A renowned vaccine inventor returns to talk about important challenges to the rapid development of a safe and effective coronavirus vaccine. It’s not as easy as we might think.

Dr. Paul Offit is Professor of Pediatrics at Children’s Hospital of Philadelphia and co-inventor of the rotavirus vaccine. Watch our past episodes with Paul here.

– Hey, ZPac, it’s Dr. Z, welcome to the ZDoggMD Show, it’s the crack of dawn here on the Pacific Coast and I have with me, returning again for a discussion on vaccine development for COVID, a guy who actually develops vaccines. He’s the co-inventor of the rotavirus vaccine, Professor of Pediatrics at Children’s Hospital of Philadelphia, Dr. Paul Offit. Welcome back, brother, good to see you.

– Thanks, ZDogg, happy to be back.

– Oh, man, all right, let’s just dive into it. What is going on with… So, you have politicians, you have scientists, you have everybody talking about, “Hey, how are we going to develop this vaccine “because we’ll never get off these lockdowns “and these rotating re-outbreaks and all of that, “even if we get it under control, “if we don’t develop a definitive strategy,” which in their mind is a vaccine. Walk us through this, what do we expect here and what are the pitfalls?

– All right, so, the best way to develop herd immunity, so that everybody in the population can be confident or a critical number can be confident that this virus isn’t gonna be spread, is with a vaccine. I mean, with a vaccine, we were able to eliminate measles from our country. So, that’s the best way. And when Tony Fauci, Dr. Tony Fauci, stands in front of, on that podium and says to the country, “I think we could do this as early as 12-18 months,” that’s surprisingly fast. You have an average length of time to go from initial research to having a vial of vaccine that’s distributed to the country is, on average, about 20 years. Our vaccine took 26 years. A little long.

– [Dr. Z] Wow.

– The notion that… The fastest vaccine I think we ever made was the mumps vaccine, where that virus was isolated in 1963 and was a vaccine in 1967. That was amazingly fast.

– Oh. Four years still, yeah.

– Four years still. So, so that’s it. The issue is, is it possible to develop a vaccine that quickly? And I think it would be fun, actually, to talk about what it takes to make a vaccine and what the pitfalls are.

– Let’s do that. And I want to ask this question. So, people talk about, “Oh, HPV vaccine was developed “too fast and it’s too new “and we don’t know anything about it.” How long did it take to develop, say, HPV vaccine and what was the process of even testing that, as an illustration?

– Well, if you count the research, it took more than 20 years. If you count just the research of development, that vaccine was test in 30,000 people for seven years before it was ever licensed. So, that was just vax facts.

– Why is it important to do that? Because with other medicines and stuff it may not take as long. Small molecules, different drugs. It can take a long time. Why are vaccines, why are we so careful with that?

– I think because we give them to healthy people. I think, therefore, they have to be held to a very high standard of safety. I think people are willing to accept certain safety issues when they’re sick, but they’re not when they’re well. And so that’s the reason. You’re giving these to healthy children.

– And are we worried now that because, and this is just to frame what you’re going to tell us about vaccine development. Are you worried now that people are so scared of this coronavirus and what it’s doing and our perception of it that they’re gonna rush into this and sign up for getting a vaccine that maybe have been rushed?

– Well, yes. I think it would. People are terrified. And they’re terrified, we tend to have this break the glass mentality. And that break the glass mentality may mean that we’re cutting certain corners or we’re not doing animal model testing or we’re not doing extensive so-called, phase one or phase two, testing where you do thousands of people, looking for issues of safety and making sure that you get a good immune response before you even get to the efficacy trial. Yes, I worry that we might do this too quickly and miss things. It’s the, the will, it’s a good one and we want to try to save people’s lives that’s great, but you want to make sure that you do it the right way. But, it concerns me a little bit.

– Yeah, so okay, so walk us through vaccine development. So, people understand what’s involved in a typical vaccine development and then we can apply it to COVID and coronavirus, SARS two coronavirus.

– So, I think you know that you can make a vaccine if natural infection protects against diseases associated with reinfection. Which is usually true. I mean, I was a child of the 50s, I had measles, therefore I can be comfortable that I will be protected against measles for the rest of my life. But there are some diseases where natural infection doesn’t protect against reinfection. Gonorrhea is a disease you can get over and over again.

– Tell me about it, Paul. I mean, wait, what?

– I don’t have to tell you that.

– [Dr. Z] Yeah, yes.

– And then your strep throat is a disease you can get over and over again. When you see that you know that it’s going to be, you’re going to have trouble making a vaccine. I think that’s not going to be true here, based on studies that were done really decades ago, with human coronaviruses. So there are four human coronaviruses that have been circulating in the United States at least since the 1960s when they were first identified. We can assume it’s longer than that. There was a study done a couple decades ago where they took experimental volunteers, people, they inoculated them with one of the types of human coronavirus and then a year later they challenged them with the same type to answer the question, were they protected? And the answer was, yes. So, I think you can be protected for at least a year, and probably years, with this having been infected with this virus, assuming the virus doesn’t mutate, and all the evidence to date is that it doesn’t mutate. So, I think we can make a vaccine, that’s good.

– Okay, so, the evidence is that it does not mutate. What kind of evidence is that? How are we seeing that? How do we determine that?

– So, it’s a single-stranded RNA virus. So, therefore, like all single-stranded RNA viruses, it’s replication isn’t highly faithful. But measles is a single-stranded RNA virus that just has one serotype. Mumps, same thing. Rubella, same thing. So, you can have a single-stranded RNA virus like this one that still has only one serotype. The way we know that is we are isolating these strains and seeing whether or not they are critically different. Meaning that, although there are sequence differences, the question is, do those sequence differences add up to a different serotype? Polio has three serotypes. Human papillomavirus virus vaccine has many serotypes. So, the important thing is to make sure you include all the serotypes in a vaccine. It looks like for this particular SARS-CoV-2 it’s only one serotype. That’s good, too.

– Got it, got it. And so because you have only one serotype, and that’s the effective immune responses to the serotype, the promise for a vaccine is actually pretty good. Again, either you include a bunch of serotypes in your vaccine or it’s something like HIV where it mutates quite a bit, and other RNA virus mutates quite a bit, etc. Is that correct?

– Exactly right.

– [Dr. Z] – Got it, okay.

– Another thing that’s good news is, you know the part of the virus you care about. The part of the virus you care about is the so-called spike protein that surface glycoprotein. Every time they show these pictures on the media you always see it, it’s sorta of the crown, hence coronavirus, and then you see these little spike proteins coming out of it. That protein is responsible for binding to cells. It’s responsible for the virus binding to cells. If you can prevent the virus from binding to cells, then you’re gonna prevent the virus from infecting the cell, therefore, you’re gonna be protected, so that’s the protein you’re interested in. And we live in an era of recombinant DNA technology. We can inoculate people with a variety of different strategies to induce an immune response against that one protein.

– Got it. So, you could create like a messenger RNA vaccine that is translated into a protein and then, ultimately, you mount immune response to the protein. So you don’t even have to use killed virus or something like that, correct?

– Exactly. So, there’s basically four strategies. One of them, just what you said. You inoculate somebody with messenger RNA, that’s translated to the protein you’re interested in, in this case the spike protein. Or you inoculate them with a DNA vaccine that then is transcribed to the messenger RNA that is then translated to the protein. Or you can inoculate them just with the protein, as we do with the hepatitis B vaccine or the human papillomavirus vaccine. Or you can inoculate them with a vector vaccine. In other words, like the dengue vaccine or the Ebola vaccine or actually, it’s a different virus, into which is cloned then the protein, the codes for that surface protein.

– Oh, interesting.

– [Paul] Or the geneocodes for the surface protein, so–

– So, it’s like a Trojan Horse virus that’s holding different genetic code that you use in those vector vaccines?

– Right, exactly.

– [Dr. Z] Got it!

– Here’s the problem, here’s the thing that I worry about a little bit. And although I don’t think it’s going to be a problem, I think we’re gonna have to prove it’s a problem. Right now, Moderna is leading the pack. This is the vaccine that Dr. Fauci talks about when he stands up in front of the reporters during these conferences. The reason Dr. Fauci likes that vaccine is that it’s a safe vaccine. It’s hard to believe that the messenger RNA would in any sense be harmful because it’s so quickly degraded from the body. Secondly, you can really scale up messenger RNA, very quickly, it’s not hard. A little trickier is the lipid, the complex lipid delivery system has not been scaled up. So, it’s gonna take a while to scale that up. I can’t imagine that’s scaled up in less than a year. That’s just the delivery system.

– [Dr. Z] Right.

– So, I think when Dr Fauci says 12-18 months, that’s amazingly optimistic. But the other thing that I think is important here is that when you present a protein to the immune system… The best way to get infected, the best way you know you’re gonna get an immune response is to be naturally infected. The problem with natural infections is you have to pay the price of natural infection, which can be death, which is a high price.

– [Dr. Z] Wait, wait, wait, Paul, let me interrupt you for a second. So, you’re telling me that my COVID-19 party that I was ready to throw… We get a COVID patient and have them cough on all of us is not the best strategy for immunization in this case?

– I think you’re the only now having a COVID party, but I could be wrong.

– An intentional COVID party.

– [Paul] Right.

– Yeah, exactly, please continue, sorry. So, because … And the reason I interrupted you is obviously the anti-vaccine people have been talking about natural immunity and having measles parties and chicken pox parties is the best way to get immunity. And you’re right, you’ll get immunity, the problem is, you pay the price which is the complications, side effects and potential death from the disease.

– Exactly. So we have two protein vaccines. The hepatitis B vaccine and the HPV vaccine. And they’re great. They’re safe, they induce an excellent immune response. The reason is that an HPV, human papillomavirus is a good example, that’s a virus-like particle. In other words, when the surface protein, which is called the L1 protein, is made in these V calls, that protein actually forms a pentamer and then it forms an actual capsid. If you look at it, it looks like the virus. If you look at the HPV vaccine under the electron microscope, it looks like HPV. So, you know that the confirmation or that the integrity of that protein is preserved on the surface. The protein in that vaccine looks exactly like it looks on the surface of that virus. That’s critical. The same thing’s true for the hepatitis B vaccine. That, too, is a so-called virus-like particle. That protein looks, in that vaccine, exactly like it looks in nature. That’s good. I worry, and I think we all are. I think everybody who is involved in vaccine, this vaccine, is concerned about the fact that that’s not going to be this protein. This protein, whether it’s a mRNA vaccine or a DNA vaccine or a purified protein vaccine or a vector vaccine, may not look exactly like it looks on the surface of the particle. And here’s why that’s a problem, the goal of… If this, there’s my fist, if this were the protein, there’s the business end of the protein, we’ll say it’s this, the part that binds to the virus. That’s the business end. If you make antibodies to that business end, you will neutralize the virus. But, you can also make antibodies to the not-business-end. The part that doesn’t bind to the virus. Those are so-called binding antibodies. So, we have the neutralizing antibodies and you have the binding antibodies. You want to make sure that the quantity of neutralizing antibodies that you have, and the persistence of those antibodies, is much greater than the binding antibodies. Because the binding antibodies could be dangerous and cause something called antibody-dependent enhancement.

– Ah.

– And we see that, I mean we saw that with the dengue vaccine. The dengue vaccine, as you may know, but the dengue vaccine, in children who’ve never been exposed to dengue before, actually made them worse when they were then exposed to the natural virus. Much worse. Causing something called dengue hemorrhagic shock syndrome. Children died because there were vaccinated children who were less than nine years of age who had never been exposed to dengue before were more likely to die if they’d been vaccinated than if they hadn’t been vaccinated.

– Oh, wow.

– That’s the problem. And that was because of antibody-dependent enhancement. Because what happens is, those binding antibodies, they don’t neutralize the virus, they just bind to it. And now we have on our cells something called an Fc receptor which then can allow that antibody, will bind the antibody and bring the virus into the cell. It’s actually a more efficient way for the virus to enter the cell than otherwise. So, what you’re doing by creating all these binding antibodies is potentially causing this antibody-dependent enhancement which could worsen the problem if you then were exposed to wild-type or natural virus.

– That makes terrifying sense, Paul. Is that what happened with RSV immune enhancement in the vaccine that was tried in the 60s?

– Yes, so that’s a little different. The RSV problem, in the 1960s there was a vaccine that was made, actually by NIH where they took respiratory syncytial virus, which causes thousands of children to die every year in this country and killed it. Whole killed virus. The same way we made the hepatitis A vaccine, the rabies vaccine, the polio vaccines. Those were all whole killed viruses. What happened was, the RSV has a fusion protein on its surface. That’s how it, it’s one of the mechanisms by which it attaches to and enters cells. That by killing it, you altered that fusion protein, making it unlike what would normally be seen by if you were infected by the natural virus. So now you have this aberrant response to the fusion protein. The same thing happened with the measles vaccine in 1963. There was a whole killed measles vaccine, that if you got that vaccine, and then you were naturally infected with measles, you were more likely to get pneumonia than if you’d never gotten that vaccine. Again, because of an aberrant fusion protein response. So, not exactly the same thing. But, again, the same thing in the sense, so you’re right, the same thing in the sense that you had critically altered that protein as compared to the way it would normally be seen in nature.

– So, excellent. Let me recap this with the regards to coronavirus. When you talk about HPV vaccine, when you talk about hepatitis vaccine, you’re saying the proteins that are made there look enough like the virus that the antibody response that we mount really attacks the business end of that protein, as opposed to the non-business end, which leads to something called an antibody mediated, actually enhancement, of the viral entry into cells, which can be devastating. So, the concern with coronavirus is, if we make this protein incorrectly, doesn’t look quite like the wild type, we could be making the problem worse with the vaccine if we’re not careful about that. Did I get that right?

– Exactly. And so the trick is, the key word that you just said was, careful. You need to make sure that you feel comfortable with this vaccine before you give it to tens of millions, and because this is a worldwide pandemic, hundreds of millions of people. So, how do you do that? Typically, with vaccines, what you do is, you do an efficacy trial. The only time you don’t do an efficacy trial to get a vaccine licensed would be like something with the meningococcal serogroup B vaccine. There’s two, there’s Bexsero and Trumenba, those never had an efficacy trial. The reason being that there’s only a few hundred cases of meningococcal serogroup B disease in the United States, so it’s not practical to do an efficacy trial. You have to do hundreds and hundreds of thousands of people, which is not going to happen. But you had a clear immunological correlate. You knew that if you had a certain level of antibodies directed against meningococcal serogroup B, that you would be protected, because of decades of research that showed you that. So both those vaccines were licensed without ever doing an efficacy trial. That can’t be true here. You don’t know what the immunological correlative protection is, or said another way, you don’t know the specific antibody response you’re looking at that tells you you’re going to be protected against this disease.

– So, you could look, theoretically, at convalescent sera, of blood of people who’ve gotten better, and say, “Okay, what IgG what IgM are they producing “that correlates to their response “to the virus,” though, right? Couldn’t you just look at that and be like, “Oh, okay, if we have those and “then they can’t be reinfected “and we do some quick study on that,” couldn’t we figure it out quickly? Or is it more complex than that?

– It’s more complex than that.

– [Dr. Z] Of course, it is.

– For all the antibody studies I’ve seen published, they’re just what you said. We have total antibody immunoglobulin and immunoglobulin G. What I haven’t seen published is neutralizing antibody. Even just that, is the immune response that you’re generating from natural infection neutralizing to the virus? I would imagine that would have to be true. I’d love to see a paper published that says that. But, I’m sure that’s true just because from what we know for human coronaviruses.

– So, again, the distinction between neutralizing and, say, binding antibodies, right? So, neutralizing, binding to the business end. Binding antibodies binding to something, some other part of the virus, some other immune response.

– Right. So all you’re looking at now is binding antibodies. When you see IgG, IgM, those were ELISA tests generally that look for binding antibodies. So that’s all you know now. So, I think what has to happen is, if we’re going to be doing this quickly, and we’re doing it quickly. I think that, I haven’t seen animal model studies published on Moderna’s vaccine. I haven’t seen that. All I know is that we did, in Washington state, a 45 person study that involved adults between 18 and 55 years of age, who were divided into three groups of 15. One got the lowest dose of messenger RNA that would then, presumably, be translated to a protein that would induce antibodies. The second group, I think just finished getting the middle dose. And now we’re doing a higher dose. Moderna is already talking about moving to phase two this spring. Well, it is this spring. So, I’m gonna assume that they’re… I would have to believe that they would do thousands of people. Once they’re clear that they have a dose, they should do, I think, larger dose ranging trials, just to make sure that’s the right dose. To make sure that they do a trial that represents the American public. So, that you know that the trial that you’ve done represents the different, percentage of African Americans, etc., in this, too. Then when you give it to the American public, you know that you’ve tested a reasonable percentage of the American public before you do that.

– [Dr. Z] Right.

– That you would at least do that and then you have to do an efficacy study, you have to, to make sure that you don’t come up in any sense with this problem of antibody-dependent enhancement. I don’t think that’s going to happen, but it is a theoretical concern. And I imagine that the best way to do an efficacy trial would be in healthcare workers. They’re the ones who are most likely to be exposed, either the most frequently or just quantity of virus, so they would be, I think, the ones who would have to do this. But it has to be a placebo controlled trial. So that you see, here’s a group of people who got the vaccine, who then were exposed to the virus. Here’s a group of people who didn’t get the vaccine, who were exposed to the virus. To make sure that the group that was vaccinated don’t do worse when they were exposed to the viruses compared to the group that wasn’t vaccinated. Which is what happened for a subset of patients that got the dengue vaccine.

– So, okay, this is very important to reiterate. In order to study that effectively, it has to be randomized, it has to be blinded. It has to be placebo controlled, which means you can’t, as a member of that trial, say I’m a healthcare professional, I can’t sign up and go, “I want the vaccine.” Because that’s going to introduce all kinds of bias just in terms of I’m self-selecting to get the vaccine, which means maybe I think I’m at higher risk, maybe something else is going on. So, you would have to randomly allocate vaccine or placebo vaccine to the groups, study enough of them because they’re at higher risk for getting the disease, and then see if it’s efficacious. That’s what you’re saying, more or less?

– Yes, and I think that in this time of panic, terror, that people would say, in some ways you said, to some extent, which is, “Hey, I want the vaccine. “I’m scared about getting and dying from this virus, “I want the vaccine.” But know this, the history of medicine is littered with tragedy, and you just want to make sure… Again, I don’t think this is going to happen, but I do think we need to prove that it doesn’t happen before we give this vaccine to tens of millions or hundreds of millions because… You’ll do the best you can, pre-licensure. I’d like to think we’ll do tens of thousands of people pre-licensure. It’s done for most vaccines. I mean, our vaccine, the RotaTeq vaccine, was tested in 70,000 babies pre-licensure. The Rotarix vaccine in 60,000-plus pre-licensure, the HPV vaccine in 30,000 people pre-licensure. I’d like to think that this vaccine is tested in tens of thousands, which doesn’t prove that you don’t have a problem but at least makes you a little more comfortable that you don’t have a problem.

– Right.

– Maurice Hilleman who I think was the father of modern vaccines said it best, “I never breathe a sigh “of relief until the first three million doses are “out there.” I think that’s always going to be true. You’re never really sure until it’s out there. There’s always risks and benefits, but you want to at least put yourself in the best position possible before you give this vaccine to tens or hundreds of millions of people.

– Yeah, and relating to that, let’s say you develop a vaccine in record time and maybe you’re pushing the limits and you’re thinking well, post-marketing surveillance is going to catch some things and hopefully we’re as close as we can. Would you, Paul, advocate that people be tested with ELISA to see if they’ve already been exposed to the virus before getting the vaccine? Or would you vaccinate even those individuals assuming that you’re comfortable with the safety profile?

– I think what would happen is that when they do this trial as an efficacy trial, I think they would initially take on only people who’ve never been exposed to the virus, initially.

– [Dr. Z] Right.

– But I do think, I’d like to think in their one-up to that trail that you would give this vaccine to people who were seropositive, meaning had already been exposed, people who are seronegative have never been exposed, as all part of the safety work up. When we did our rotavirus vaccine, we started in doing our safety testing as we got to progressively larger safety and immunogenicity trials, we initially started in seropositive adults. Then we worked our way up to seronegative adults and seropositive adolescents and seronegative adolescents, all for a vaccine that was going to be put in babies. And then we worked our way down to babies. But, when we did those ranging trials, meaning trying to figure out which dose this was, that was the best dose, that was thousands of people. So, I mean maybe I’m a bad sport because it took 26 years for us to develop a vaccine. But, I do think that it is important to develop this vaccine quickly, but it’s also important to make sure that you look as closely as you can to make sure that you’re not going to deal with problems down the road. And I just worry, in this era of panic here, that we, not we as researchers but we, as a public, would be willing to accept something that hadn’t been thoroughly tested.

– And that makes perfect sense, because if you imagine you’re inoculating healthy people, en masse, in a population, if you have a .5% complication or mortality rate from the vaccine, that is pretty much about half as bad as being infected with the wild-type, right? If everybody got infected. So, it’s just a magnification of numbers if it’s not safe. So the idea that, listen, you’ve been through this vaccine development process, phase one, phase two, phase three, efficacy, dosing trials, large numbers of people, safety, then putting it out and breathing the sigh after three million doses, all those things you’re talking about. In this case, people are talking about compressing that into a record, maybe unattainable, timeline because we’re so scared of this virus which is causing havoc around the country. But, the question is, could we make the problem worse if we overdo it? What do you think is option B if, in other words, would you just like to see it more carefully studied in a quicker timeframe, what’s the solution to that?

– I think that if you find that there’s, let’s say with messenger RNA vaccine, that there is this problem with antibody-dependent enhancement, again, I’d like to say, don’t think that’s going to happen but I just think we need to make sure it doesn’t. It’s going to be hard. You now know that the purified protein approach whether it’s with mRNA or DNA or with purified protein itself or with the vector vaccine, is not, is a problem. So another option, see, dengue’s a good example because with dengue vaccine, what they would be, it was Sanofi, actually, initially made the first dengue vaccine, the only currently licensed dengue vaccine. The way they made that was they took the yellow fever vaccine, the yellow fever so-called 17d vaccine. That’s the yellow fever vaccine. And then they took out a region and then inserted this pre-envelope, an envelope region for dengue. And they did it for each of the four dengue serotypes. You basically had four yellow fever vaccines into which was cloned this gene they coded for the surface protein of the four dengue serotypes.

– And that’s the business of the virus, yeah?

– Exactly.

– For dengue.

– It’s the binding protein.

– [Dr. Z] The binding protein, yeah, yeah.

– It’s the cell attachment protein.

– [Dr. Z] Got it.

– But what happened was, is because it was a yellow fever vaccine as the backbone, I think that the confirmation of that dengue protein wasn’t exactly as it would have been on dengue. So how do you solve that problem? And I think that problem’s been solved. I think it was solved by Takeda. What Takeda did was they took dengue type two, weakened it in the laboratory, so now it can’t cause disease. They weakened dengue type two in the laboratory. Then they, what they… And that was the dengue type two vaccine. Then they took that backbone and then inserted into it type one, three or four. So now you had four strains, which were all dengue two except inserted into that was the surface protein for one, three or four. So four strains. And see, there, because it was a dengue background, now the confirmation was much more like it would have been seen on dengue virus. And so then when they did a trial, and this was published in the New England Journal of Medicine recently, when they then did a trial, what they found out was they didn’t have the problem with antibody-dependent enhancement. They solved the problem. So were that to be a problem here you could make the same argument, that you would use a, say, a attenuated coronavirus. Something where even if it was an attenuated human coronavirus, something where the expression of that surface protein was very similar to what would be seen in the natural virus. It’s hard. I think when I hear, like there was recently a couple researchers, one in Boston, one in Pittsburgh who were working the laboratories with mice said, “I think we’ve got the vaccine.” That is a healthy disrespect for what it takes to make a vaccine. I mean the reason, as an academic I think I’m allowed to say that.

– [Dr. Z] Yeah.

– But there’s sort of the research, then there’s the research, then there’s the research of development then there’s implementation. It gets harder and harder. When you get to the research of development, mice aren’t men. I think that probably David Weiner, who’s my favorite vaccine researcher at Penn says, “Mice lie and monkeys exaggerate.” I think that’s exactly right. The research of development is you have to do proof of concepts, you have to do dose maintenance studies, you have to write buffering agents, write stabilizing agents, write vial, you have to do real-time stability studies and then comes the hard part. Which you do have to mass produce it in a way that is absolutely consistent from one batch to the other. These aren’t small molecule drugs. This isn’t amoxicillin where you can just say, “Yes, this is 50 milligrams in the tablet.” The process is the product and you have to make sure the process is the same all the way along, and that’s hard.

– Ah, ah, ah, ugh. Paul, why is science so hard? Why is it the tiny changes in the confirmation of these proteins can have massive downstream effects on the efficacy of the actual vaccine? Why aren’t things just black and white? Well, because that’s the nature of the world, right? So, then the question is I’ll throw back at you, it may be… If I’m reading between the lines here, which isn’t a between the lines, it’s what you’re saying, this is not as easy as we might be thinking it is, based on what people are saying. What should we do? Obviously we continue working on the vaccine, full-court press. Is there another approach to attenuating this disease outbreak that we obviously have to simultaneously work on? Is it antivirals, what would you do in this case?

– Well, certainly, what we’re doing which is we are studying antivirals, whether it’s Remdesivir or Favipiravir or this hydroxychloroquine, which I’d be surprised if it works but it’s testable.

– [Dr. Z] Right. But we’re doing that. We certainly know that for some patients who have so-called cytokine storm, or ARDS, that they do make large quantities of interleukin six so there is a monoclonal antibody directly against that called tocilizumab. That’s good. But, I think what we need to do, I think Dr. Fauci’s right, I think that by picking mRNA vaccine he’s picked the one that’s probably the easiest to scale up in terms of the mRNA itself. I do think that lipid delivery system is not so easy but again, doable. Especially if everybody cooperates, all the manufactures cooperate to do what they can to fill, even with multi-dose vials, I think the filling would take a year. But in any case, the… That’s it. And just make sure that to the best degree you can, which is to say tens of thousands of people that you have obviated the question that some people are concerned about, this so-called antibody dependent enhancement. And when you have and you put it into people you’ll do post marketing or post licensure or whatever you want to call it, surveillance. To make sure it’s not there. The other thing I just hope happens, I hope they don’t bypass the FDA. I hope the FDA gets a chance to look at this. And I’m not speaking on behalf of the FDA in any sense, although I am on the FDA Vaccine Advisory Committee, so were this to go to the FDA, our committee would see it. I’m not speaking on behalf of the FDA, I’m not speaking on behalf of the FDA. This is just me, personally, speaking. But, I do think that it would be of value to make sure that it comes to the FDA, in part because that’s probably the best chance for the public, actually. It’s an open meeting for the public to see those data and to look at the data for themselves, as well, so they can see what everybody’s doing.

– Those insights are really something that you don’t hear in the sound bite related press that we’re seeing people talking about this stuff. So, that’s extremely helpful, Paul, to hear from somebody who’s actually developed, invented, developed these vaccines and sits on committees that looks at them. So, that’s super helpful. Any other thoughts around vaccine before I ask you some other questions?

– No, I think, well, look at that vaccine, the movie “Contagion,” which appears to be the most downloaded movie now. Who was the hero of that movie? Vaccines were the hero of that movie. Ian Lipkin was, I think, the medical advisor for that and so, at least in that movie it took six months to make a vaccine which was better than the movie “Outbreak,” where I think it took an hour. So, it’s a little better but it’s still a little more out there. Also, Elliott Gould as a virologist, I’m sorry, I just never saw that but that was just me.

– Maybe they should have just cast you, that would have been amazing. You know Dr. Drew apparently was cast in Sharknado Four so, there’s a precedent. Now speaking of Dr. Drew, let’s ask a question here. You and I have had conversations about, okay, what’s the best approach from a public health standpoint to manage this outbreak? Is it locking everything down, is it putting everybody in quarantine, is it closing the schools, is it that? And we had a previous conversation where we talked about some of things from a speculation standpoint. Maybe there’s a more targeted way, maybe we have to get the initial outbreak under control since we didn’t test correctly. How’s your thinking, has your thinking evolved on this as we’re seeing what’s happening in New York and all of that? Or do you have other thoughts on how we’re handling this currently?

– Well, I think the lessons from China and South Korea and Singapore and Japan were locking down works. China, if you believe those numbers and I don’t believe the case numbers. Let’s assume the death numbers are probably also low, but I can’t believe they’re that low. They stopped the spread of that virus. I’m sure there are tens, if not hundreds, of millions of people in China, a population of 1.4 billion people, that are still susceptible to this virus. I can’t believe everybody’s now immune to this virus, it doesn’t make sense. Yet they were able to stop it. So I think the lockdown, shelter in place strategy, whatever you want to call it, is of value and I really wish we’d done it across the country right at the beginning and hard stop. I’m not sure that we had to close schools. Singapore never closed schools, initially. I think they did more recently. And they still were able to get on top of this outbreak. And the CDC, initially, also never recommended closing schools. They didn’t think it would affect the epidemiology. But that aside, I think locking down did matter, we unfortunately are doing it sequentially, not all at once. So, we’re getting these…

– Yeah.

– Sort of waves that come up–

– Rolling lock outs, yeah.

– That’s right, it’s like rolling sand. We’re one of the people, my sister’s son is living here with us now, in this little communal home we have. Our shelter in place communal home. But, he lives, works in New York City and he, his friends are sending him pictures of the subway that are packed with passengers. They still haven’t really, really locked down. I do think it would help were we to have a federal government that actually had a policy that was made clear. That there was a very quick directive early on that we needed to lock down to stop this, based on what we’ve learned from all these other countries. But that didn’t happen.

– Yeah, so the horse is out of the barn a bit now. And the idea about school lockdown is interesting because, like you said, the Koreans did not lock the school–

– [Paul] Singapore.

– Singapore? Singapore did not lock schools down initially. They’re doing it now, I think because they’re seeing resurgence in cases from returning travelers, correct?

– Exactly.

– And so what are your thoughts on this whole mask debacle? CDC’s saying, “Don’t use masks.” Surgeon General’s saying, “Don’t use masks.” Public, talking about the public. Now saying, “Oh, go ahead and wrap your face “in whatever cloth you have.” I have thoughts on this but I’m curious what yours are.

– If you’re in the hospital, and you’re walking into the room with somebody who has this infection or somebody who has tuberculosis and is coughing, or has extremely drug-resistant tuberculosis, even worse, and is coughing, you don’t just wear this surgical mask. You wear the N95 respirator, so you have complete seal over your nose and mouth so you’re not going to be able to catch this. Similarly, if you have the infection and you’re worried, you think that could spread and could hurt people, again, you should that respir… Frankly, not leave your house. But the surgical mask, you can breathe in and out on the side of that, so it’s not perfect. Also, it starts to get wet, which makes it a little more porous as well. So I think the downside of the surgical mask, the biggest downside, is the people who are mildly infected think, well, now I’m protecting others by wearing the surgical mask. That’s a bad idea. I wonder where people are, first of all, these personal protective equipment and masks, etc, are not readily available. The hospitals are having trouble getting these masks, so I’m not sure how the public’s going to get them, so we’re not supposed to wear these cloth bandanas or cloth masks. I think the best thing you can say about it is, it reminds you that you should try to steer clear of people, I’m not sure how well it would work.

– Yeah, my main concern with this is that people are going to get a false sense of security, they’re going to touch their face more because they’re going to be fiddling with the bandana. They’re going to grab the bandana by the front, which is potentially covered with whatever filth they’ve been breathing in. And they’re really not going to believe the government and they’re going to try to get real masks, which is going to make it more shortage for healthcare professionals. Without really a lot of science saying, actually in the wild this actually helps. You can look at all kinds of raw particle data and this and that, but in the wild, does this help? “Oh, well, in Japan and in Asia they wear these things “and look, they’re controlling it better.” Dude, they’re doing everything different than we did at the beginning. So, it’s really impossible to say this. Now, I see people walking around with cloth bandanas, talking on their phone like this, touching the phone to their face and I’m like, “This is not, that’s not how it works. “That’s not how any of this works.” So, that’s my concern. I understand why they’re doing it, but I have a lot of deep reservations about telling the public stuff like this. As opposed to just, “Hey, stay home, social distance. “Don’t get on a packed subway, that’s dumb.” The ship comes into the harbor, the U.S.S. Comfort, don’t crowd together with a bunch of people going, “Look, it’s the ship that’s going to save us,” breathing in each other’s face at a ratio of this. Has your thinking of how this thing is transmitted changed at all? How do you think the thing is actually, the predominance of transmission. How’s it occurring? Is it air, is it fomite, what is it?

– And so what I think it’s respiratory droplets and fomites. I think those are the two biggest. Wash your hands, cleaning surfaces, trying to maintain some distance, I think that’s all of value. And I think that’s how countries were able to stop its spread. So, I think it is stoppable I just think, I just was hopeful, last time we talked, that I felt people were now going to be sheltering in place, that that was going to happen much more uniformly and I’m not sure that really did happen. Because what we’re seeing now with, say the, I think 8,500 deaths we had as of this morning in the United States, that’s more reflective of what we were doing three weeks ago.

– Right.

– Because it has an incubation period of five to 10 days, then if you get sick, then you get sicker, then you get intubated, then you die. I mean, that takes a few weeks. I think this is, what we’re seeing is what we did three weeks ago, so I keep thinking, when did we really take this seriously? Because I think then, three weeks later is when we’ll start to see coming off the curve. Because we’re not coming off the curve. We have, we had a thousand deaths till March 26th, on March 28th, two days later, we had 2,000 deaths. That’s a doubling of two days. That’s a two day doubling period, that’s really fast. Then by April the first, we had 4,000 cases, so that’s a four day doubling period. And I was hoping that that was a trend, we would go from two to four to six, because as Angela Merkel said, “Give me a ten day doubling period and I think “that the hospital discharges “will exceed hospital admissions.” I think that’s probably right. See, there’s a country, actually, that tries to do things like come up with policies and rules to help people understand how it is that we’re doing, instead of setting arbitrary dates. Let’s do April 12th, Easter. Let’s do April 30th. Well, you know, just, let’s do June 10th. According to the governor of Virginia. Let’s have a rule to figure out how we’re doing this. But, so today it’s 8,500, which again a double period of four days. So, we’re not, we’re still at four day doubling. Germany’s at five, five and a half day doubling. Italy is at a eight day doubling, so they’re actually starting to come off the curve.

– Come off the curve, yeah. Wow, so and this makes perfect sense then, what we’re seeing there were some earlier reports that the Bay Area is bending the curve because they were quite quick in lockdown, and I’m hearing our public health officials are pretty hard core. I think there’s a political side, always, so the more liberal Bay Area is more into, “Hey, let’s have a government, actual policy “that sets behavior,” whereas in other parts it’s like, “Oh, no, heck no, we’re America.” And so, it’s an interesting experiment to see from a health standpoint what’s a more effective thing. Now, I actually think, when I’m talking to my hospital colleagues, they’re preparing for a massive surge because we have not, I don’t think yet, bent the curve here. But, but, I think we have a good chance of, when I walk out in the street, I don’t see people in each other’s faces. I see Home Depot staggering people to enter the thing. People seem to be behaving reasonably well where I am, which is encouraging. I don’t know how it’s going in the rest of the country.

– Yeah, we’ll see. Philadelphia’s not too bad, actually. Too, I work Children’s Hospital, Philadelphia’s not bad at all. We have the lowest census we had ever since I’ve been there for the last 30-plus years because, first of all, this is not really a disease that seriously affects children. We see kids coming in the ED, emergency department, but not into out intensive care unit.

– So, I want to wrap this up with one thing I want to talk about, and this is kind of a preface to what you had worked on prior to all the COVID stuff, which is a book on over treatment. And about how a lot of what we do in medicine really doesn’t help. In this setting, where we’ve shut down a lot of outpatient and elective stuff, we’ve gone to telehealth, we’re seeing, I’m not sure we’re seeing an uptick in mortality or bad outcomes from less interaction with elective medicine. So, it will be interesting to see, kind of as a grand experiment, what it is that we’ve been doing that doesn’t help at all and could have been scrapped. How we can get paid to actually do the things that do help and transform our system. I’ve been going on rants about the administrative technocracy and how we’re paid to do dumb stuff and how we’ve been led, doctors have been, as a calling, have been destroyed. We have to do our part to go, “Well, what is that we do “that actually works and let’s do that.”

– Yes, it’s interesting. In the last three weeks, typically, U.S. has about 55 total deaths, 55,000 total deaths a week, total. And I’m not talking about COVID or flu, I’m talking about total deaths, 55,000 a week. Over the last three weeks, it’s been 45,000. With 10,000 fewer deaths a week. Why? We’re not driving. And homicide rate has gone down. So that’s a just, stay inside, never leave your house and you’ll live longer.

– You know, and I don’t mean to laugh at so many deaths, but I’m going to say this, as a statistic. This is a remark… What you just said is one of the most remarkable things that has come out of this is that we’ve lowered our death rate in the United States, at least in the short term. Now, we’ve also destroyed the economy, we’ve also destroyed livelihood, so that’s going to have ripple effects that may increase the death rate long term. But this is a grand, unintentional experiment, the likes of which America, the world, has never seen. And there is a part of me that thinks that there will be a silver lining, that we figure out some things that we’ve been long overdue to figure out. So, hopefully, that’s true. What do you think, Paul?

– I think we’re going to look back on this a couple of years from now and there’s clearly going to be heroes and villains in this whole story, I just don’t think we quite know who they are yet.

– It’s you and me, we’re both the heroes and the villains, Paul, let’s just own it and license the movie rights. I want Vin Diesel to play me, though, because, I mean, just go figure. Paul, dude, it’s always great to reconnect and talk. I think we should try to do this regularly as information evolves, if you’re down for it.

– I’m down for it, sounds like great fun.

– It’s great, and you’re such a treasure and a resource and I love talking, so hit me up anytime. In the meantime, ZPac, do me a favor, share this video because this is straight up science that you’re not going to get on sound bites on the news. Please become a supporter of the show, it really helps us out. Stay safe, keep watching our videos about how we can help other healthcare professionals stay safe and have a voice. Because when this is done, if we, Paul, if we lose this opportunity to transform medicine, I will never be able to sleep again. So, this is our chance. Never let a good crisis go to waste. I think this is a pivot for us and the nation. All right, guys, I love you. We out, peace.