protection, which it didn't we knew that the vaccine worked we knew there.
Safe and so we could submit it for licensure to the FDA. But as you go along things are much more expensive you go from sort of millions to tens of millions to hundreds and hundreds of millions. And then you Mass produce the vaccine after you found out that it works
and as a general rule the process we just described going from a preclinical model in animals to the completion of a phase 3 trial with the FDA approval of an agent. Here's the rule of thumb I use please correct me on the vaccine side. I generally say that's 20 years and 1 billion dollars.
Hours and that's usually on the drug side. Is it about the same on the vaccine side? Yes,
15 to 20 years with at least a billion dollars. That's right.
So let's now talk about coronavirus and just understand that in January of 2020 when the sequence of the RNA identifying this as a novel pathogen a coronavirus named now SARS Covey to shows up and by March, I guess it becomes pretty clear.
This is not going to be contained which means any strategy towards containment is going to fail it became readily apparent that a vaccine was going to be a very important piece of the strategy. Basically at that point. It was going to be herd immunity without vaccine or herd immunity aided by vaccine. If you're staring down the barrel of it's going to take 20 years in a billion dollars. That's not a very appealing strategy because it basically says it has to be herd immunity without a vaccine meaning this virus has to sort of rip through a population without it.
It if I could ask you to put yourself back in your mindset in February or March of last year. What would you have said if I asked you at the time Paul How likely is it that a vaccine will be developed to at least thwart in some way this virus and to how long will it take? What would you have said then?
I would have said it was two years. You do have to give credit to the administration for one thing operation warp speed what they did was they basically took the risk out of it for?
Coverage with the government said is with both varta, which is part of Health and Human Services the World Health Organization The Gates Foundation and others, but in this country the government said, here's what we'll do. We'll pay for phase 3 trials will pay for mass production at risk meaning will mass-produce. This vaccine will make millions of doses of vaccine without knowing whether the vaccine Works without knowing whether it's safe and showing a willingness to if it neither works or isn't safe will throw out those tens of millions of doses. No pharmaceutical company would ever do that. So now you're basically had it Phase 1 trials you
I pretty much went right to phase 3 trials which company would never do went right to mass-produce in which a company would never do and that's what meant having a vaccine in hand in January. It is in all likelihood that we will have a vaccine that is rolling off the assembly line into the arms of Americans by early next year. I mean so year and a quarter to make a vaccine with only having the virus in hand in January that's remarkably fast. It's unimaginably fast, but it's the government that did that so
Quote to them.
Let's talk a little bit about some of the different ways in which vaccines are made again. There's so many different ways to skin this but one way is you actually deliver the RNA of the coronavirus in a vehicle that then gets taken up by our DNA and it creates enough of an immune response that we create an immune response to it. How do you think of that overall strategy?
So there's any good news about this virus? It's that we know the
The part of the virus the protein and the virus that attaches the virus to cells if you can prevent the virus from attaching two cells in theory. You should be able to prevent the virus from infecting cells or said another way. In fact, the you that protein is despite protein. It's the protein that emanates from the surface of the virus and gives it its Crown like appearance hands coronavirus. You also know the gene that codes for that protein. It's an mRNA virus meaning messenger RNA virus single-stranded messenger RNA virus, like rubella or German Measles. So the
Four strategies to make this vaccine or all based on that knowledge. We know the gene that codes for that protein take the MRNA strategy, which is the most naked and obvious which is that you basically take the messenger RNA which codes for that protein you injected into people it's taken up by the cell and the cell cytoplasm outside the nucleus. It enters the so-called ribosomal system and its translated to a protein which is excreted. So that's a little your body makes the pro despite the coronavirus Pike protein then your
he makes antibodies to the spike grunting that's very similar strategies the so-called DNA vaccines and then these so-called replication defective seeming or human Adeno virus vaccines or replication competent vectored vaccines all have the same strategy in mind which is introduce the gene that codes for the coronavirus poked by protein induce your body to make that Spike protein and then your body will make antibodies. These are so-called genetic plug-and-play vaccines. The reason that they're the first ones to come out.
Because they're the easiest to construct and the easiest to mass-produce. It doesn't mean they're going to be the last best vaccines, but that's why they're going to be the first vaccines.
One question I have for you on that Paul is given the instability of RNA. I've always been kind of surprised that they work. I can understand why DNA could work but given how unstable RNA could be when you take a single strand of messenger RNA and deliver it what allows it. I mean this might sound like a silly sort of technical question.
What allows it to make its way into our cells into the cytoplasm head over to the ribosome and then get translated ultimately into protein.
So anybody who works with messenger RNA and elaboratory stores messenger RNA at minus 70 degrees Centigrade or in liquid nitrogen because as you say it's an incredibly labile molecule, it breaks down within moments. Frankly. I've
burned myself on said Vats of liquid nitrogen many.
In the lab. Yeah,
so to get around that problem these vaccines the messenger RNA vaccines have to be encapsulated in a complex lipid delivering system which stabilizes them to some extent the moderna has been able to figure out a way to both store and ship and store at minus 20 degrees, which is just freezer temperature, but Pfizer know they're going to ship and store it - 70 - 80 this or Ultra cold chain, which we've never done in this country, which I think will be a challenge so you have to constantly maintain
Maintain that product on dry ice once you throw it out and put it in the refrigerator. It can't be there for more than a day before you give it. You're right. I think the lay bility of messenger RNA will be Challenger and just one sort of nerdy virologist thing that I'd like to say as a nerdy virologist is that when you're infected with this virus, you'll shed infectious virus for a week. Roughly you'll shed infectious virus week. You'll be PCR positive eliminates chain react positive. You can be P0 positive for three months what you're detecting in the back of the throat is
Infectious virus its messenger RNA. That's what you're detecting which means because it's so quickly degraded. Why would it be around so much longer and the answer is the virus is continuing to make messenger RNA but not making whole virus particles. Why would it do that? I mean this virus continues to surprise. I think
let me make sure I understand what you just said because I never actually thought about it that way you're saying that let's say I take the moderna vaccine. I'm getting a bolus of mRNA.
My body is going to just take that and incorporate it and start kicking off protein, but it does two things. It doesn't just take it like one single transcribe piece of mRNA and translated into protein and be done with it. It actually incorporates it back into the DNA and that cell of mine continues to transcribe and translate is that what you're saying for
months the MRNA will amplify itself in the cell true
which cell epithelial cells like
Which of my
cells muscle cells will be inoculated in your arm. It'll be the muscle size and then to some extent also antigen presenting cells like macrophages dendritic cells.
Okay, that's kind of interesting to think about because why would it show up in a throat swab? How is it making it all the way to the epithelial cells in my throat or in my nose or
wherever I guess I'm trying to do everything when you're naturally infected with Soros Kobe to do that virus then reproduce itself over and over again part in the back of your throat and it makes and
Infectious virus particles and enters your cells a tree transcribed its translated and then it makes new virus particles. But what happens is it's only making new virus particles for about a week and then it stops making infectious particles anymore. But you still have messenger RNA in the back of your throat. You can four months which means the virus is still there. It's still in the Cell It's still making messenger RNA but it's not making a whole virus particle anymore. That's weird. I don't know of any virus that does that I'm not sure it says anything about the messenger RNA approach. I mean messenger RNA does
Talk to you in your body, but then it's quickly broken down as this all messenger RNA and your bottom. It'll be curious to see what happens with this. I mean we're going to learn a lot with this strategy will see whether it applies to other vaccines possibilities and we'll see whether or not we run into a problem
moderna that you mentioned is obviously one of the frontrunners in this and I think that's in no small part to the fact that one of their Partners is NIH that's you know, National Institutes of Health here in United States has bankrolled to the tune of about a billion dollars as you said as a non uh partnered with anyone else beside
sides
moderna. No just begun. Its they're constructed moderna uses the nucleoside analogs that are used in That vaccine that was all developed by a couple researchers at the National Institutes of Health actually National Institutes of Health as far as I know holds the patent on that vaccine
and they basically entered phase 3 this summer, correct? I mean, I think they're fully enrolled aren't they?
They enter the end of July as far as I know. They're fully enrolled. It's hard to know. I mean, it's always trying to read the tea leaves on this stay strong. Okay
what anyone else on the MRNA?
Gee that you think is I mean Moderno is probably the leader
correct mode or 9 V both.
Let's talk a little bit about the Pfizer platform. How does it differ
whereas majority gives a hundred micrograms per dose in a two-dose series Pfizer gives 30 micrograms. So it's not the same nucleoside analogs and I'm curious to know I'd love to hear a scientific presentation on why Pfizer needs to ship and store it - 70 which is going to be a challenge as compared to modernist shipping and snoring and - just - 20 they are
Constructs so they're given a different amounts and we'll see to what extent any of them work or safe.
Now Pfizer is doing a phase 2 phase 3 combined is that
correct? They sort of all our I mean you sort of went right sort of skip through face to write the phase three really they all did that.
Do you think that that distinction Paul from a logistics standpoint is going to matter in other words when we start to think let's just assume for a moment that the moderna vaccine and the Pfizer vaccine have equal f
See in the real world. So in a phase 3 trial we see call it a 70% reduction severity of infection in those receiving the vaccine over the placebo. Would we agree that that's a win? Yes. Okay, all other things being equal is the need to transport tens of millions of doses of something basically in liquid nitrogen going to pose a
challenge so won't be in liquid nitrogen, but it will be on dry ice. Is that going to pose a challenge? Yes.
I think what worries me in this a little bit is that when you do the studies which visors doing in the darkness doing you can be comfortable that the companies are very good at overseeing this shipment and storage of that product and they're making sure that the investigators they've got the special package in which this vaccine is stored there constantly maintaining dry ice that doesn't worry me and when it stalled out and put in the refrigerator, it can only be there for a day when the vaccine then gets distributed to the the world under natural conditions through the United States under natural conditions. How is it going?
Distribute probably at least in part in like large chain pharmacies are the pharmacists going to be as good at doing what was done during the trial because certainly as you said at the beginning, I mean, these are mRNA is labile and if it degrades and it certainly has the capacity to degrade will we get less efficacy effectiveness of the vaccine in a real-world situation than we did in a experimental situation.
Yeah, I guess TBD your best guess of how those companies are.
Signaling when we're going to see data. I mean, it depends in large part on how active the third wave of this is because this is one of those things where the more people that get exposed the more quickly. We see the difference between the placebo in the vaccine.
The company technically doesn't know what's going on in the trial. I mean technically the company the CEO for example doesn't know who's gotten vaccine who's gotten Placebo doesn't know who's gotten sick and who hasn't gotten sick doesn't know how many cases.
Of disease of a colonel sibo group of actually group doesn't know that the data safety monitoring board knows knows which is composed of a group of academics and researchers who are not affiliated with the company not affiliated with the government.
These are being run through large. CR OS I
assume yes depends on who's doing it but yes
for listener clinical research organizations, when large companies or even academics to clinical trials, they usually contract out with companies that are exceptional at all. The stuff that Paul is talking about which is the logistics of how do you actually
ship this thing from A to B and make sure it goes perfectly. How do you get the blood drawn this person and measure this and all these things and so that's not an expertise that a company wants to build in-house. They typically Outsource that and it's those companies that are it's a part of that is the monitoring that presumably there's a power analysis that's gone into this that said look we're going to enroll 30,000 people. We know half of them are going to get a placebo half of them are going to get an active agent. We've stratified on some level by age. The inclusion criteria probably says we want people between ages
Is X and Y of a certain this many of them to be of this health this many of them to not be of that Health. We think the exposure risk at this stage of the virus is meeting at this life cycle the virus. We think there's this many more people that can be exposed. The are not is something do you think that they can at least it back into an answer which says Hey by February we should know this good or bad or is that simply something that just can't be known a priori
My Hope Is that the
These companies do what was recommended actually by the NIH active group. That was put together by Francis Collins, which is it depends on whether it's 1 to 1 or 2 to 1 trial meaning to vaccine recipients for everyone Placebo recipients or one-to-one. But if that's true, you need at least around between a hundred and forty seven and a hundred and sixty people to get sick in the trial in order to be able to say you can so-called reject the null hypothesis the null hypothesis is this vaccine doesn't work to reject the null hypothesis.
I have statistically significant robust evidence that says it does you need 90% confidence interval to be able to say that you need about a hundred fifty people now they to safety monitoring board. They're looking all the time in real time. So they know when they feel you've met a safety or efficacy standard and then they call the company and they say, okay now you can submit this vaccine. What would be for a typical vaccine which not this vaccine? You can submit it for licensure with a biologic license application. That's not these vaccines these vaccines were.
All going to be permitted for use under emergency use authorization. It's different and that I think is what scares people at some level because they saw what happened with for example hydroxychloroquine, which didn't work. Now it's been shown clearly not to work to treat or prevent disease that it was approved under a you a or a convalescent plasma, which is to say antibodies taken from people who survived the infection which again was heartily approved by the FDA through this emergency use authorization. Also with the no evidence that it worked what's weird about
This is that people are doing the same kinds of trials. They would do for any vaccine large placebo-controlled trials yet. It's still not going to go through a biological license application mechanism. It's going through you a just because of time I think it's because the FDA would not typically license a product that was studied for this shorter period of time. So yeah because of
time can you just explain to people what the EU a is I guess by now most people have heard the term emergency use authorization. It's been granted to not just medications, but frankly to even testing modalities. Oh this serology tests. Just got to you a this PC.
Our test just got a UA. What does it actually mean?
It's a permission to use something which is to say that even though there aren't clear data showing that something is safe or effective or that it's a diagnostic clearly works. Well, we're going to allow it under this condition because we're under duress with this covid-19 pandemic. So we're going to put it out there with the hopes that it works actually wrote an op-ed piece that I submitted to the Philadelphia Inquirer yesterday that I just heard before this show that is going to be published. I think it's Sunday on the Philadelphia Inquirer, but the
Trying to make in that piece as it how big of a risk we take if we're going to be studying these vaccines for four months five months six months and we're going to be putting them out there into millions and arguably tens of millions and hundreds of millions of people. Are we taking a risk? And I think in terms of Effectiveness, you're only going to know that have actually defense effective for a few months. You don't know whether it's effective for nine months or a year or two years. You don't know that I don't think that's a huge risk. I think it's likely that it's effective in the short term. It's probably effective in the somewhat longer term. I don't think it's going to be effective for
Kids, but I think it's likely to be effective at least for a year or two or three. I think I mean we'll say and worst case scenario. You could give a booster dose. That would be the worst-case scenario but then safety which is what everybody worries about. I mean have you really studied it enough to say whether it's a I'm on the fda's vaccine advisory committee. We had our meeting on October 22nd and that dominated the meeting that 9 our meeting was dominated by the fda's basically asking us. Are you comfortable as a committee allowing you threw you a knowing? We're not going to have a certain amount.
Out of data would you'll have basically usual have to month follow-up after the last dose for safety issues. Is that enough time? Personally? I think the answer is yes, I do. I mean if you look at the serious side effects that vaccines occasionally cause like polio caused by the oral polio vaccine which occurred in one and 2.4 million doses. We're narcolepsy a disorder of wakefulness that was caused by the squalene adjuvanted flu vaccine that was given in Europe not in the United States which occurred in roughly one in fifty five thousand doses.
Ida pinilla lowering the platelet count that occurs with measles containing vaccine which occurs in 1 and 25 thousand doses or something called visceral trophic disease, which is basically sort of multi-system disease caused by the yellow fever vaccines. Basically yellow fever caused by the yellow fever vaccine, which occurs in about one in a million doses are Guillain-Barre syndrome, which is this ascending paralysis, which can affect your ability to breathe that occurs in about one in a million doses of the influenza vaccine. How soon did you know that mean how soon did you know about those serious problems did you know?
Out of the two months and the answer is yes. I was going to CDC conference call yesterday with group of folks that are associated with the advisory committee for immunization practices. And we collectively could not think of a serious side effect that was not picked up after 2 months. So I'm optimistic that that would happen here as well.
When you think of all of the different types of vaccines. We just talked about the MRNA vaccine will get to sort of the viral vectors the inactivated or attenuated variance and then obviously just the proteins that are delivered. I want to go through these in some
Dale and use it as an exam to talk about the companies. Are there any of those classes you worry about more than others from a risk standpoint? For example, some of the live attenuated viruses have been the ones that go on to cause it isn't polios live attenuated.
Correct? The oral polio vaccine was a live attenuated by relaxing.
Yes, right. And so that's presumably why you had even though it was a minuscule risk. You still had some risk of getting polio. So do you look at those four categories of vaccines equally from a safety
question. I'm not sure we
Enough about mRNA DNA replication defective humanists. I mean Adeno viruses to say here are the things that I worry about though. I worried that you've had three clinical holds for these vaccines. You have one clinical whole with Johnson & Johnson's product, which was a replication defective adenovirus 26. So Adeno virus is a virus human virus that causes a variety of clinical disease has Type 26 just means it's one of the many types of adenovirus human viruses that causes replication defective means that the virus has been genetically engineered
So it can't reproduce its own but it has also been genetically engineered so it contains a gene that codes for the coronavirus by protein so that when you're inoculated with that vaccine the cell takes up that particle which does not amplify itself. It enters the nucleus at then is transcribed. It's transcribed the messenger RNA the messenger RNA is translated to a protein and that protein is an excluded. So it's good news bad news. The good news is its replication defective therefore it can cause disease because the virus is reproducing itself. The bad news is its replication effect.
You have to give a lot of virus to get enough of those virus particles into the cell to make the protein you're interested in about 10 billion virus particles per dose. That's a lot of virus. That's why it is that side effect profile can be a little rough, meaning fever including high fever and then symptoms associated with fever chills headache muscle ache and that was seen fairly commonly, especially after the second dose with these vaccines,
which is also part of the issue with some of the genetic engineering stuff. This is a little off topic but the use of adenovirus
for genetic engineering even 20 years ago at chop right them. And that's a big part of what kind of got into some of the trouble there, isn't
it? Yes, that's it. I mean I'm at pain. So we're all thinking the same thing, which is Jesse gelsinger.
Gelsinger Yeah God, I still remember that story like it was yesterday. It's got to be at least 20 years. It
was inoculated with a replication defective adenovirus type 5 that cluded the gene the coded for one of the liver enzymes that he was missing. He was missing a gene and allowed him to take the ammonia. That is a consequence of
Protein metabolism and excretion from his body. So the ammonia would build up in his body and then he would get very sick and go into a coma occasionally. So but he died. I mean he died because he had a massive size fo called cytokine response with something called interleukin 6 at a time before we had antibodies directed against interleukin 6 that would have saved his life and we all lived through that and it really set gene therapy back. If it's any consolation the amount of replication defective adenovirus. He got was long rhythmically greater exponentially greater than the
Math that we're currently giving here, even though 10 billion sounds like a lot. It's still about one three-hundredths of what he got. But again, you're going into an upgrade population with when you put something into millions of people you may find something out that's untoward. So yeah, that worries me. The clinical holds word me a little bit the to clinical holds that were for replication defective Simeon adenovirus, which was the UK AstraZeneca vaccine. We're both because of neurological issues. The first was so-called undiagnosed multiple sclerosis the second
Transverse myelitis, which is an inflammation of a segment of the spinal cord the mechanism by which both of those diseases happen is the same which is that you make an immune response really to the sheathing of your nerves and particularly one protein undeceiving of your neuro smiling as a protein multiple sclerosis is relatively common, but transverse myelitis, isn't that occurs, maybe 1 in 200,000 in the general population that trial was about 18,000 people big at the time which is the say 9,000 people got vaccine and they saw that case.
Was adjudicated to be likely to be coincidental and not causal. But it does worry you a little bit that because it certainly was a statistical Zarate and you'd like to know what the problem was with Johnson & Johnson's vaccine which you don't this is the problem with these things
and they're both in the same
class right there. Both replication effect
land of ours. Yeah exactly while we're on that topic aren't these the same classes that were actually approved in Russia and China doesn't Russia and China each have something that they've approved for limited use.
Already in this category.
Yeah, so China had a replication defective add 5 adenovirus type 5, which they actually had approved for use in the military. I'm not sure to what extent they've done it because it seems they've gone in the other direction now and I'm looking just at a inactivated viral vaccine that seems to be their focus now.
Yeah, I was going to say do we have any data? I mean not that we would have any data from China necessarily, but we don't know how many people received that outside of an actual clinical use and if there's been any other safety defects noted. I
mean I have heard they have given it to tens of thousands.
Of people but what I haven't heard is a result of the face three trials why I'd like to see whether or not it actually works would be nice to say and then the Russian to the gamma Leo Research Institute in Moscow has also replication defective adenovirus vectors and also is a two dose vaccine, but the first dose is replication defective add 5 the second dose is replication defective add 26 that's their vaccine Vladimir Putin came out in the end of August and said we are going to now start giving this to our public the Russian public. We have checked all the boxes which near as I could tell that
I was doing a small phase one trial that hadn't even started doing phase 3 trials yet. So I'm not sure what's going on in Russia. It's hard to know what's going on. I know that I got a call from a Venezuelan reporter who said that that Russian vaccine had been shipped to Venezuela for you. So I don't know what's going on out there, but you really would like to wait for phase 3 trials to at least prove safety and efficacy at some level before you start giving it to the general
population. The other big player here is Merck, although they're a step behind right there. Mostly Phase 1 at this point they became
Did that has made it through phase one
yet. I've heard of two candidates one is the replication competent vesicular stomatitis virus which although reproduces itself in your body doesn't really cause disease. That's what they use for their Ebola vaccine that was marched of Allah vaccine, but they also apparently are interested in using their measles vaccine virus as a vector for this as well. So I haven't seen any data
yet. But again just summarizing where we are. We've got moderna and Pfizer is the big guns on the MRNA front. We've got Johnson & Johnson and then AstraZeneca with Oxford as
Big guns on the adenovirus / viral Vector front is that fair? Yes as the leaders. Okay. So then the next sort of category is let's just give you the protein off the virus itself. Let's just rip off a spike protein give you a whole bunch of them and when your body sees those it's not going to be threatened by them. I mean it's going to be threatened appropriately to make an immune response, but obviously the protein by itself can't hurt you because it has no genetic material with which to take over your cells is it
General rule. How does that strategy work? When you think of other non coronavirus applications?
Right? So what's the strategy we used to make the hepatitis B vaccine with which we have had experienced since the 90s early 90s. It's the strategy we use to make the human papillomavirus vaccine which has been on the market since mid two thousands around 2006. It's a strategy we used to make one of the influenza vaccine so called flublok, which is also been around for years. You have the Comfort at least of having a lot of commercial experience with that strategy. They're made using recombinant DNA technology. So
The case for example of the hepatitis B vaccine or the human papillomavirus vaccine. You take a yeast plasmid which is just a small circular piece of DNA you clone into that the gene you're interested in which as we've said now million times when the show the coronavirus Gene that codes for the coronavirus Spike protein you then sort of transfect that into yeast cells actually just common baker's yeast and as the baker's use reproduce itself and also makes that protein which you purify in the case of flublok, which looks like it's closer to the strategy that's being used by sanofi.
GSK collaboration there. What you do is you take a basically an insect virus so-called bacalao virus you clone into it again the gene that you're interested in the coronavirus by protein Gene and then you infect insect cells and then that protein actually forms rosettes as it's excreted from the so that's where you make flublok which I actually got this year as my influenza vaccine and I'm still alive that's quadrivalent. It's quite a value.
So you mentioned obviously sanofi GSK. That's one of the big guns. They're not in phase.
Yet are they they're going to start that next
month. They'll go back. This is the other one that does purified protein and carbs those
two and Novak's is in Phase 3.
That's why I heard.
Yeah, but GSK sanofi is next month for phase
3 Novak's was enrolling in November. They started and sanofi was starting to roll in December. So should be soon.
Is there anything about this approach that tends to go really wrong me not being a virologist and not knowing much about vaccines.
Of the three approaches we've discussed so far I guess the for because we've already alluded to what the fourth strategy is, which is a live attenuated virus. The protein based delivery seems the most benign is that necessarily true?
I think that's fair. It's just a purified protein. Certainly. We have a lot of history decade's worth of History doing that approach successfully if you look at Shing Rex, which is again a purified protein. It's just one of the proteins from varicella zoster virus that vaccine actually works better.
Then the live attenuated viral vaccines last of Acts when dredged essentially is replaced us today.
We basically two years ago said we're done. It's a hundred percent switch to Shangri box now jinguk's rather. Yeah,
which is amazing. I mean, you know, typically historically live attenuated viral vaccines always work better than a single protein. The difference was the adjuvant string Works has two powerful a judgments
which we sort of separate I think by like six months or
something. No, no, they're all part of that vaccine. So one is mono phospholipid a the other is the so-called US 20
One that's all part of the varicella zoster virus glycoprotein. E.E. Has these two a judgments that are all part of the vaccine.
Oh, I see but we give Chinooks into is the second one. Just a
booster you have to do is write the same thing. You think that it's contains the understood. Okay, the adjuvant that's being used in a Nova batch product is actually similar to the Adventist ringers product. So you wonder if you had to take a guess. Maybe this would be the vaccine that would be best for older people because that vaccine Works remarkably. Well in older fingers does
so this brings us to our first
With category then which again we talked about which is these attenuated or live attenuated vaccines or inactivated vaccines. Now, this is something where I think China has a number of products in the pipeline. I don't believe that there. Is there a European or American counterpart in this space
that I know look like all the inactivated vaccines are coming out of trying to and they've got a lot with it you could argue that could be the first vaccine that is commercially available. If you will the first one to have a clear phase 3 trial.
At least you should for my understanding for how much many people have been immunized in China already.
So let's talk a little bit about some of the other things that are going on here. We I think I have to be honest. I'm very surprised I think in March of this year. I did not think it was plausible that there would be a vaccine on the market within a year. In fact, I probably would have used the words impossible. If you said to me in March can there be a vaccine?
Year, and by the way, that wasn't just based on the financial thing. I mean when I asked you that question earlier Paul, you alluded to how the government financially completely D risk to the operation and I won't diminish that in any way shape or form. I just didn't think it was going to be from a manufacturing standpoint possible enough to make enough GMP stuff at volume and actually put it into clinical trials. I was like, there's no way like, there's no way in 12 months.
We can get there. Well, it turns out I was wrong. We're probably going to have vaccines on the market by January. So let's start with a question about genetic drift. What do we know about how much the Genome of this thing is moving. So it's a
single stranded RNA virus and like all single-stranded RNA viruses. Its replication isn't terribly faithful or said another way it probably mutates to some extent every time it reproduces its own. The critical question is does it mutate in a manner that causes a functional trend?
And by functional change, I mean more or less contagious or more or less virulent or from the standpoint of the vaccine. Does it mutate away from the vaccine so that immunization or natural infection one year doesn't protect you the following year, which is the influenza story influenza is also a single stranded RNA virus segmented RNA virus, but measles is a single stranded RNA virus to those moms and they have different genotypes. Meaning that there is drift as you say to cause there to be different strange but never has measles really changed its ear.
So type so the vaccine that we're in 1963 still works today. And so the question is which of those is it going to be this fire is going to be influenza-like or is it going to be measles like I'm going to predict having to make a series of predictions as long as you don't hold me to them. I would say that I'd be surprised all the virus continues to surprise it is going to be more than a single 0 type disease in other words that a vaccine that works now could well work next year and the year after
that. Let's just make sure everyone understands what you said because you said a lot of interesting.
Important stuff there single-stranded RNA is to put it mildly A little sloppy that means every time this guy reproduces itself. It makes a little bit of a mistake. Sometimes those mistakes don't mean anything. Sometimes they do it's yet to be determined. There's two things at least that matter with respect to the Fidelity with which it can reproduce one is does it change the properties of how the virus responds either making it less toxic to us as humans or more toxic or
pathogenic to us as humans. I think it's definitely too early to say if that's happening one way or the other but the second property about its ability or inability to replicate itself perfectly is if it makes so many changes in its replication cycle. It might look so different year after year after year that our immune system even if able to maintain robust immune cells that recognize the virus may functionally be duped by it because it looks so different.
And each year, that's why we get flu shots every year and we get MMR once even though they're both single stranded mRNA viruses. You're basically saying if you had to guess this is going to be between them. So it's not going to be changing so dramatically every year that we would need to go through this exercise. Annually. Is that what you're
saying? Yeah. I'm going to predict actually it's going to be more measles like that. It's not going to drift and in a manner that is means that the vaccine no longer works. That'll be my prediction, but I
I've been wrong about this virus before
us the good news is I mean, I think we're getting to about a year on this thing. And I think the virus were seeing today does not look meaningfully different from that which was identified in January. So hopefully that speaks in your favor. Do we have a sense of how these vaccines are working at the real molecular level? Obviously, we love to look at immunoglobulins as a proxy for immune response. So hey this generated IGG and IGM, but there's been
A lot of talk about the solubility of those things and are those immunoglobulins actually active just because they're present do they actually have The Binding capacity to the virus to actually eradicate it of course, there's been a lot of talk about T cells and how some people might be getting less aggressive version of covid because perhaps they had some T cells that recognized a separate virus a separate coronavirus that they may have had six months sooner. What's
You're thinking well, what's the latest thinking on those hypotheses and
ideas this virus ours Kobe to is essentially a bat coronavirus that just reared its head in Wuhan in the middle of November of last year and now has swept across the world and made its debut in the human population. We are infected with human coronavirus has all the time. I mean, there are four strains of human coronaviruses that circulate they were first identified in the early 1960s or no doubt circulating well before that they cause respiratory
Meaning congestion cough runny nose, occasionally more severe disease pneumonia they account for probably about 15 to 20 percent of the diseases that we see in our emergency department or in our hospital every year and that's pretty much invariant. The question is because the human coronavirus is do share some similarity to This Bat coronavirus, which is recognized by so I called helper T cells does your previous experience with human coronavirus which we pretty much all had a mean something to us in terms of protecting us against this virus. I don't think so.
There's my sense of it in terms of what works. I mean, I guess I'm very simplistic on this based on my experiences with rotavirus. I think the trick is keeping the virus from buying two cells. It's really the way the measles vaccine Works whether most vaccine works, right? Umbrella vaccine Works where the varicella or Chickenpox vaccine works. If you can prevent the virus from binding your cells, you can print the virus from entering cells. So when you make antibodies over those antibodies directed against the so-called part of the spike protein receptor binding domain of the spike protein that is neutralizing the virus. We want to neutralize
As the virus you don't want to just bind to the virus you want to neutralize it so it can't attach the cells and that's the business end of the tsar's Covey to spike protein. Is that so called receptor binding domain? So that's the question and the other question. I think that people are worried about is that antibodies can fade over time even after natural infection. So, what does that mean for a vaccine if antibodies fade and this is a little complicated, but when you are inoculated with a vaccine or when you're naturally infected with a virus, it's not just that you make antibodies you induce immunological memory, so you
Have memory B cells the kind of cells that make antibodies were memory T cells and so they're sort of like the base of the iceberg with the end of eyes being the tip of the iceberg. Do they matter? They do matter especially for longer incubation period diseases. So for really short incubation period diseases like rotavirus meaning the time from when you're infected to when you get sick Roto virus influenza respiratory syncytial virus, those have short incubation periods. This is one of the medium length incubation is around six seven days measles as much longer sort of 10 to
As for longer incubation period diseases there's enough time then for Activation and differentiation of memory cells to become in the case of B cells antibody secreting cells. So it's still would work. I think that's where we're going to be here. So I think memory is important. So when people talk to me about how nervous they are that antibodies are fading. I'm not sure you should be nervous about it yet. Let's wait to see what happens as we move forward with these vaccines.
Yeah. I think that's a great Point Paul and I think there's really two points you made there that speak to that the first is
It's not antibodies that probably matter its neutralizing antibodies and frankly. We don't have commercial tests for that. So, I don't know how much it matters that you're serology tests. That's measuring IGG and IGM levels over time is changing when that's not actually or certainly not necessarily the thing that we care about we care about neutralizing antibodies not antibodies. Your second point is just spot on which is unless somebody is sampling bone marrow looking for B cells that have memory again.
This doesn't matter and we at least if there's one upside to having the long incubation period which has allowed this silly virus to replicate like crazy and spread around the world. At least. It's that the immune system gets some chance to rev up against the I guess I always think of it that way like biology usually take something and give something right. It's like if this thing had no time between when you were infected and when you got sick you probably get sicker because you wouldn't have any of that memory response.
Yes, but at least it would have been contained. We're sort of have the opposite problem. That's a glass-half-full way to look at this. I suppose
let me offer one thing just hopeful because I as you get older you get sort of Grimmer, but I'm gonna try and offer some hopeful thing but it appears that especially in men. There were two papers in science that showed that when you're infected with this virus are scoby to that. You can actually make antibodies directed against interferon, which is a protein that your body is immune system makes to help fight viruses. That's where the name comes from. It interferes with the ability of our stuff infect cells.
Thinking is that that may be one reason why men are more likely to suffer and die from this disease than others this offers. Hope for the fact that a vaccine may be better than natural infection because it's unlikely that the vaccine would do that there certainly are examples of vaccines that are better than natural infection. This may be one of them for some reasons for Hope here.
Do you see any differences in male versus female and vaccine or do you think no, I mean there's nothing that has been published to date that has suggested a gender disparity between this now as
a general rule men tend to
to die and boys tend to die at a greater frequency than girls for most infectious disease. We are the weaker sex or is Murphy Brown used to say that silly little Y chromosome.
Do you think that's a response to a greater cytokine response or what do you think accounts for that difference? I'm not sure even when we age match and we match for morbidity. We don't know. Why
were the weaker sex. Let's admit it
did off-topic blood type. There was a lot of talk earlier.
About anti a antibodies potentially being a little bit protective. Do we have more data on that hadn't seen it. It's a you know
that having type O blood would be some level protective because you can make anybody say or be types. I think I would still put that in the hypothesis unproven
category. Okay. Do we have any data on the robustness of the immunologic response at least based on phase two metrics in different demographics starting with young versus old?
Old obese versus non obese or some other metric where it's going to matter because at some level there's going to need to be some rationing of this right. It's not like vaccine gets approved on Wednesday and on Thursday 300 million copies of the vaccine show up to everybody's doctor. So whether we like it or not, there's a slow roll and a partition to how this happens. What do we know about it? And that sense in terms of how people are responding to it and who's most vulnerable and who should be getting
it? Well the National Academy of Medicine in the advisory committee for
Relation practices at the CDC have come up with their first tier group, but it's huge the first year group includes healthcare workers. It also includes other essential Personnel, like people who work in mass transportation or grocery stores or pharmacies or work in law enforcement or said water purification at includes people over 65 who when they get infected or more likely to die and includes people with certain high-risk medical conditions like obesity, which is probably thirty percent of the American population and IBT.
He's and chronic obstructive pulmonary disease Etc. If you add that all up it adds up to about a hundred and fifty million adults, which is half the adult population in the United States what you are going to require a two dose vaccine, which is already 300 million Doses and that's not going to happen immediately. So how do you partition that I don't know. I mean, I'm one this Commonwealth of Pennsylvania group that tries to make decisions like that. I'm on our Hospital group to try and make decisions like that. I think it's going to be a real learning curve that's associated with
Rolls out. What are we prepared to do about that is this going to produce social unrest it sounds crazy. But have we ever experienced something like this from Healthcare delivery standpoint?
No, I mean this is a virus that's killed 230,000 people. So this may be sort of like the end of the movie Contagion where people like breaking down doors trying to get a vaccine where vaccines where the hero of that story. I think there is going to have to some level be a rationing in terms of who gets what and how it's going to be done and I don't know.
It's really complicated. Right so moderna is basically the NIH Pfizer J&J AstraZeneca an ox running these companies have presumably never been in a situation to have to say here's where this shipment goes to this Pharmacy versus that Pharmacy or this City versus that City. I mean not to dwell too long on a seemingly strange question, but we're not that far from when this is going to happen. We're only a couple months away from that
potentially. So it's the Department of Defense that's going to
To lead it operation warp speed for determining where these vaccines get distributed, but they'll be distributed to the states and then the state's I think will decide how to sort of a portion. It's my sense of it. The CDC initially had sort of four states in one city, which was Philadelphia actually to try and do kind of this test program for how it would be distributed now Pfizer is not an operation Works B vaccine so they may have a different distribution strategy, but I think you're right. It's going to be a real challenge. Plus it's a two dose vaccine.
Plus you it means you have to get people back for the second dose and it's going to some of these vaccines are going to be stored at minus 70. It's going to be really a challenge to see how we get it out there. I mean we had one issue in our house, which was easily resolved, which was should we mandate to vaccine for Hospital workers? No one for the Practical reason that we probably won't have a lot of vaccine into I think that with the novel vaccine strategy like messenger RNA or these replication defective viruses. I don't think you really can fairly mandate that I think you really should wait till it's out there a little more. There's going to be plenty of people who are going to be perfectly.
To take these vaccines and then we'll have a few million doses out there and we'll have a better sense of things Maurice hilleman, why considered the father of modern vaccines having either done the primary research and development own nine of the 14 that we use said it best. He said quote I never be this eye relief until the first three million doses are out there. So we'll see
personal question. Would you take the vaccine right now?
Not till I see the data the good news. I'm on the FCU vaccine Advisory board. So I will see the data and if I feel confident that the say
Safety issues look good issues will good for people my age. I mean, I'm over 65. I want to feel I'm adequately represented in these trials
at a sample size of 30,000 of which let's say a third of them are over 65 with 10,000 people over 65 having no adverse effects in three months make you feel comfortable enough to take
it. I think it would. Yes.
Okay, and I'm going to point something else out to The Listener who can't see you you at least look to my eyes.
Very healthy 65 year old you look like you're about 55. You're not overweight. I assume you don't have diabetes. You look like a model of health. So are you really that high risk aside from your age? And if so, why are you taking it? Just like, okay. So do you still believe that age by itself is enough of a predictor of morbidity beyond the obvious comorbidities that tend to track with age, but presumably at least let's just assume you don't have them you're not that I'm asking you to disclose any
Medical things but you're about as healthy as 65 year old as there's going to be out there.
I would take it not because I necessarily think I'm going to die from this virus. It's because I think that way I feel between taking a vaccine and wearing a mask and social distancing. I dramatically decrease having to suffer this virus. I mean the virus. Yes, it's a killer and yes, it can cause pneumonia which could tell you what scares me the most about this virus is that it can cause vasculitis. I mean who would have predicted that it causes us multi-system inflammatory disease of children.
And it can affect the called heart attacks and cause strokes and can cause liver or kidney disease because it causes vasculitis. So why does it cause vasculitis? It doesn't really enter the bloodstream fewer than one percent of people infected with this virus have so-called by Irina. So it induces your immune response to damage anything little cells that line blood vessels and because every organ in your body has a blood supply every organ can be affected. I mean those so-called long haulers at least in part of probably determined by a vasculitis, maybe even at low level that's what scares me about. This is not a virus that
Get some kills you and gets out or gets in makes you sick and gets out. There are longer term effects with this virus and it should be taken seriously. I mean, I think when the administration's occasionally says things like you need to embrace this virus or live with kind of you know, this kind of notion that the virus would eliminate Itself by population induce immunity, which is never happened for a virus before I think they sort of ignore the fact about the long-term measures of this particular virus about this isn't flu.
I think of all the sort of lingering tail events of this virus the one that probably
Concerns me the most is some of the cardiomyopathy that we're seeing persistent especially in young people on a personal level. I've just had to strike a balance between living my life, but still trying not to be Reckless and to me that's a really bad outcome. Right is is the probability that I'm going to die from this low. Yeah, it's staggeringly low, but there's some risk that I can't quantify of cardiomyopathy or some lingering respiratory thing that never fully resolved.
It impairs quality of life. I guess the real question is just the trade-off between how efficacious in the real world. And therefore I guess effective is the better word. Do I think this vaccine is relative to what other risks? I think what I'm hearing from you that I actually find heartening is at least using history as a guide within a few months of this vaccine coming out and entering the real world, which we can think of as phase for well think of that as post-market surveillance phase.
Or we're going to have a pretty good sense of it and most of us listening to this podcast are not going to be the guys getting it on day one just due to this simple Logistics of it. Like I'm not going to be in the first million doses of this vaccine. You aren't going to be in the first million doses of this vaccine. There are people frankly who are at much higher risk that deserve to be there and I guess we'll have a better sense of it. But I think that this discussion for me Paul is also interesting because it really frames that for different.
Of strategies that one can go about doing this who the players are and what the risks are potentially in each of them and why maybe a sanofi product ultimately might end up being safer than say a J&J product the devil's in the details and I think it's going to matter is how do these things look six months after they've been on the market. The other thing I wanted to ask you about is is there ever going to be a time when we're going to be immunizing children against this virus? I mean, what do we know today about kids getting?
Infected by this
we know the children are less likely to be infected and when they're infected are less severely infected. I'm you know, the people less than 21 years of age in the United States make up about 26% of the population yet. They account for 0.08 percent of the deaths that said about a hundred twenty least the last morbidity mortality weekly report showed that about a hundred twenty children had died from covid-19. That's not very different than the number of children that died from influenza last year, which was around a hundred forty and that's what it usually is.
Anywhere hundred forty hundred fifty hundred sixty in that area. So it's no more or less fatal than influenza for children to can cause long-term problems in children with the so-called m is see disease of children. So I think there is a compelling desire to make a vaccine for children. So how to do that now all the trials initially were done in people over 18, so we weren't studying children initially now recently fives are sort of dropped the age to 16 and they drop the H to 12. So they're starting to look at younger people.
So the question is then what happens and this is applies broadly what happens if a vaccine is approved 3ua Pfizer's already said if that happens for them, they're going to start to immunize their control group, which means now you lose information about safety and efficacy moving forward.
Why is that Paul is that basically as a thank you to the control group and basically a
crossover look at what that does
from a scientific standpoint. You just lost your test case, but what is the rationale for doing that?
I think it's a thank you for being that and that may have been part of the
When they signed up for the trunk, I don't know. Yep. Got it. Okay to get to the children. This could be done in one or two ways. It could be done as a placebo control trial. So same way we do adults. We're can be done as immuno bridging studies. Meaning that you actually find out there is an immunological correlative protection adults. It is a certain level of neutralizing antibodies. It's evoke and if you give to Children a certain dose that you find that you get that level of neutralizing antibodies and so then you just move forward and then you look retrospectively because not all children will be inoculated at the moment that you start.
And inoculating children, you can see whether or not it's pretty good is basically the same way that it worked with the Ebola vaccine. I mean that wasn't a prospective placebo-controlled trial unless I have people just started getting vaccine and because not everybody got it at once you could get a sense of the fact in this by knowing who got the vaccine who did so that may be it when we had the FDA vaccine advisory committee meeting October 22nd. The FDA was very clear about this that when you approve something under emergency use authorization, which is the same sort of permission. You would give to an investigational new drug. You were really under know.
Ethical obligation to vaccinate a placebo group you are and nor are you under a legal obligation to no longer do placebo-controlled trials now, I'm not sure how that's going to play out. You can see for example, if somebody is 70 years old, they see that this vaccine works and they were in the placebo group. They can say I want this vaccine. So with the FAA has argued for is why not just make it an expanded access issue or extended access which is what used to be called compassionate use access, but do it that way and I think that may be the way this plays out. I don't
I'm making a bold prediction by saying I think the first vaccines may not be the last best vaccines but you have to know that you have the last best box and you have to know that down line and maybe a vaccine it's 90% effective and you can't know that unless you do it as a placebo trial. And again if you're going to do it with the other vaccine as the trial thing that would require a huge trial. I mean really how you be hard to prove it.
You actually wrote an interesting paper this summer about the role of fever in fighting infection in children.
I was really surprised at the results and I got to tell you it's kind of changing the way I think about how much Tylenol I kick around the house. You want to talk a little bit about what that paper showed while we're on the topic of kids,
right? Yeah absolutely book called Overkill when modern medicine goes too far and that's the first chapters or in defense of fever. They treating fever can prolong a worse analysis. And the reason is that pretty much everything that walks crawls flies or swims on the planet can make fever. Why do we do that? We do it
because our immune system actually works better at a higher temperature. It's not because viruses or bacteria die more quickly to higher temperature. It's because your immune system works better B cells make antibodies more efficiently. Neutrophils are white blood cells that form pause can travel to areas where bacteria are in kill bacteria more efficiently. So if that's true, if your immune system works better at a higher temperature than are there studies done showing the people who are given anti fever medicines like Tylenol or Ibuprofen. Do they do worse and the answer?
Redundantly, yes, and in the world of vaccines when people choose to treat fever with anti fever medicines when they've gotten a vaccine you have a lesser immune response. I mean over and over again. This has been shown yet. We just can't help ourselves because we want people to feel better or we want ourselves to feel better. But know this that you are hurting one part of your immune system. When you do them,
is there a danger at some point Paul of kids having fevers when the temperatures get too high. I mean, I always feel like that's the one thing that scared the hell out of
Of medical students or residents was you'd see those kids with febrile seizures. And so you have that image in the back of your mind of that kid in the ER that seizing and then God forbid they go on to have some neurologic consequence. And so you're sort of hardwired to think. Well, God forbid. I'm ever going to let a child have a fever again. What's the risk of that? And at what temperature is that something that a parent needs to be aware
of so called febrile seizures are benign. I mean, my daughter actually had a febrile seizure. They're generally short-lived. They don't have long-lasting sequelae and it's not the height of the temperature.
The rapid rise in temperature that causes that so it's not hide any for the most part. I was like most I think physiological fevers don't cause harm your body is not interested in hurting you in that way. Now environmental fevers can heat stroke. I mean, he labor or the athlete or the soldier who's out there and heavy gear and on a hot day and is not able to dissipate heat through sweating. They can suffer Strokes. I mean, it's, you know, you can die from heat stroke some facts about 600 people die from heat Strokes every year. So environmental fevers can do that but not physiological fever. So again, I think
You jump with the not just very hard to watch this case action our Hospital. The boy soccer player was hit on the head. He had a clot in a vein so-called thrombosis and then had that got infected so called thrombophlebitis with staff the merciless the sort of hard to treat staff travel to his brain and cause AB C's of travel to his lungs and cause obviously he's accreditors Bone and Joint cause absence. We were treating with an antibiotic Bank of my students should have treated that but he was continually positive iPod blood cultures that continue to show he was shedding bacteria and everything.
Every two hours we were rotating, you know, either Tylenol or Ibuprofen. Finally. I met with a boy. I met with the parents. I've never this nursing. I said stop treating his fever just give his body a chance to have every part of his immune system working for him and then within really about a day and a half is no longer shining back there that may have been complete coincidence. It's not a proof in any sense, but you couldn't convince the parents of that. They thought we were Geniuses by doing it that way give us immune system a chance to work as good as a Kent why cripple his neutrophils ability to ingest and kill bacteria by giving him.
Anti fever medicine we think we're helping.
Is there any scenario than pollen? Which I mean that's a pretty compelling case. Is there any scenario under which you would recommend taking something like Tylenol?
I think if somebody cannot handle the metabolic strain of increase of Tate, I mean because you increase your basal metabolic rate a certain percentage for every degree Centigrade increase in your fever. It's like 12% increase in BMI for every degree Centigrade. But so if you have chronic lung disease chronic heart disease and metabolic disease that makes you unable to handle that rods temperature sure. I think that's weird.
But otherwise no,
wow so suffer it out.
Huh? Yeah, that's that boy. I love this point. He was like as a teenager young teenager, and he he was just Brave he was okay fine. Everybody was in we were going to do this thing and nurses were in we were going to ride it out. And then he the
better. Alright last thing I want to say on vaccines just a clinic close the loop on this are there viruses besides the obvious like HIV and even hep-c. I guess we're just vaccinating them is either impossible.
Alors outright dangerous. I mean there was something about RSV which we've talked a little bit about that. I mean RSV is really common but there's no vaccine to RSV is that just that it's not cost-effective or was there sort of a more technical issue with it or a risk associated with creating vaccine towards
it the more technical issue of creating a vaccine there were two events that occurred in the 1960s one was with our see where Bob tronic head of the laboratory of infectious diseases at NIH wanted to make an RC that saying this is a virus that causes them.
Your
cousin at 5,000 deaths every year in the United States primarily in young children, especially premature children, they use so let's make an RSV vaccine. He took the virus screw it up and activate it with formaldehyde to the same way that Jonas Salk made his polio vaccine and then gave it to babies and what he found was that children who got that vaccine did worse they were more likely when they were then exposed to the Natural virus. They were more likely to develop pneumonia more likely to be hospitalized and the case of two children more likely to die than children who never got that vaccine same thing happened with the measles vaccine in
In 63 take the virus grow it off kill it with purify killed with formaldehyde that to cause children to have an aberrant immune response directed against that measles virus that causes atypical pneumonia. So they were more likely to get pneumonia in children never vaccinated that was ultimately taken off the market. The reason that may be relevant to today to sort of scoby to today is that both of those virus are viruses respiratory syncytial virus and measles have a fusion protein. That's how it attaches to cells refuses to sell. So to tsarskoe V2 and as
Here's protein. So people are always a little nervous about an inactivated vaccine and it's because you sort of change the confirmation of that Protein that's ours Covey to protein. So it didn't really look like it looked on the natural virus. So that's always in the back of people's minds with Fusion proteins. So you asked me earlier what sort of safety things I'm worried about that actually is one of the states
and that would be more of a concern. I'm guessing with the live attenuated virus as opposed to the other three classes or would you still worried about that in the MRNA and the viral vector v
viruses I worry about it with all them you're worried that the confirmation as made an under these conditions mRNA or DNA or replication defective cars or Cole killed hours or recombinant DNA generated proteins that it's different. It's critically different than the way it sits on the virus. Surface
Paul. This is if unbelievably fascinating discussion. I'm glad I waited on this you and I were going to speak a couple of months ago obviously for so long. I've wanted to have a deep dive on the vaccine stuff, but I feel like this was the right time.
Do it at least to be able to speak about it with more clarity and to really be able to say look by the time someone's hearing this. We're really on the cusp of these vaccines being out there in early 21, but it's not a switch. It's not a binary thing. It's not like we're going from no vaccines to everybody gets vaccines and there's perfect information and there's no risk. This is analog in delivery analog in Risk. I mean, it's analog and pretty much everything other than
approval. Yeah. I think we're going to learn a lot with that.
Thanks for asking me I enjoy this really I don't think I've ever done a podcast this long but it was definitely fun. And in fact, I thought you said two hours ago. Oh my God to have somebody to live through this it really flew. I am just surprising.
Well, I appreciate your time and your willingness to sit down for so long
pal. My pleasure. Thanks for having me.
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