Arnold S. Monto, MD, chaired the US Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee (VRBPAC) meetings in December that led to Emergency Use Authorization (EUA) of the Pfizer/BioNTech and Moderna vaccines. He joins JAMA's Q&A series from the University of Michigan School of Public Health to discuss experience to date with the 2 products and what's next in vaccine development. Recorded January 11, 2021.
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>> Howard Bauchner: Hello and welcome to Conversations with Dr. Bauchner. Once again, it is Howard Bauchner, Editor in Chief of JAMA, and I'm joined by Arnold Monto. Arnold is the Thomas Francis Collegiate Professor of Public Health at the University of Michigan School of Public Health. He's a physician and an epidemiologist. Welcome, Arnold.
>> Arnold Monto: Glad to be here.
>> Howard Bauchner: In addition, Arnold is the acting chair of the Vaccine and Related Biological Products Advisory Committee that many of you have heard much about over the last couple months. So Arnold, what's it been like to be acting chair of this committee?
>> Arnold Monto: Well, it's quite an experience. The committee, the VRBPAC, I was on it until last January and rotated off, and they asked me to come back to chair these panels reviewing the new COVID vaccines, and it's very different from the quiet event we used to have, usually have in a room in Silver Spring at the headquarters of FDA because we're on for eight or nine hours in succession.
>> Howard Bauchner: So Arnold, so many questions about vaccines that have emerged since the last time I spoke to Dr. Fauci and Dr. Offit. So let's start running through some of the major questions. Obviously, the new variants, and the question is whether or not these vaccines will be effective against the new variants. What's your sense of that?
>> Arnold Monto: My sense is what everybody has read, that the variants do have changes in the spike protein but not enough to make the vaccine not protective. We'll know for sure since people are getting vaccinated, and there's a lot of disease especially in the UK, about protection, but it looks like it should work, and we'll know more definitively probably in another couple weeks. I know that since these vaccines can be modified pretty easily, they're looking at a scenario where a variant might develop which would not work, but we don't think that this one is going to be a problem.
>> Howard Bauchner: Arnold, the rollout in the US I think has surprised many. It certainly surprised me. I thought the first 10 or 15 million doses would go a little more smoothly. You know, it's hard to get up-to-date, daily data, but it appears as though there's 10-plus-million doses available but not administered. You know, Arnold, you've been at this for four decades. You have an enormous amount of experience through many other epidemics. You're a world-renowned flu vaccine expert. What's your sense of what's happened over the last couple weeks?
>> Arnold Monto: I don't think anybody is ready for this, and I think this is the ultimate demonstration of problems with the American healthcare system, which is fragmented, which probably has some of the wrong priorities. We're all into billing and everything else. Flu vaccination is probably the closest thing we have to what we're trying to do now because people come, they get vaccinated every year. This can be handled, but everybody knows where to go and how to get it. The supplies are there. This is totally new, and I think we totally underestimated the challenges that this would provide because we're really not as organized as countries which have healthcare as a more systematic component of the government.
>> Howard Bauchner: Are there quick fixes, Arnold?
>> Arnold Monto: I'm worried that there aren't. I think there needs to be more attention paid to some of these problems. When I first heard about Operation Warp Speed and that the military were going to be involved, I was hoping that the government, in one way or the other, were going to be involved not just in getting the vaccines to the states but actually in the delivery process. We can do it. It has been done. Well, for example, if you go back to when smallpox vaccine had to be given in New York back I think in the 1940s, they can do it if you have attention and all hands on deck in terms of the distribution. We've done it for vaccine development, but we haven't done it for distribution.
>> Howard Bauchner: I want to talk about another of the intricacies that have come up about the various vaccines. So I just received an email just before I came in, and it said, "Howard, you never talk very much about pregnant women and vaccination." I'm a pediatrician. Four million births a year. You have a vast amount of experience with influenza where there's been a question about vaccination. Can you talk about what is it that you would recommend to one of your own children if they were pregnant or a friend or a colleague called you? Is it safe to be vaccinated during pregnancy?
>> Arnold Monto: Well, let me give you the bottom line and how I come to these kinds of recommendations. I think a pregnant woman should look at her risk group and get vaccinated as she would if she were not pregnant. By that, I mean that if somebody especially has underlying conditions, I would have no doubt that she should be vaccinated. I think that when vaccine is available for the general public, a pregnant woman should be vaccinated. By that time, I hope we have more information about some of the theoretical risks, and there are always theoretical risks, especially about the first trimester. Looking at the flu story, we've come from most pregnant women not being vaccinated to pregnant women being the highest priority for WHO to be vaccinating.
>> Howard Bauchner: Questions are already coming in. You know, the UK is going to experiment with lengthening out the distance or the time between -- for Moderna and Pfizer; we'll get to the other vaccines -- from three weeks to, I don't know, six weeks or two months, from four weeks to six weeks to two months. Do you have an impression of that experiment?
>> Arnold Monto: Well, I'm glad you used the word "experiment" because it is an experiment. And I've heard spokespeople from the UK defending it, saying, "Oh, we know from immunologic studies that the vaccine may even work better if we allow more time between the first vaccination and the second." We've got to go on the data, and the data we have is from the clinical trials. There are hints in the clinical trials that, yes, you do get reasonably high protection late after the first dose, but we really don't know that in terms of large numbers. And when you start talking, there was another discussion about halving the dose, and when you look at those studies, you find 15 people in each group looking at the antibody titers with half the dose of what's in the Moderna vaccine, which is the one they were talking about. So we go on the science. We go on what we have, and that means that the vaccine should be given according to the schedule, and it may be -- and we can do this with small studies -- that we can delay it, but we can't do that right now.
>> Howard Bauchner: Arnold, President-elect Biden announced that he was going to release a large number of the vaccines as quickly as possible. I think the number was a hundred million. I was surprised to hear that for a number of reasons. What was your impression when you heard that?
>> Arnold Monto: Well I was surprised to hear that because it actually followed the strong statement from FDA, which reiterated that vaccines should be given according to the schedule that was used in the clinical trials, the trials that gave us the information that we have. I think we need some clarification because my impression is that the problems we are having in distribution are not based on availability of doses as much as in problems with the American healthcare system being as flexible as you need to be in dealing with something which is unprecedented, namely trying to vaccinate, well, right now, those who have contact with = lots of individuals because of their work plus, more important, the older individuals. That's the group for many states where we are right now. And it isn't doses. It's getting people in, even through known medical homes. And I hesitate to think about what happens for much of the population which really is not well-connected to medical care systems.
>> Howard Bauchner: Arnold, now I know these advisory committee meetings are scheduled, and the FDA under Steve Hahn's leadership has been excellent about releasing a fair amount of data to the public for many of us to look at it before the meeting. I know one meeting in January has been cancelled. The second one is still tentatively scheduled. Do you know if you'll be considering either the J & J or the Oxford AstraZeneca vaccines at any of the upcoming meetings?
>> Arnold Monto: There's really no information even for us beyond what we read in the media. Basically, the advisory committee is a jury, and we get the same kind of information a little bit earlier than what is put publicly on the FDA website. So we're all looking at the same data. The importance is the transparency of the data, and we don't even have control over the agenda. You may have noticed that there was a very long agenda for the Pfizer review, which constricted our discussion time at the end. The FDA learned from that, and we had much more time available, and the Moderna advisory allowed much more discussion about the key points. Another key point is going to be maintaining the placebo groups for licensure, and that's something which really hasn't been settled yet. Because, remember, these are emergency-use authorizations. We need to get the vaccines licensed in the usual way. Otherwise, when the emergency goes away, the authorization goes away. So that's the next step which a lot of people haven't even thought about.
>> Howard Bauchner: So at least for now, you don't anticipate seeing any new vaccine date, at least as of today, January 10th, that you'll see it at the next FDA advisory meeting that's scheduled there in late January.
>> Arnold Monto: Off the record, the meeting in late January has already been canceled.
>> Howard Bauchner: Ah. All right. Thank you. So that will roll -- I think you're probably fair to say that, so it doesn't sound like we'll see if another vaccine is --
>> Arnold Monto: That just came in an hour or so ago.
>> Howard Bauchner: So if another vaccine is to be approved, it probably won't be until February.
>> Arnold Monto: Correct.
>> Howard Bauchner: Okay. Social media is a kind of form of gossip, Arnold, and I think as you know, although we don't have very good data about what percent of patients who are infected with COVID-19 are acquiring long-term symptoms, the so-called long-haulers, there's been some concern that perhaps the vaccine could induce such a clinical condition. Has there been any evidence from animals or the clinical data that that could happen?
>> Arnold Monto: No, there hasn't been any evidence of the kinds of side effects we were worried about. There were some theoretical issues about antibody enhancement. It was seen in some of the trials -- not trials, but in laboratory animals back about five or six years ago working with the SARS and the MERS vaccine, but that concerned principally non-neutralizing antibodies, the presence of non-neutralizing antibodies. But we've seen total agreement or near-total agreement between binding antibodies and neutralizing antibodies here, and we know that the efficacy is very high, better than anybody anticipated. Remember that the guidance from FDA was talking about emergency use approval or even licensure with 50% of efficacy, and we were all happily surprised to see the efficacy that's been found.
>> Howard Bauchner: Let's say the goal is to vaccinate 200 million Americans as quickly as possible, certainly by the spring, the summer, so next fall there's a sense of normalcy that returns. You're at the University of Michigan with Preeti Malani, an associate editor, and getting people back to college, getting children back to school, which is still going to be problematic through May or June. And we still are uncertain about the supply of the Moderna and Pfizer vaccines. They're optimistic, 20 million doses a month, but that could be problematic. Is there an approach, Arnold, where you would test individuals to see if they were infected or asked if they were infected, and those people, rather than getting vaccinated, would go to the back of the line? Does that make any sense to you?
>> Arnold Monto: Well, I think we have to put into context and into the models because a lot of what we see and talk about herd immunity is based on models, which, in turn, these models are based on assumptions. And what I hope we can see is some data on more recent seroprevalence studies so we find out what proportion of our population has now been rendered immune by infection. It isn't just vaccination which is going to stop the pandemic; it's going to be overall immunity. And the only good part about what we are seeing with these major infection frequencies, certainly in some regions, is that this will provide some degree of immunity. You have to remember that epidemics end. Even flu pandemics typically end after 10 or 12 weeks, the first wave. We've not seen that with this virus, and it may be because of its weird transmission patterns. But we've got to have more evidence and to throw this into the equation a bit more actively than we have. Getting back to your first question, going to the back of the line if you're infected, that gets to be very cumbersome. We've not done it with anything else simply because it requires an even more cumbersome system of testing people and categorizing them. Let's hope we have enough vaccine to just go ahead and vaccinate whoever comes up in line. We know it is safe for a previously infected individual to get vaccinated.
>> Howard Bauchner: Arnold, so, you know, you've had a three-, four-decade career in vaccinology, SARS, Ebola, influenza. What have been the surprises around this pandemic?
>> Arnold Monto: Well, I call this a weird virus, and the reason I call it a weird virus is the transmission patterns have been very strange. Maybe these new variants, which transmit better, won't be quite as weird in their transmission patterns, but the idea of super-spreading individuals and non-super-spreading individuals, households where either everybody gets infected or nobody gets infected from an infected individual. Also, the pan-system involvement in the clinical setting, I don't know that anybody really expected to see this, and certainly there wasn't enough information from SARS, which is caused by a very closely related virus, to ready us for what we have seen. And one of the advantages now is that, with clinical experience, they're much better able to handle the cases than they were at first, which really a lot of the lethality was based on the novelty of this kind of infection.
>> Howard Bauchner: Has the sparing of serious disease in the vast majority of children surprised you?
>> Arnold Monto: A little bit, and the reason I say a little bit is that, the same thing was seen in SARS. I actually was in Beijing. The day I arrived was the first day there were no new cases, and they considered my arrival lucky. But I had some follow-up with people in the capital pediatric hospital, and they did serial surveys after the SARS outbreak and did not find very much evidence of infection in children. And then we saw the same thing here. Now, this is very unusual for a respiratory virus, which you as a pediatrician would be well aware of. Usually, children are the major sources of not only infection but transmission in the community. If there's anything standard about flu pandemics, it's the fact that young children are at particular risk of severe morbidity and mortality. And we saw the opposite here, and this is very unusual for a respiratory virus. Maybe it has to do with some kind of receptor issue. I hope we can work this out to try to figure out why this is. It's very strange from the standpoint of the way we usually think about these viruses.
>> Howard Bauchner: Do you think, Arnold -- So in February, we and other journals published research letters about asymptomatic spread, and I still think we as a journal could have done a better job announcing to the world what that meant. I really do think we could have done a better job. We had gotten a number of pieces from Asia to say, "Why don't you just mask? It has no morbidity." Has asymptomatic and pre-symptomatic spread been a surprise?
>> Arnold Monto: Asymptomatic and pre-symptomatic spread was a real surprise, the magnitude of it. And again, part of the problem was the experience with SARS, but you have to remember we didn't really have a diagnostic test for SARS. PCR was in its infancy at that point, and most of the experience, most of the cases were clinical cases that were recognized. But even so, SARS could not have been controlled the way it was if asymptomatic transmission, infection and transmission, was as common as it is with this virus. I think this was a real change from the SARS virus, even from the start, and part of our problem was what had been experienced with SARS and the lack of our ability to recognize what was going on right away. And I think this may have been something which evolved. Again, we don't know about variants, but to me, there must be an enormous amount of asymptomatic transmission. The other thing that's a surprise is there are data -- and I don't know how to really factor this in -- that there is better antibody response with severe infection than with asymptomatic infection. Infection is infection is what we've always been taught.
>> Howard Bauchner: Arnold, I don't think anyone anticipated that the late fall and now the winter would be as difficult as it has been. I had interviewed Dr. Fauci just before Thanksgiving and asked him to comment on Thanksgiving and Christmas, and Tony said, "Oh, Howard. I don't want to predict Christmas. Let's get through Thanksgiving. It hasn't gone very well." We've seen very little flu. I think people were vaccinated by flu, and I think the social distancing data from other countries -- Soon as you begin to social distance, you see a decline in flu, so it hasn't been this combination. January's been terrible. I mean, the numbers are overwhelming, and in certain areas of the country -- one of our associate editors, Ed Livingston, is in Los Angeles. The bed counts are extraordinary. What is your sense of what January, February, and March are going to look like? The rest of January, February, and March?
>> Arnold Monto: You know, as somebody who works with flu, I believe in seasonality, because we don't understand everybody's got their favorite variable that they look at, whether it's relative humidity or absolute humidity or heat. But in the temperate zones, flu is highly seasonal, except when there are pandemics. But even in a flu pandemic such as in H1N1 2009, it decreased in transmission in the summer. We know and we published data just this past March on seasonal coronaviruses. They are sharply seasonable. And these are the coronaviruses that cause mainly common colds, and they transmit mainly from December through March, April. And I'm concerned -- first of all, I was surprised about the summer prevalence of this virus, the SARS-CoV-2 virus. I'm not as much surprised about what we're seeing here in the winter because we have, I think, seasonality thrown on top of winter behavior, less ability to be out there in the environment where transmission is less likely. So we've got a double whammy here: the natural seasonality of this virus plus the inability to do things which we might have done, like eating outdoors and things of this sort during the summer. So February and March are going to be difficult months. The only thing that may help us is the fact that, at least in some parts of the country with percent positivity being as high as it is, we may see immunity building up in the population, and I think we're going to see different patterns in different parts of the country based on that. I don't know. We all speculate based on what we see. Maybe the New York area, which was heavily hit in the late winter, early spring may be one of the reasons why that area has been relatively spared recently, is because of what happened in vulnerable communities during that period. Certainly the CIRA prevalence studies that showed that maybe only 20, 25% were immune wouldn't suggest that that would be the case, but we can all speculate.
>> Howard Bauchner: This is Howard Bauchner, Editor-in-Chief of JAMA, and I've been delighted to be joined by Arnold Monto. Arnold is a Thomas Francis, Jr. Collegiate Professor of Public Health, University of Michigan School of Public Health. He's a physician, an epidemiologist, and he's currently acting as the chair of the Vaccines and Related Biological Products Advisory Committee meeting. Arnold, I want to thank you for your service. Why did they re-enlist you? Why do you think they re-upped you?
>> Arnold Monto: Well, there's usually a story behind the story, and the FDA is terribly worried about any conflicts of interest. The person who is the current chair of the committee is involved as the principal investigator of one of the Moderna studies, and she couldn't be the chair because she's in conflict, so they asked me to come back. Actually, what happened was, they asked me to be a consultant because they know I've worked on these viruses and on coronavirus, and then I got another phone call, and I was asked if I'd be willing to chair. And I thought a little while and said, "Well, it's going to be a real challenge, but it's going to be an interesting experience," and I agreed.
>> Howard Bauchner: Has it been intellectually exciting?
>> Arnold Monto: It has, because it really puts a lot into a new framework. I think the public, especially the medically aware public, is beginning to realize how vaccines and drugs and whatever get approved, and we have this system in the United States, which is I think unique, where FDA approves, says you can use a vaccine. But then the ACIP, which pretty much reports to CDC, tells everybody how the product should be used. And the concept of integrating both of these elements is a tricky one, but we can see how things have worked out where we wouldn't have approved the product if we didn't know that CDC was following on with telling people how the vaccine should be used and who should be prioritized.
>> Howard Bauchner: And your sense of how the FDA's done under Steve Hahn's leadership, and then David Mark's group, who I know provide you with a great deal of information. What's your sense of how the FDA has done over the last couple months?
>> Arnold Monto: I think they've done very well based on the environment. They could have been pressured into approving without going through the standard procedures. As a matter of fact, there was so much concern about this that some states were talking about putting their own approval mechanisms into place. But they stood up to the kind of pressure they were getting, and now there is very little concern about the approval process. We could have had a total mess if they had succumbed to the pressure they were under and try to short-circuit the approvals. People are concerned about how rapidly the vaccine was developed, and that's an easy one to explain because they've put in parallel some of the procedures which are usually done in sequence, and we were extremely lucky that the spike protein was as much involved with protection, which made the vaccine development much more easy than it would have been otherwise. But if there had been a short circuit on the approval, can you imagine the kind of mess we would be in now, and rightfully so, about people concerned about what was going on with the product that we were trying to deliver.
>> Howard Bauchner: Again, this is Howard Bauchner, Editor in Chief of JAMA. It's been Conversations with Dr. Bauchner, and I've been joined by Arnold Monto. Arnold, again, thank you for joining me, and thanks for re-enlisting.
>> Arnold Monto: It's a pleasure to be with you. I'm not so sure about -- The nine-hour meetings are a little bit hard to take sometimes when you're sitting in a chair for most of that time.
>> Howard Bauchner: Right. Take care and stay healthy, Arnold.
>> Arnold Monto: Thank you.
>> Howard Bauchner: Bye-bye.
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