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Paul A. Offit, MD, of the Children's Hospital of Philadelphia, returns to JAMA's Q&A series to provide an update on progress in COVID-19 vaccine development. Recorded October 27, 2020.
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>>> Howard Bauchner: Good morning and welcome to conversations with Dr. Bauchner. It's Howard Bauchner, and once again I'm joined by Paul Offit. Paul's a physician, the Maurice Hillman, Professor of Vaccinology at Perelman School of Medicine at the University of Pennsylvania. A world renowned vaccine expert much in the news recently, and Paul's here to talk about the recent advisory committee meeting, the Vaccine and Related Biological Products Meeting Advisory Committee Meeting that was held last week. Welcome, Paul.
>> Paul Offit: Thank you, Howard.
>>> Howard Bauchner: So, Paul, before we get to the meeting, I have already mentioned that I wanted to talk about two other issues that really have been in the news every day. The first is the large number of cases. I think people, you know, Dr. Tony Fauci has been on, Bob Retfield's [assumed spelling] been on. So many people have been so concerned about the winter months. It's gotten cold quickly. Sixty, 70,000 cases a day. Death rate's still low-ish in comparison to the total number of cases, but hospitals are filling up as our ICU's. Is this what we have to face for the next six weeks, two months, three months? Paul, what's your sense?
>> Paul Offit: Yes, this is what everybody always feared. And although the death rates aren't currently up, with hospitalizations and ICU rates up, you can assume deaths will follow. I think this, you know, this was billed as one would have imagined when it first raised its head in Wuhan that this is an [inaudible] virus, a respiratory virus like flu, like paraflu, like RSV, that would be worse in the winter months and then would abate in the summer months. I think what surprised me and I think a lot of people was that this [inaudible] virus, spread by small droplets actually still raged in the summer months in hot and humid climates, like Florida, Texas, Arizona. But I think everybody expected what's going to happen now. Worse, you know, this will also face to some extent a flu epidemic as we do every year. Now, maybe that with masking and social distancing, we'll have a lesser flu epidemic than typically, but it's definitely gonna be a twin-demic now, which wasn't true last year.
>>> Howard Bauchner: Paul, over the weekend, Tony, for the first time talked about national legislation around masking, something the White House has really resisted. Scott Gottlieb had a piece yesterday in the Wall Street Journal supporting that. Are we there? Is that where we need to go to, national mandate on masking?
>> Paul Offit: To say that the White House has resisted [laughs], no mask is a nice way to say it. I mean, they've done everything they can to downplay the importance of mask or social distancing. It's the only thing we have. It's the most and arguably the most powerful thing we have. I mean, I was on service last week. There were patients we saw who either had or were suspected of having COVID-19. If you gave me three choices of what to do, I could either be six feet away from that patient, or if I couldn't be six feet away, I could either wear a mask or get a vaccine. Number one, six feet away. Number two, if I have to be close to the person, wear a mask. Number three, get a vaccine. Assuming the vaccine is about 75% effective, a mask worn correctly is more effective than that. So masking is really an important thing to do. The problem is, is I think that the nature of this country. We sort of were founded on individual rights and freedoms. You have people say it's my freedom not to wear a mask or say it another way. It's my freedom to catch and transmit a potentially fatal virus, which it isn't. But I just think it's very hard in this country to enforce it and get people to do it. But at the very least, the president and vice president who have a platform, who've been given a tremendous platform can at least demonstrate good behavior, which they refuse to do.
>>> Howard Bauchner: I don't know all the amendments, but I can't remember an amendment that somehow protected the right not to mask. And I say that, we're both are chuckling about it. But you know, we manage with seatbelts. Okay, we finally convinced everyone. I mean, none of my friends, none of my children would ever get in a car and not put a seatbelt on. And somehow masking is taken on an entirely different life of its own.
>> Paul Offit: Yeah, it's become a political statement. I think this is probably the only country in the world where masking is a political statement. It's been hard to watch.
>>> Howard Bauchner: And I know we want to get to vaccines. But the other issue that's come up, and you and I chatted just briefly about it before, is the so called Great Barrington manifesto and then the Snowden document response. And some have said the White House has embraced it. Let everyone become infected, protect the elderly, protect the most vulnerable, and you get to herd immunity. Comments?
>> Paul Offit: Yeah. I think the White House has embraced -- the White House doesn't have a plan. So now suddenly herd immunity induced by natural infection has become the plan, right? But the premise is wrong. The premise is that a virus could can affect enough people in the population, that would provide immunity such that that essentially the virus would put itself out of business. That's never happened. That's never happened for any virus. So historically there's no support for it. Secondly, if you had to pick the perfect virus for which it would happen, it would be measles. I mean, measles is 10 times more contagious then this virus and SARS-COVID-2. It has an [inaudible], you know contagiousness index of close to 20, where this is less than two. Two, measles induces lifelong sterilizing immunity. You are protected against all manner of infection, including asymptomatic infection, that's not going to be this virus. And nonetheless, despite that, before there was a measles vaccine every year there would be about one to two million cases of measles. There would be 50,000 hospitalizations, and there'd be 500 deaths from measles. So there's no such thing as this Great Barrington declaration. Plus, about 30% to 40% of the population is really at high risk.
>>> Howard Bauchner: Right.
>> Weight, 65, obese. I mean, we all supposed to stay indoors for the next couple years while we're doing this. It just doesn't make a bit of sense.
>>> Howard Bauchner: Right. So let's turn to vaccines. I have a list of questions, but I wanted to give you a chance to summarize what you thought were the key exchanges between you and the FDA and the committee, so if you could comment. But the other thing is some of the committee members do have conflicts of interest, because they consult to different companies. Have they've been excluded from these meetings? I just wanted to clarify that for our listeners, because that's a big issue.
>> Paul Offit: Yes. Sorry. Three voting members were excluded from this meeting because they either were consulting to a company or they were on the Data Safety Monitoring Board for a company.
>>> Howard Bauchner: Okay. The key exchanges. What do you think the key exchanges were, Paul, from the meeting last week?
>> Paul Offit: I think the tension in this meeting was this. These are not going to be licensed products, they are going to be essentially permitted for use under emergency use authorization. And permission is the right word. It's the same that would be given to say an investigational new drug, it's the same permission really. But it's being given to give -- permission is being given to vaccinate 150 million Americans initially, which is obviously something we've never dealt with before. And I think that when the public hears, or frankly, the medical community hears the word emergency use authorization, they think correctly of hydroxychloroquine, which was approved or permitted through emergency use authorization when there were no data suggesting that it worked. And now there's clear data that shows that it didn't work to either treat or prevent the disease. And so, the FDA then withdrew its permission through [inaudible]. And addition with hydroxychloroquine, you know, 10% of people who got that drug could have, you know, cardiac toxicity, specifically arrhythmias. Then you had the convalescent plasma fiasco. Again, no data showing that it worked, and nonetheless that was permitted for use. So I think that's what people hear. They hear emergency authorization for vaccines, and therefore vaccines are going to be allowed to be used with the same flimsy or lack of evidence for these other two products. But that said, the trials that are being done for this vaccine, these vaccines are typical of any licensed product. I mean, you know, Pfizer's doing a 44,000 person trauma. Moderna's a 30,000 person trial, Johnson and Johnson's is 60,000 [inaudible]. That's like any licensed product. So why not do this as a licensure? Why not submit a biological license application, and then license these vaccines by the method, we always do that and drop the word, the phrase, emergency use authorization. And the reason is, and I mean, for example, the human papillomavirus vaccine trial was a 30,000 person trial. A rotavirus vaccine trial. The Rotarix rota tech trial was a 70,000 person trial. The [inaudible] pneumococcal vaccine was a 35,000 person trial. The difference between those trials and these trials was length of study. So the HPV vaccine was a four year, I'm sorry a seven year study. I mean, our rotavirus vaccine [inaudible] was a four year study. This at most will be a six month study. And the FDA would never license a vaccine with only six months of data. Not so much so for safety, but it's really with safety they just want two months after the last dose. I mean, even for diseases like [inaudible] syndrome, you would see that within six weeks of getting a dose. So it's not safety so much, its efficacy. I think you just can't license something with that little efficacy data. And if you put a vaccine out there, with only six months of efficacy data, or frankly would be less than that, more like three, four, or five months of efficacy data, I just think that you may be unpleasantly surprised, that is either very short lived or not as robust as you imagine. So that's why. You have some people have now said, well, we'll just do these studies for two years. But on the other side, you know, 225,000 people died of this virus. I mean, with HPV 5,000 people died a year, with rotavirus 60,000. I'm sorry, 60 people died a year. So that's the tension is how much uncertainty are we willing to live with knowing that we're facing a virus that's brought us to our knees?
>>> Howard Bauchner: Paul, can we just go back to the safety because, you know, I did listen to and read snippets of the meeting, the two months safety data statement that, you know, side effects like [inaudible] in the past have shown up generally within two months. That's with traditional vaccines, these are novel vaccines. So I do think is their broad agreement that you would expect side effects or adverse events like Guillain-Barre to show up within two months given that these are novel vaccines? I do worry that the public may not believe that two months is sufficient safety data. What's your sense of that, Paul?
>> Paul Offit: That's a great question. So Stanley Pearlman actually was brought in as a temporary voting member, and his expertise is in Coronavirus immunology. And he argued that vaccine induced immune pathology that was seen, for example, in animal models with SARS, Covi-1, and animal models from MERs, that he would think you would need about four months to see that.
>>> Howard Bauchner: Okay.
>> Paul Offit: And, you know, but if you look back at something like the measles vaccine, the inactivated measles vaccine that was brought into the United States in 1963, was found to actually cause this sort of unusual atypical measles which actually increase your risk of pneumonia, you had an unusual rash. It really took a few years to figure that out. So I think you're right. I mean, you have in this virus SARS COVI2 this unusual virus that has already caused a number of sort of clinical and pathological changes you would not have expected, which we are now meeting with vaccine strategies that have pretty much no commercial experience. I mean, I think we are going to have a learning curve here. But the question is, how much --
>> Paul Offit: -- [inaudible] to live with in the meantime. I mean, so, for example, that person in Brazil who died during I think it was Johnson and Johnson's --
>>> Howard Bauchner: Yeah.
>> Paul Offit: [Inaudible] J and J's trial in Brazil. When we heard that there was a death in a vaccine trial, everybody held their breath, and then were able to breathe a sigh of relief when we realized that it was someone in the placebo group. Well, you know, because he was in the placebo group that's probably why he died. He died of COVID-19. I mean, but for the flip of a coin, he ended up in the wrong group. I mean, I think it's less likely he would have died had he been in the vaccine group. And so, that's always the tension we're working with here.
>>> Howard Bauchner: I mean, if you lengthen the efficacy data out to six months, then you do gain safety data for six months.
>> Paul Offit: That's right. It's true.
>>> Howard Bauchner: So I mean, if you match them together, then you gain much more information about safety. Now, what's the process? So you have this discussion last week, how does David Mark and his group at the FDA then take it in? Because Moderna has said they're going to qualify for a EUA in November, December. You and I talked about it beforehand. I prefer they stop making that statement. They have no idea if they'll qualify for a EUA. That's not up to them. They will apply for a EUA. I think some of the other companies have been more appropriate in their statements that we are warming up, we will apply for the EUA in November, December. Moderna said they'll get one. I don't know how they know that. Does the FDA Now think about what your recommendations or suggestions were about letting the efficacy data go for another two, three, four months before they think about a EIA, or to approve it as a normal biologic product?
>> Paul Offit: I think what the FDA wanted to get from this advisory committee was what we thought about this the EUA the way that it's currently set up. And i think where the rubber is gonna meet the road here is how we handle these interim analyses. So the first interim analyses will be when 34 participants get sick. The second abnormal analyses we run 60 when 60 get sick. But I really do think that the NIH active group that was put together by Francis Collins, when Peter Gilbert and other statisticians put together what they wanted from these trials. They wanted basically, at least, if the trial was going to be two vaccine to one placebo, two to one --
>> Paul Offit: -- that ratio. They wanted at least 147 participants to get sick, which then with at least a 90% confidence interval, you could say it was effective at 50 or 60% effectiveness. And if it was going to be a one to one, they wanted at least 160 people. That's where I'm coming from. And I think that's where also people on the committee are coming from. We are I'd like to think that we are going to be really low to approve this or to recommend approval through emergency use authorization with just 34 or 60 participants getting sick.
>>> Howard Bauchner: There's a couple of questions have come in. I want to return to one or two, the other kind of ethical issues that have come up. Like, do people in the placebo group get active vaccine and then does that create follow up problems? But what let's put that aside. There's questions. So, you know, JAMA published the article about the more traditional vaccine from China, which my sources tell me has actually now been used in many hundreds of thousands of individuals. And then, no one really knows much about the Russian vaccine. Can you come in on either the Chinese vaccine that we published on or the Russian vaccine? Do you have much knowledge about them?
>> Paul Offit: Well, again, I mean, and I know how they're constructed. What I don't know, though is what the results of the phase three studies are.
>> Paul Offit: I mean, those are doable [inaudible]. I know the Chinese have given this to tens of thousands to hundreds of thousands of people.
>> Paul Offit: This inactivated vaccine. Russia has this replication defective. Initially, it's two different viruses. One is a replication effect of human enterovirus type five, followed by a dose of replication defective [inaudible] adenovirus type 26, which they've now actually sent to Venezuela for use. Again, if there's a certain nationalism to this. You can see where countries will then provide vaccine to their allies, as well as their own citizens. So I think there's going to be a nationalism overlay to all this, but I don't know. I mean, it's not that hard to do phase three studies. Let's see what the phase three studies show.
>>> Howard Bauchner: Do you have any sense that either the Russian or Chinese vaccines have to apply for approval either through the FDA or the EMA or not likely?
>> Paul Offit: I think the FDA generally has been low to approve vaccines for American citizens that haven't been tested in Americans historically.
>>> Howard Bauchner: So then, let's go on to some of the ethical questions that did come up. So, for example, you know, you'll have 150 or 200,000 individuals in the three major trials. Half will have been assigned to placebo. You then approve the drug, either three in a way or the traditional process? Do the placebo recipients are they first stop for the vaccine?
>> Paul Offit: Yeah, Pfizer actually made an announcement.
>> Paul Offit: If they go through a EUA, they're going to vaccinate the placebo group. That obviously upset the FDA. I mean, the Marion Gruber actually talked to us at that meeting, had two slides that specifically said "realize that under an EA, you are under no obligation to provide vaccine to the placebo group." The problem with that is, and here's the tension. On the one hand, you could understand how, for example, someone who's over 65, that now sees a vaccine that let's say 60% effective could say, look, I want that vaccine. It's now approved at least through this mechanism, I want this vaccine. On the other hand, if you eliminate now placebo groups going forward, you're not going to learn about these other vaccines in near the same manner you would. And let's make the assumption, which I think is not a large assumption that, the first vaccine is not going to be necessarily the last best vaccine, either with regard to safety or efficacy. How are you going to know that? If you have a vaccine initially that's 50% effective, and then down the line there's a vaccine that's 80 to 90% effective, how are you going to learn that? And that is the history of vaccines. I mean, the first vaccine that comes out is invariably not the latest best vaccine. So that's what I think's worrying people.
>>> Howard Bauchner: Cody Meisner, you're a pediatrician, I'm a pediatrician. Cody's on the committee, he brought up the issue of children. I mean, your lifelong commitment has been vaccinology in general, but more specifically in children. How's that gonna play out with respect to children and young adults? Do you have a sense of that yet Paul?
>> Paul Offit: Cody was concerned, Dr. Meisner was concerned that we have this, you know, this [inaudible] disease in children. And the concern is that this SARS, COVI-2 spike protein is acting as sort of this super antigen that induces this sort of multi-system inflammatory response. And that we're not going to get around that by vaccines that essentially cause your body to make SARS COVI-2 spike protein, and they make antibodies to spike protein. I actually don't feel that way. I think that that's unlikely to happen. And in either case, I think on the one hand, you could argue that people less than 21 years of age account for roughly 26% of the population, but only 0.08% of the deaths. Clearly, children get this virus less frequently. And when they get it, they get it less severely. But they do get it and they can die from it, but a little less than the rate that they die from influenza, for which we also immunize them. So I do think that we are going to need a vaccine for children. I do think eventually we're going to need to test the vaccine in children before we give it to them. I think one of the sort of concerns by the committee was do we really need to test them, or can we do immuno [inaudible] studies? In other words, if we have an immunological correlate, and if you make this level of neutralizing antibodies, we say that children can make this level of neutralizing antibodies that that's good enough. There were some members of the committee that thought that [inaudible] bridging was fine, others that didn't. So that's yet another sort of tension.
>>> Howard Bauchner: Crystal ball. The presidential election is next week. It's on Tuesday. Hopefully by Wednesday, Thursday, or Friday, we will know who is president. Now that's early November. And then an EUA is filed in late November or early December by one of the three or four companies. If President Trump is reelected, how do you think it will play out?
>> Paul Offit: I'm choosing to believe, and maybe I'm naÔve in this, that this process is not going to be subject to the same sort of political influence that hydroxychloroquine and convalescent plasma were for the main reason being that the first two were treatments. This is a preventive measure that most of the people who are going to be getting this vaccine are healthy young people who are unlikely to document this virus. There's already enormous resistance and skepticism about this vaccine. I think people are going to wait for a clear message that this vaccine is safe and effective before they get it. And even then, even people that are educated about this vaccine may wait for the first few million doses to get out there before they can feel more comfortable getting this vaccine.
>>> Howard Bauchner: That's many of my relatives. I mean, they keep asking me, will I get vaccinated? I'll go, well, I have good sources of information about safety. But many of my friends and relatives who said they'll wait. You know, they're not excited about going first. Okay, so let's take the presidential election. And hopefully you're right. I do think the scientific community, and I've been very impressed with Steve and David about their insistent about a scientific process, not subject to interference by the White House. So let's say an application comes in for an EUA in November, December. The committee once again, at that point, you will actually see data. Is it at that point that you would recommend, please do not approve the EUA? Please go to the normal process, wait another four months for data? What actually happens when an EUA is submitted to the FDA? What becomes the role of the committee?
>> Paul Offit: Right. I think that the ship has sailed on this. I don't think that there's enough will among the committee to say we're not buying into this EUA process. We want to wait for biological license application and licensure process. That was the result of that last meeting. The people they had disagreements about what we were going to do -- what we require for a EUA, but [inaudible] was going to be an EUA was clear. So that's not going to change. And I think in order to get a true license, they would really need to do the study for a couple years.
>> Paul Offit: That's not going to happen. So the question is what level we're going to accept as enough people that are participants that have gotten sick that we then are comfortable saying let's go. You know, one story about this, because I think it is relevant, even though it's an old one, but I'm an old person. You know, the polio vaccine in 1955, there are mirrors that to that vaccine. I mean, one is that that a lot of transmission was from people who were asymptomatic and infected that you didn't know about. That's actually the main reason it was transmitted. But there was -- Jonas Salk did his studies in Pittsburgh. He inoculated 700 people. He found that this inactivated vaccine was great in inducing an immune response [inaudible]. Well, we waited for phase three trial, waited for that phase three trial. There was 420,000 children got vaccine, 200,000 children got placebo. And it worked. And Thomas Francis stood up at the [inaudible] and said, "Safe, potent, and effective." And that headline was on the headline was on the front page of every newspaper in the country. Well, the question is, how did he know was effective? The reason we knew it was effective was that 16 children died of polio in that study, all in the placebo group. Of the 36 children that got paralyzed in that study, 34 were in the placebo group. I mean, those were first and second graders who by the flip of a coin ended up either dying or being permanently paralyzed. I mean, those many of those people would be alive today. I was a first and second grader in the 1950s. I mean, that could have been me. My parents didn't volunteer me for that trial. But you know that's how you learn that something's effective. And just realize that then when we're talking about a quarter of a million people having died roughly from this virus this year, and it's only going to get worse, I think moving forward, that that's the price you pay for learning, something's effective.
>>> Howard Bauchner: An old colleague of mine, who you know very well, Jerry Klein tells the story about when they opened up the envelope about the H flu type B vaccine. And all the cases were in the unvaccinated group. And he knew that they were looking at saving the lives of upwards of 10,000 children a year. I forgot what the number was 10 to 1 or 9 to zero, he realized that they had a life saving vaccine. I want to turn and I don't know how much the committee focused on it. More and more coming to the attention of what logistics is going to look like. The National Academy of Medicine [inaudible]. We've published papers from both of those groups. It's very clear the first 20 million doses are going to go to the large community of healthcare workers. And most of that will be distributed through hospitals. I'm generally comfortable thinking that hospitals regardless of what temperature the vaccine needs to be kept at or how quickly it needs to be administered, that hospitals are capable of doing it. But you are a pediatrician, and you know how complicated it is to ship, store, administer, and track vaccines. What's your sense of where we are on the next hundred million people? Not the first 20 million where I do think it will be hospital based and we will be capable and competent at it. It's the next hundred million, Paul. Do you have a sense of that?
>> I think it's going to be a real challenge. I mean, not just the shipping and storing at minus 70, which means making sure that the dry ice is constantly replenished. Something we've never done in this country for a vaccine before. It also means identifying who those people are that are in that second wave, meaning other essential workers. And, you know, people who are over 65, and people who have certain health problems, how do you identify them? How do you make sure they come back roughly a month later? Some vaccines are 21 days later, another vaccine's 29 days later. It's going to be hard. And do you give this to large chain pharmacies? Is that how you do it? Or do you sort of set it up as a the same way that we have set up testing centers? You know, that you just have these individual special purpose centers that you set up to do this who were only doing this? I don't know. I think it's going to be up to -- it's not going to be the federal government --
>> Paul Offit: -- get to decide. I think it's going to be at the state and local level that this happened.
>>> Howard Bauchner: Yeah, the reason I'm so concerned about is I went and got my vaccine at one of the local pharmacies, but they need to track who I am. It needs to go into my EHR, I need to get a second dose. If I have an adverse effect someone needs to know that which vaccine I got in on what day. And we don't have the most efficient healthcare public health Electronic Health Record system in the US. It's very discombobulated, and that that's what's making me nervous about the logistics. And then, the last is, you know, it appears as though McKesson is going to be the primary shipper. And I have yet to hear how they're going to distribute it to the 50 states. And we know that we ran into tremendous problems around Remdesivir. And I know there's already concerned that the monoclonal will go to the people who can pay for it. So, again, I think those are the details that are coming across my desk and people are concerned about.
>> Paul Offit: It's going to be a learning curve associated with this. So I'm sure there's going to be a lot of stumbling. And looking back, we'll see ways in which we could have done this a lot better.
>>> Howard Bauchner: Paul, when's the committee meet next?
>> Paul Offit: Unknown. We were asked to agree to three dates in November and three dates in December that we would set aside then with the presumption that one or more of these companies are going to be submitting for an EUA, and that we're going to need to meet ad hoc to discuss that. So I think in the next couple of months we are going to be seeing companies submitting for this. If dreams could come true, all I ask is this. Let's have at least 150 participants that got sick. That's all I ask.
>>> Howard Bauchner: Paul, you've been an extraordinary guest on Conversations. You've been on many shows. On behalf of the medical community and the public, I just personally really want to thank you. I think you've really tried to educate people about vaccines, acknowledging how restless people are about them. Restless about the pandemic in general and the vaccines. And I think it's people like you, speaking with clarity and experience that can help to reassure the American populace that when we get to a vaccine, it will be approved because it is safe and it's effective. So on behalf of the medical community, I really want to thank you.
>> Paul Offit: Thank you, Howard. Nice to say that. Thank you.
>>> Howard Bauchner: So this is Howard Bauchner. It's been conversations with Howard Bauchner. I've been talking to Paul Offit, the [inaudible] and Professor of Vaccinology at Perelman School of Medicine, University of Pennsylvania. And I must add a pediatrician, a fellow pediatrician. Thanks, Paul. Stay healthy.
>> Paul Offit: Thank you. You too.
>>> Howard Bauchner: Bye-bye.
>> Paul Offit: Bye-bye.
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