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Coronavirus Vaccine Development

Paul Offit, MD, of the Children's Hospital of Philadelphia, discusses principles and progress to date in COVID-19 vaccine development. Recorded June 1, 2020.

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>> Howard Bauchner: Hello, and welcome to Conversations with Dr. Bauchner. It is Howard Bauchner, editor in chief of JAMA, and it's a distinct pleasure. I'm here with Paul Offit. Paul's a fellow pediatrician, so this should be a very friendly conversation. Paul is the director of Vaccine Education Center and professor of pediatrics in the division of infectious diseases at the Children's Hospital of Philadelphia, the Maurice R. Hilleman professor of vaccinology at the Perlman School of Medicine, and clearly one of the world's leaders in the development of vaccines and vaccine immunology. Welcome, Paul.

>> Paul Offit: Thank you.

>> Howard Bauchner: So for our listeners, we'll stream questions, but I just want to make sure they know that the questions need to be related to vaccines. Sometimes people end up streaming questions that are unrelated to the conversation at hand and then feel frustrated. So Paul, I've already mentioned I wanted to go through five specific topics over the next 30, 35 minutes. Before I start, I just wanted to mention we have published in this area "Adverse Consequences of Rushing a Sars-CoV-2 Vaccine" by Trogen, Caplan, et al, "The Equitable Distribution of COVID-19 Therapeutics and Vaccines" by Bollyky, Gostin, and Hamburg, and then planning for COVID-19 vaccination program by DeRoo, Pudalov, and Fu. Paul, what are the phases, the traditional phases, of vaccine development?

>> Paul Offit: So the first phase actually is preclinical. In other words, what you hope is that you can develop an animal model to study the disease -- that in this case, you would inoculate a mouse or a monkey or a hamster with SARS-CoV-2, that they would develop signs and symptoms similar to those that occur in people. So now you have an animal model to work with, which really can move things much more quickly. Now you can see whether or not the idea for what you have for a vaccine works and, more importantly, what aspect of the immune response is associated with protection in experimental animals. So it gives you a good idea. You prove the concept that your vaccine could work in people. Then you go to sort of phase one trials, which initially begins as a dose-ranging trial. You want to sort of get a sense of what dose is inducing a consistent immune response that you think is going to be protective, although you haven't proven that yet.

>> Howard Bauchner: Human beings.

>> Paul Offit: Human being. Sorry. Yes, human being. People. So you go from mouse or monkeys to people, remembering that animal models are only so predictive. As a friend of mine says at the Wistar Institute in Philadelphia, "Mice lie and monkeys exaggerate." Always true. [Laughter] So now you're in phase one, where you do dose-ranging in people. You want to make sure, and that's -- you saw this with Moderna. They did that early on. They had sort of 45 people in the Washington state area getting sort of low, middle, and high dose to show that dose roughly that you're looking at so as you move to the bigger trials, you've locked into a dose. Then you do sort of bigger and bigger sort of phase one, phase two trials, mostly looking at safety. Safety, safety, safety. And then you're -- you want to make sure that this dose that you think is the right dose is consistently inducing an immune response that you think is protective, and then you get to the key part, which is the phase three trial. This is the -- if the proof is in the pudding, the pudding is a phase three trial, a large, prospective, placebo-controlled, safety and efficacy trial. For our vaccine, the rotavirus vaccine, that was a 70,000-infant, prospective, placebo-controlled, 11-country, four-year trial to prove that that vaccine was what it was claimed to be, which was safe and effective, and that's the only way you know whether something is effective. The immune response may or may not be predicted. Half the vaccines that are out there right now don't clearly have immunological correlates for protection. So that's why you have to do a phase three trial.

>> Howard Bauchner: How far along -- now how many vaccines are there approximately in development, and how far along are some of them?

>> Paul Offit: Well, there are more than 70 companies that are actually across the globe interested in making a vaccine, and they've done the strategies that are typically used to make a vaccine as well as a couple other strategies that have never been used to make a vaccine. So, for example, there is -- there are companies that are looking at taking the virus and inactivating it, which is the way we make the polio vaccine or the hepatitis A vaccine or the rabies vaccine, take the virus and weaken it, which is the way we make the measles, mumps, German measles, chicken pox vaccine. Just take the part of the virus we're interested in, which is the spike protein, that protein that emanates from the surface of the virus. That's the protein that attaches the virus to cells. Now if you can prevent the virus from attaching to cells, you can prevent it from infecting cells or infecting you. So that's the way we make the hepatitis B vaccine or the human papillomavirus vaccine. Then there are strategies that really haven't been used to make vaccines, which is you can take just really to the genetic material, either as messenger RNA or DNA, that then codes for that spike protein. So the person makes the protein. You're not giving them the protein. You're giving them the genetic material that then instructs them how to make that spike protein, to which they make an antibody response that hopefully is protective. Then the last strategy has been to take viruses that are either weakened or unable to reproduce themselves and then insert into that, re-engineering that virus, so that it expresses the -- that spike protein, because you give it the genetic material, and that's the way a number of these companies make, and those are the easiest ones to make. I think the reason that you hear the most about the mRNA vaccine or the DNA vaccine or these replication-defective adenovirus vaccines is because they're the easiest to make. So I think that's why you hear about them first, but I just would want to warn people that, you know, what you want is you want the best and safest vaccine, which may not necessarily be the first vaccines.

>> Howard Bauchner: The -- so that's the science, which was going to be my second question. So there appears to be four different types of vaccines being developed, and do companies bet on one type, or do they bet -- do they develop more than one type?

>> Paul Offit: They typically bet on one type. I think what's a little wearing for me in all this has been, you know, it's science by press release.

>> Howard Bauchner: Yeah.

>> Paul Offit: You just hear press release after press release, and it's a little unnerving. There is -- was a Chinese group that published a paper in the Lancet recently which was the first paper published in a medical or scientific journal that described the -- what the results they have with their vaccine. They used a replication-defective common cold virus, adenovirus, specifically serotype five, and at least you could see the data. Otherwise you're just trying to look through the opaque window of press releases, which is frustrating.

>> Howard Bauchner: Just going backwards for a second, when you talk about phase two trials, how large are those in comparison to phase three trials?

>> Paul Offit: Yeah. So typically phase two trials are hundreds or low thousands. Phase three trials are tens of thousands.

>> Howard Bauchner: And phase two trials are, again, around immunologic response, some safety data, because you've immunized a few hundred to a few thousand, but not effectiveness in the real world, correct? Is that accurate?

>> Paul Offit: That's exactly right. So safety -- small safety and immunogenicity trials, but you don't get to effectiveness until you have a placebo group.

>> Howard Bauchner: Right. So for the last few weeks, we've been hearing about these human challenge trials. Before -- I forgot to ask you at the beginning. What committees do you sit on?

>> Paul Offit: So the -- Francis Collins put together through NIH a committee called the ACTIV committee, A-C-T-I-V, which stands for Accelerating COVID-19 Technological Innovations and Vaccines. So our job is to try and facilitate -- accelerate the development of a vaccine. We meet often during the week. And then I'm also on the FDA's vaccine advisory committee, the so-called VRBPAC committee, but again, this is -- and that committee would always be involved in licensing a vaccine. I think these are not going to be FDA-licensed products. They're going to be FDA-approved products through the Emergency Use Authorization.

>> Howard Bauchner: Right. So human challenge trials.

>> Paul Offit: Yeah. You know, it's -- it sounds like, on the surface, that that would really speed things up. The problem with human challenge trials is the FDA holds, reasonably, a very high bar for doing them. You have to prove that the dose that you're giving is analogous to the dose that someone would see out in the real world and to the mechanism by which they're acquiring it is analogous and that the virus that you're giving them, which you remember is being grown up typically in cell culture, is analogous or virtually identical to the viruses that people are going to see out there. So that in combination with the fact that you're giving a potentially lethal virus without a rescue drug -- I mean remdesivir, although it shortened the duration of illness, was not shown to save lives, at least in that initial NIH trial of more than a thousand people. So the sense I'm getting right now is that the feeling is that we're not going to be speeding up the process by doing challenge trials because the regulatory burdens for proving that you're really mimicking the clinical situation is very high.

>> Howard Bauchner: Does that approval for that type of trial -- does it rest with an ethics committee, say at CHoP, or does it rest with the FDA?

>> Paul Offit: I think it rests with the FDA. I think the FDA would have to approve those kinds of human challenge studies before you did them. I mean we've done human challenge studies --

>> Howard Bauchner: Right.

>> Paul Offit: -- before. We've got it for -- with respiratory syncytial virus. We've done it for influenza virus. We've done it for bacterial pathogens like gonorrhea and parasites. But, you know, often there are rescue drugs for the bacterial or parasitic infections. We don't have that for this virus.

>> Howard Bauchner: Are there any robust, larger phase two trials ongoing -- a few hundred to a few thousand?

>> Paul Offit: Yeah, I think that's already started. I think Moderna, for example, the mRNA vaccine, is now moving into phase two. So yes.

>> Howard Bauchner: And so that will conclude when? Are those two months, three months, four months? I'm going to try to get a sense of a timeline, a realistic timeline, for a successful vaccine.

>> Paul Offit: You know, I think months, a few months. I think the -- my sense is that these large phase three placebo-control trials, which will be sort of 20,000 vaccinees, 10,000 placebos, that'll start in hopefully the first week in July, and they're -- you know, it's at least the ones that were supervised, and the NIH ACTIV group is supervising, are the ones that were funded or supported by BARDA, which is, you know, part of Health and Human Services.

>> Howard Bauchner: Right.

>> Paul Offit: Those will get -- those get priority.

>> Howard Bauchner: And would you call them phase two, phase three, or would you call them a phase three trial?

>> Paul Offit: I think we're moving into phase three in July.

>> Howard Bauchner: You are, and that's that 20,000 plus 10,000, whatever the number is. Now what happens if there's little disease over the summer?

>> Paul Offit: Yeah, well, that's a problem. I mean, you know, the only way you're going to know whether or not these products are effective is if you have a representative number of people who get sick in the placebo group. Not only is the summer a problem, but, you know, you have to make sure that you're picking sites where there is ongoing infection and, preferably, there's about to be an outbreak, although, you know, you don't want people to be sick, but that's the only way you're going to know whether or not that this works, and the NIH has access not only to all the clinical sites in the United States but also to many clinical sites in the world, so I do think they're going to be able to move fairly rapidly on this. So I really would be surprised if you had sort of data in hand, convincing data in hand, by the end of the year.

>> Howard Bauchner: Okay. So those studies start July, August, whatever the specific day is. How long do they go on? When do you begin to accrue meaningful data from that type of study?

>> Paul Offit: It all depends on how many people in the placebo group get sick. That's going to determine, I think, the -- how big that study is. You may need to do more than 20,000, 10,000. You may need to keep recruiting. It's hard to study something that doesn't happen, and so, you know, you have to make sure in the placebo group that you have a representative number of infections.

>> Howard Bauchner: And when you say 20,000 and 10,000, you and I mentioned before we came on air that, you know, the immunologic response is going to be different in children, young adults, and then older adults, and we know the high-risk group. High-risk groups have been well-defined since the initial publications months ago. It's older people with comorbid conditions and certainly people in nursing homes and skilled nursing homes. So in the 20,000 and 10,000's summertime study, will there be a distribution of ages in terms of people who are vaccinated?

>> Paul Offit: To some extent, yes. There's certainly an interest in looking at people who are older since those are the ones who are most likely to die from this virus. My sense, though, at least through the trials we're talking about -- and I should also emphasize that some companies, obviously, are going to be doing trials on their own, without the auspices of the NIH group and not only in this country, but in this world, and so there will be differences, I think, in who is included in those trials based on which companies do it, but I can tell you at least my sense from the NIH trials is that the children probably won't be initially included. They'll sort of be included once this -- these vaccines -- and I think it will be more than one vaccine -- once these vaccines roll out and then people are being inoculated. I think it's then and only then that children probably will be tested, at least in this country.

>> Howard Bauchner: So over the summer, we begin to accrue more information, but how valuable that information is will depend upon how much disease is in the area where people have been vaccinated. Is that an accurate statement?

>> Paul Offit: Yes, that's exactly right.

>> Howard Bauchner: And then do they just add more and more numbers to the initial phase three trial if there's simply not enough disease?

>> Paul Offit: Yes. I mean all these trials have a sort of futility index that you've gotten to the point where you just haven't gotten enough people to do this. I mean, you know, I was fortunate to be part of a team at Children's Hospital of Philadelphia that created the rotavirus vaccine RotaTeq. That trial was large in part because the previous rotavirus vaccine had been found to cause a safety problem, specifically intussusception --

>> Howard Bauchner: Right.

>> Paul Offit: -- which is the intestinal blockage. That trial was originally designed to be a 40,000-child trial -- 20,000 vaccine, 20,000 placebo -- but there weren't enough cases of intussusception in the placebo group, so they -- then it became a 50,000-person trial, then a 60,000-person trial, then a 70,000-person trial, until you could say with confidence that the vaccine didn't cause intussusception.

>> Howard Bauchner: And theoretically, the same thing could happen here?

>> Paul Offit: Yes, exactly.

>> Howard Bauchner: Okay. So you're finished, I don't know, October, November, December. You think you have an element of an effective vaccine. It's not going to be 100% effective, will it?

>> Paul Offit: No. That would surprise me. I mean as a general rule, when you talk about sterilizing immunity, meaning protection against not just moderate to severe disease but even mild disease associated with reinfection or just reinfection that's associated with asymptomatic disease, usually it's the disease that -- where viremia, a virus in the bloodstream, is an important part of pathogenesis and incubation periods are relatively longer. That's when you get sterilizing immunity. Measles vaccine causes sterilizing immunity. Usually for these respiratory viruses that have shorter incubation periods, where virus in the bloodstream is not part of pathogenesis, usually there you get protection against moderate to severe disease associated with reinfection, which is fine. I mean that would be great --

>> Howard Bauchner: Right.

>> Paul Offit: -- because it keeps you out of the hospital. It keeps you from dying. I'm sure that would be an acceptable outcome. You'd like an efficacy to be at least 70% before you roll it out there, but I think you make an important point. It's we're going to have to manage expectations, I think, when this vaccine goes out there, because, you know, vaccinating, say, 20,000 people is not the same as vaccinating 20 million or 200 million people, and you may find out something that was much rarer post-approval of these vaccines, and also, I think, in terms of duration of immunity or duration of protection, that's also probably only going to be found out post-approval.

>> Howard Bauchner: Right. That will take six months, a year, 18 months, where you have to keep measuring effective neutralizing antibodies, correct?

>> Paul Offit: Correct. Exactly right.

>> Howard Bauchner: Okay. What's Operation Warp Speed?

>> Paul Offit: Yeah. So Warp Speed is run by the administration. It's essentially a mass-production facility. It's what the administration's doing is they're saying we are going to mass-produce this vaccine at risk. We're going to make tens of millions of doses, not knowing whether the vaccine is safe, not knowing whether it's effective because then if we find out that it is safe and it is effective by doing these phase three trial, then the vaccine can sort of roll right off the assembly line into people's arms without having to wait. This is not novel. This is exactly what happened in 1955 with the polio vaccine when Jonas Salk's polio vaccine was tested in 1955, it was given to -- 420,000 children got the vaccine, 200,000 got placebo. That trial started in 1954, and it finished in April of 1955. During that time, five companies were actually paid by the March of Dimes to mass-produce those vaccines, all made the same way, but to mass-produce those vaccines in the hope that the vaccine would be shown to be safe and effective. So this is Warp Speed Two. We've done this once before.

>> Howard Bauchner: So the study supported, I'm assuming, by the NIH, although NIH and HHS are not identical, but I'm assuming the studies that are optimistic, your committee on ACTIV, they're going to simultaneously create the capacity to produce large amounts of the vaccine. Is that what I'm hearing?

>> Paul Offit: Yes, and all the things that come with mass production, which is -- I honestly think it's the hardest part of making a vaccine is mass-producing it. It's easy -- it's much easier to make, as Jonas Salk did -- make vaccines for 700 people, children, in the Pittsburgh area than to make it for tens of millions of children in the United States and the world, and so you have to have the right buffering agent, the right stabilizing agent. You have to have the right vial. You have to do real-time stability studies to make sure that when the vaccine leaves the manufacturing plant that the time it takes to get from the tarmac to that the person's arm is not -- does not cause any problems, because remember, when you're shipping vaccines, you know, they're going to be exposed to high temperatures and low temperatures, and you have to make sure that you have a stable product, especially for something like messenger RNA. You know, the good news about messenger RNA is that it very quickly degrades inside your body, so I think it's likely to be safe. The bad news is it quickly degrades outside of your body, I mean, so you have to make sure that you put it in what is essentially a complex lipid delivery system to be able to make sure that it's stable, and that's not easy to do, and that's not easily scaled up. So I think we're going to learn as we go here.

>> Howard Bauchner: And I know the US is making bets. Do we -- does the US then own that vaccine or some portion of that vaccine?

>> Paul Offit: I'm not sure how that works legally. I would say just ethically and morally, how much more information do we need to know that what happens in other countries affects us, and, you know, that if we are able to make this vaccine, that we would be -- not only serve our own population, but also serve all those populations in the world where these outbreaks are occurring, because what happens in the world affects us. I think we don't need any more information than what we just saw over the past few months to know that.

>> Howard Bauchner: No. The notion of the planet being a smaller place has come home over the last few months. Other comments about the issue of equity, Paul, about the distribution of the vaccine? When I talk about equity, people often talk about low- and middle-income countries. I worry about it within the US. Do you have any sense of how it will play out in the US and then in terms of countries outside of the US?

>> Paul Offit: Well, I think the way it should play out in this country is that when we have a vaccine or vaccines that appear to be safe and effective in phase three trials that the CDC will step in and say, "Okay. Here's priority group number one, healthcare workers, people who work in nursing homes, people who work in meatpacking plants, people who work in grocery stores, pharmacies. They're the first group who needs to get this vaccine," and then work your way down to, you know, progressively lesser and lesser at-risk groups. That's the way it should work. You worry that -- you know, that the system will be perturbed at some level because everybody's going to want this vaccine if it is safe and effective, and you feel like it's going to be like that scene in Contagion at the end, you know, --

>> Howard Bauchner: Right.

>> Paul Offit: -- where people are subject to a lottery.

>> Howard Bauchner: Right. Also, early on, around testing, it seemed like certain people in the US were able to get testing who were not healthcare workers, who were not at high risk, and I think some groups are concerned that that may play out again with the vaccine.

>> Paul Offit: Right. I think it's going to be -- I mean I think I'd like to get to that point where that's a problem, --

>> Howard Bauchner: Right.

>> Paul Offit: -- where we have vaccines that work and appear to be safe, and then -- and to get it out there. There are -- there's so much -- never before in the history of this world has there been so much interest, expertise, money, and companies interested in making this product. Never before has that happened before, so I'm optimistic we're going to have a lot of vaccine.

>> Howard Bauchner: But even with Operation Warp Speed, you don't anticipate that a successful phase three trial will lead to 300 million doses a few months later?

>> Paul Offit: No. I think it will be -- I really do think it's going to be more than one vaccine. I think it'll be several vaccines, and these are likely two-dose vaccines. So, you know, you're talking about 330 million people in this country. That's 660 million doses eventually, although, again, I think we should distribute it in a manner that -- to save those who are most likely to die from this virus.

>> Howard Bauchner: There are numerous questions, but I have a one or two more questions for you. I mean probably no one in the country is more familiar with the kind of vaccine-hesitancy world, which has increased in the US and around the world. I know the WHO just listed it as one of its major concerns. We have vaccine refusers, a small, very small number, but then the number of vaccine-hesitant families has increased. You and I are both pediatricians. You've been an outspoken proponent. Vaccines are incredibly safe. There's a remarkable track record of safety. There is the unusual untold event, and we have the Vaccine Injury Compensation Program in the United States, which I think most people would say has been very successful. In terms of this vaccine and vaccine hesitancy people, how do you think about it, Paul?

>> Paul Offit: So I think we ask a lot of parents in this country. We do. We ask them, in the first few years of life, to give their children 14 different vaccines, which can mean as many as 27 inoculations during those first few years of life. It can be as many as five shots at one time to prevent diseases most people don't see it using biological fluids most people don't understand, yet most people in this country, most parents in this country, sign on to that. You know, 80 -- you know, high 80%, low 90% rate. So I think that we have, I think, generally, the confidence of parents in this country, but as is true for anything you put into your body, you should be skeptical. I mean I'm going to be skeptical about these vaccines when they come out. I want to see the data. Everybody should want to see the data. So I do think your point is a good one. I think there's a lot at stake here. I guess I put sort of anti-vaccine activists -- activism in a separate category.

>> Howard Bauchner: Right.

>> Paul Offit: I mean those folks are much more conspiracy theorists. I don't think there's any amount of data that will ever convince them that vaccines are safe.

>> Howard Bauchner: Right.

>> Paul Offit: I'm talking you about the reasonable level of skepticism --

>> Howard Bauchner: Right.

>> Paul Offit: -- that anyone should have before putting something in their body. So we do have the confidence, I think, of patient -- of parents and the public, but I do think we put that on the line here, and we better make sure that before we inoculate, you know, millions of people, tens of millions, many of whom are going to be healthy young people who are unlikely to die from this virus, that we make sure we hold it to the highest standard of safety and efficacy before we put it out there, and that does worry me. You know, we are coming up into an election year. The -- you know, the Warp Speed that we've talked about is under the auspices of the administration. I just worry, and I hope I'm wrong -- I hope this is just my own paranoia -- you know, that the administration, as an October surprise, would be willing to sort of reach their hand into the Warp Speed bucket and say, "Look, here's a magical vaccine that's going to work for you" when it hasn't been adequately tested. Now as long as we play by the rules, as long as we have the phase three trials we need to have, then we're good, but I just do worry about that.

>> Howard Bauchner: Yeah, I do hope, and it would be a tragedy if there was political pressure, particularly on the FDA, to approve a drug using any of its various policy levers when the committee of people like you and others would say the data don't support it. That would be a tragedy.

>> Paul Offit: The FDA is involved. I mean they are involved with our -- you know, so our NIH so-called ACTIV group, and representatives from the FDA are clearly involved with these companies, making sure that they meet certain standards. So that's good, but it won't be a licensed product. It won't go -- at the end, it won't go through the typical FDA licensing process, which is typically a ten-month process, and for expedited reviews, it's a six-month process. That's not going to happen here.

>> Howard Bauchner: So what will be the lever? What will be the mechanism? You and I have talked about it, but I wanted our listeners to hear it.

>> Paul Offit: The lever that will ultimately get --

>> Howard Bauchner: Lead to approval for a vaccine, do you think?

>> Paul Offit: Right. So I do think it's a lighter touch by the FDA than what it would typically be with a licensed product. I -- there is a little less control by the FDA than there would be otherwise. Hopefully that won't matter, but, you know, you do worry a little bit when it is a lighter touch. I mean the hydroxychloroquine story was -- it was not a pretty story, and I think the FDA sort of stood back from this product, which had been licensed for other uses, but not for this use, and I think stood back when I think -- arguably, and it's always easy in retrospect, I really do think they should have argued for prospective placebo-controlled studies before putting that product out there, which ended up doing more harm than good.

>> Howard Bauchner: Yeah. I said last week when I was doing another live stream, I don't think the scientific question about the effectiveness of chloroquine is answered. It may not be answered now for a host of different reasons, but I still think it's valuable to test it within a randomized clinical trial, not outside of a randomized clinical trial, and I think that's true for many drugs. I've probably reviewed 50 papers suggesting yet another drug for COVID-19, and what I've responded to individuals when they complain if we don't publish their paper is that what your -- you're suggesting that this works. It needs to be subject to a randomized clinical trial, because it's going to be the only way you answer the question, or you may end up in the fall with no answers to any questions.

>> Paul Offit: Yeah. I think people have the false notion that when somebody's sick that you can't hurt them. That's not true.

>> Howard Bauchner: Right.

>> Paul Offit: If they're sick, they either get better, stay the same, or get worse. You want to make sure you don't take people who are going to get better or stay the same and make them worse, which you can do with any drug.

>> Howard Bauchner: Right. Andrew Caleo [phonetic] made the case that if you give an experimental drug to someone and it's not part of a clinical trial and they do well, you say it was because the drug was successful. If they do poorly, you say it was because of the disease, not knowing it could have been an adverse effect from the drug itself.

>> Paul Offit: Exactly.

>> Howard Bauchner: Questions. Let's go through a few of them. There's actually quite a few, and I'm not surprised, and they are related to vaccines. Why are we optimistic about a vaccine that's a -- one -- that a -- one, a first-of-a-kind mRNA vaccine, two, a first-of-a-kind coronavirus vaccine?

>> Paul Offit: For a couple reasons, I think. Well, I'm not sure I necessarily think that the mRNA vaccine is it. I'm glad that so many different approaches are being used, and we'll see which one is the best. I'm optimistic that a vaccine can be made for a couple of reasons. One is that when you look at the human challenge trials with human coronaviruses that were done many years ago, that if you were -- if you were infected with a particular stereotype of human coronavirus and then challenged with that same stereotype that a year later, you were protected. So that's good. Two is the virus, although it's a single-stranded RNA virus and does mutate to some extent, it's -- this is not flu. I mean this is not the kind of virus that's going to mutate so much from one year to the next that you're going to need a yearly vaccine. This is more like the other single-stranded RNA viruses like measles and mumps, where I think it's going to be a single serotype. And three, you know the protein you're interested in. You're interested in that spike protein. You're interested in making antibodies to the receptor-binding domain of that spike protein. I think we can do all those things, so I am really optimistic we can make an effective vaccine and optimistic we can make a safe vaccine. We just have to let the process play out.

>> Howard Bauchner: Let's see. Which vaccine will be made under Operation Warp Speed? This is feels like Star Trek, but -- warp speed -- but go ahead.

>> Paul Offit: That's -- I think that's where warp speed came from.

>> Howard Bauchner: It think it has come from Star Trek.

>> Paul Offit: So I think the ones that are being made -- oh, the BARDA one. So I think the Moderna vaccine, which is a messenger RNA vaccine. I think Johnson and Johnson's vaccine, which is a replication-defective adenovirus 26 vaccine, and then the UK Jenner Institute vaccine, which is a replication-defective simian adenovirus vaccine. I think those three, and then Pfizer also has an mRNA vaccine that may be made under that auspices, but that's as far as I know.

>> Howard Bauchner: For the phase three trials to start in July, are there plans to recruit enhanced numbers of Latinx, other groups -- African Americans -- known to have higher infectious rates for whatever reason?

>> Paul Offit: As a general rule, when phase three trials are done, the FDA insists that those trials mimic the human population -- that you have the kind of genetic diversity that you see in the human population in those trials. So I know there's an interest in doing that. The other thing that's interesting is they also are going to be including seropositive people -- in other words, people who've already been infected -- just to make sure that there's not any sort of immunological enhancement, and I mean this in a negative way -- sort of immunological pathology associated with giving a vaccine to somebody who's already been infected. So I think both will be included.

>> Howard Bauchner: Right. That will be important, because obviously otherwise you'd have to test 300 -- well, you'd test 300 million plus people to know if they've been infected before you gave them the vaccine, so it seems like including those individuals will be important.

>> Paul Offit: Right.

>> Howard Bauchner: Are persons with conditions that might put them at greater risk from a vaccine -- autoimmune conditions -- will they be excluded from the safety testing? This also comes up every time when we talk about new drugs or new devices. Children, pregnant women always come up, about whether they should be included or not included.

>> Paul Offit: As a general rule, they're excluded -- people who have serious illnesses, people who are pregnant. In this case, I think children also are probably not going to be included in the original round of these phase three studies.

>> Howard Bauchner: Okay. One other question, and then I need a crystal ball a bit. The Sweden experiment: Do you have any views on it? My cousin and his wife live in Sweden. I've spoken to them at length about it, but I'm curious if you have a sense of what Sweden's tried to do by a combination of herd immunity and trying to protect some of their elderly population.

>> Paul Offit: Well, it's an experiment that doesn't seem to have worked well. I mean if you look at their count, among the 240 countries in this -- on this planet, they, in terms of deaths per million, are one of the worst. Their bet, and I think it was a bad bet, was that there would be enough sort of population --

>> Howard Bauchner: Yeah.

>> Paul Offit: -- immunity that the virus then wouldn't spread. I don't think that's true. I think what you're -- the only way really to stop the spread of this is with a vaccine. I mean, you know, with measles, for example, I was a -- I'm a child of the 50s. When I was six or seven years old, I had the measles. That protects me for the rest of my life, but -- and that was all of us who got measles were protected for the rest of our lives, but every year, there was this susceptible cohort. Every year, 2 to 3 million people got measles. Every year, 50,000 would be hospitalized and 500 would die. So I just don't think that was a good idea, frankly.

>> Howard Bauchner: So Paul, you and I have -- we've already talked about your greatest concern is reaching into this bag for some vaccine in the fall, sometime around the election, but the other question, obviously, that comes up -- I mean the events of the last two or three days have been just so profoundly disturbing for many reasons, and then the summer comes, and then school and college, people return to work, maybe working in a place or at home. Do you -- the second wave, which so many people have talked about -- do you have any sense, independent of a vaccine, what it may look like in the fall?

>> Paul Offit: No, it's a great point. I mean we've had sort of this bi-prong public health disaster. The first was the suffering and hospitalization and death caused by the virus. The second is going to be what is massive joblessness and everything that comes with massive joblessness -- food insecurity, increase in domestic violence, increase in child abuse, increase in depression and suicide. You're already starting to see that, and I think a lot of the -- this rage that you're seeing, actually, as city after city suffers, you know, fire after fire is part of that -- is just they -- you know, it's just a perfect storm of joblessness and hate and, you know, just frustration with, you know, the way that African Americans were treated by the police. It's just this awful storm, and I do think -- the thing that upsets me, actually: I'm on the board of trustees of the Franklin Institute of Philadelphia, which is a science museum, and we're trying to figure out how to reopen, and I think, you know, one thing that I'm trying to impress on the senior staff there is that the minute you reopen, the minute somebody walks in that door, they're taking a risk.

>> Howard Bauchner: Right.

>> Paul Offit: The minute somebody goes to school, they're taking a risk. They go to --

>> Howard Bauchner: Right.

>> Paul Offit: Whether it's an elementary school or high school or college. That's not the goal. The goal is not to prevent all future COVID-19 deaths. They're going to continue to happen. If you want to prevent them, then stay inside for the next two years. Assuming we're going to have to go back to work, there is some risk in that. All we can do -- the smartest thing we can do is figure out the best way to mitigate that risk by wearing masks, you know, doing good hygienic things, staying social distancing as much as you can. That's what we can do. That's what should be talking about the most, and, you know, I feel like we're losing that a little bit in this notion of zero risk, which just isn't possible.

>> Howard Bauchner: Yeah, no, that notion of mitigation versus elimination. There will be no elimination of risk. It will just be mitigating it, and, you know, one of the advantages: We know the high-risk groups. That's the other thing. I mean it's not like they've been difficult to -- or escaped detection. They've been so consistent since the first initial reports in JAMA and the other journals, it's been remarkable. It hasn't changed at all. I mean there's that new childhood condition that will raise parents' concerns, but again, we have numerator data, we have case series, but we know so little about how often it occurs. Michael's reminded me to mention that tomorrow, hopefully, if there's no disruptions to his schedule, Tony Fauci will be joining me again at 11:15 Central Time, so I guess that's 12:15 Eastern Standard Time. Paul, you've done vaccines for a long time. You've -- and I thank you on behalf of children and families and the pediatric and family medicine community. I thank you for all the work you've done trying to make people understand the benefits and challenges of vaccines. You've been just a remarkable individual over the last two or three decades. Closing comments about vaccines and COVID-19?

>> Paul Offit: Yeah. I think there's a lot at stake here. I think this goes one of two ways. The way I hope it goes is we do what we need to do in terms of doing the right kinds of studies and that we can explain to people what we have or don't have as these vaccines roll out. If we rush it, if we put something out there into people's arms before we know everything we need to know or every -- as much as we can reasonably know, then I think we could do harm, and I just am hoping it goes in the first way. I think there's every reason that vaccines are going to be the hero of this story, but we have to be attentive to the science, and we have to be humble. That's the thing that upsets me the most -- is that bat coronavirus had just made its debut in the human population. We've already been surprised by a couple of things. We're surprised that it's as contagious as it is. We're surprised about, as you mentioned, this childhood sort of post-infectious multi-organ disease, and another thing that's surprising is that some people who have clinical disease never really develop adequate neutralizing antibodies. Why is that? So realize that nature gives itself up slowly and grudgingly and often with a human price, so keep your head down, do it the right way, and I think that will come out okay with this, because I'm absolutely optimistic we can make a safe and effective vaccine.

>> Howard Bauchner: This is Howard Bauchner, editor in chief of JAMA. This has been Conversations with Dr. Bauchner. I usually sign off with a kind of formal, "This is Paul Offit, who's all of these things," but I just want to read what the last comment is, Paul: "Dr. Offit is the immunization rock star." Paul, thanks for joining me today.

>> Paul Offit: Thank you.

>> Howard Bauchner: Bye-bye.


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