To get more vaccine to more people more efficiently, UCSF School of Medicine's Robert M. Wachter, MD, recently urged giving a single dose now and deferring the second dose until more vaccine is available. Paul A. Offit, MD, of The Children's Hospital of Philadelphia, disagrees. The two discuss the pros and the cons of the plan and alternative responses to road bumps in the US vaccine rollout, on JAMA's live Q&A series. Recorded January 19, 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 it will be vaccines, vaccines and vaccines. I'm joined by two stellar remarkable individuals, the first who has been on numerous times. Paul Offit. Paul is the director of Vaccine Education Center and a professor pediatrics in the division of infectious diseases at Children's Hospital of Philly, Philadelphia, is a Maurice R. Hilleman Professor of Vaccinology at the Perelman School of Medicine. He is also on the advisory board, the FDA Advisor Committee for vaccines. The other is Bob Wachter. Bob is an old friend, most famous as being the father of hospital medicine. Bob is professor and chair of the Department of Medicine at UCSF where he is the Holly Smith Distinguished Professor in Science and Medicine and a Benioff Endowed Chair in Hospital Medicine. Welcome Paul. Welcome Bob.
>> Paul Offit: Thank you.
>> Robert Wachter: Thank you.
>> Howard Bauchner: So, let's start with an issue that has emerged over the last couple weeks. I think, Bob, you in part stimulated it with Ashish in a number of pieces in popular press. And I think Paul has weighed in on that issue. So you just gave me the data, 30 million doses released, 15 million doses given, 15 million remain warehouse somewhere, although the rate of providing the vaccine is on a daily basis. Shots in the arm are going up. And the question has come up whether or not, let's say we have 20 million doses more available on February 1. Should people get the second dose when they're supposed to? Pfizer Moderna vaccines three and four weeks, or should that second dose be held given -- and not be given on time, spread out, so another 10 or 20 million people who would have been getting their second dose, those 10 or 20 million people should get their first dose. Bob, have I captured what you and Ashish were talking about?
>> Robert Wachter: Yeah. I think the key there -- there are a couple of key points, Howard. One is that we and no one credible I have heard is arguing that people should not get two doses. That part's clear and I think inviolable. Paul, I'm sure, will agree with that. The second, and the reason Ashish Jha and I wrote the piece in the Washington Post about this was I was hearing too many people say we should stick with the plan because it's the plan. And I invoked in the article, I invoked the Mike Tyson principle, which is everyone has a plan until they're punched in the mouth. And it feels like we're being punched in the mouth. The rollout has been extraordinarily slow and sluggish. The surges are huge and now maybe beginning to plateau, but 4,000 people a day dying of COVID and more than 9/11 every single day. And the entry of the new variants into the mix in the United States increases the pressure to move things along. And so, at leas the models that I have seen raise the possibility that if you have a choice of vaccinating tens of millions of people and getting more people to get their first dose sooner, and get them from 0% immune to perhaps 80% or 90% immune, you might save more lives than giving the exact same number of doses to people who will get from that 80%, 85% immune, to 95% immune with the second dose. Again, the argument is not to give people only one dose. You need the second dose to get to 95% and for more durable immunity. But we really are trying to stimulate a conversation, get out of this box of just saying we should only do this because that was what was studied. You know, the epic see of the first doses were also studied. It wasn't the overall intent of the trial, but we got -- we have good data on the level of protection that people achieve just before they receive dose two.
>> Howard Bauchner: So Paul, when you hear Bob present that, I can understand the argument. I think it's pretty simple that, you know, we have 20 million more doses on February 1 to give it, to give rather than giving 10 million that would represent second doses, 20 million people would get their first dose and those 10 million people would be spaced out to, you know, two months or three months. How do you react to it, Paul?
>> Paul Offit: I think it's largely a problem of messaging. I think the way people hear that is that one dose is 80% or 90% effective, which isn't true. Here's what we know, we know that, as Bob said, when Pfizer did its trial it gave a first dose and then three weeks later it gave a second dose. Well there was time then to see whether or not people got infected between the first and second dose and whether you were more likely to be infected if you got a placebo than vaccine. And what they found was that and in that three-week period of time the vaccine was roughly 52% effective. And with Moderna it probably, because it was a longer period of time between dose one and dose two, depending on how you sliced it, but there was at least somewhere in the vicinity of 80% to 90% in that four-week period of time. You also know that after one dose you have an immune response, a neutralizing antibody response in your circulation that is considerably less than found after the second dose. You clearly get a booster dose with a second dose and you get a T-cell response. Depending on which company we're looking at, you get either get a T-helper cell response in one company or the other T-helper cell and cytotoxic T-cell response, which suggests, as Bob alluded to, that you're going to have longer term immunity. And not that you might have longer-term immunity, you will have longer-term immunity with that second dose. So if Bob is saying let's get as many first doses out there as we can and if it's delayed a week or two then at least you vaccinated that many more people and the second dose isn't given at three weeks, but four weeks, or instead of four weeks, it's five weeks. I don't have a problem with that. What worries me is that there are going to be people that are going to hear this and say "You know, I'm 80% to 90% effective. That's not that different than 95% effective. I got my dose. I'm good. I had to suffer a little bit with that first dose. Why bother getting the second dose?" That worries me, because they would clearly be less protected. Also, because there is a lesser neutralizing antibody response, you could argue, as virologists have, that you could be selecting for a variance more if you have a weaker immune response that a stronger immune response after the second dose. So I think Bob and I aren't that far apart, as long as we both agree that you can't wait very long, because if you're talking about waiting instead of waiting a week or two or three weeks later, then you're talking about two months, three, months, four months later, I think that's a problem. And there was just a paper that -- not a paper, but a news report that came out in Israel and I think we need to look at the data more clearly, they feel that that first dose was not nearly as effective as they hoped it would be, because now they're seeing sort of outbreaks in thousands of people, where they hadn't expected that to happen when they had so many people that were given dose 1. But again, one needs to look closer at that. I think the basis of Bob's argument makes sense, with the exception of the fact that there would be people who don't get a second dose in a timely manager or worse, manner, or worse don't get a second dose at all.
>> Howard Bauchner: Now Bob, it's a bit unfair, I mean Paul is one of the world's leading vaccinologists. You are a scholar. But it's a bit out of your field, but how do you respond to Paul?
>> Robert Wachter: Well, I have to say that most of what I know about vaccinology I learned from Paul.
>> Howard Bauchner: Right [laughs].
>> Robert Wachter: So it is very hard to argue with him. And I guess I have one question for Paul, which is that 52% figure about the efficacy of the Pfizer vaccine. Is that over the course of the entire three weeks, in which case it's integrated, that includes the first ten days where you essentially have no protection, because my impression looking at the curves and the numbers was the relevant numbers, not what your overall level of protection was during those first three weeks. It really is, what was your level of protection the minute before you got dose two and that you were closer to the 80% to 90% range? So, I loved that clarified, but then I'll go ahead and answer your question, Howard.
>> Paul Offit: Yeah, no I think that's right. And I think also with the Moderna the reason it was higher, at least overall, was because you had another week. So, I think that probably drove it up as well. Just what worries me though, is if you look at those phase one data, the level of neutralizing antibodies was clearly less and there weren't detectable [inaudible] responses until you got that second dose. So you need that second dose. And this is really to me a messaging issue. Just to let you know, what happened, I was on the PBS News Hour like a week ago Friday and when the Biden plan got announced, as you know, we're going to get as many first doses out there as possible, I, on the PBS News Hours, said, "I think this is a -- this is taking an unnecessary gamble, because you're gambling you're going to be able to have enough vaccine out there to get that second dose in a timely manner." And the next day I was talking to David Kessler who said to me, "This is" -- who is now going to be the new Moncef Slaoui, I think, you know he's going to take over -- I don't think it's going to be called "Operation Warp Speed" anymore, but yeah so, but he said, you know, "This is not the plan. The plan is a two-dose vaccine." And in that same day, Saturday, there were two people from the Biden transition team, one was Michael Osterholm and the other was Celine Gounder, who both got on TV and said, "Look, this is a two-dose vaccine. You're getting it three to four weeks later." Because they felt they had a messenger problem. So, that's the way it played out.
>> Robert Wachter: Yeah, and I guess I would say in that piece and in subsequent interviews I've done I completely agree with Paul that if the modeling, and as you say Howard, common sense says that if you have a choice of giving more people that first dose and if in fact you bring them to 80% or so protected, you are probably better off than giving more people the second dose with a relatively small amount of incremental protection. But if that comes at the cost of people not coming back for their second dose because they heard the message that that's all I need, that the reminder system somehow was good enough to get them to come back in three weeks, but somehow fails at two months, which of course is possible. That they see this as yet another curve ball and just like you told me that masks didn't work and then you told me they did and you told me I needed to clean my mail and now you're telling me I don't. And I'm just so confused that I'm just not going to get vaccinated. And I'd say the mutant thing is yet another example. There are a number of uncertainties here that one would have to weigh in deciding whether this is a good idea or not. And Paul's very good at this and very smart and I respect his opinion a lot. And it is not like Ashish and I wrote this and said, "This is a slam dunk." It would be crazy for us to not follow this plan. It really was, I was just hearing too many people saying this is the plan and we're going to do it because it is the plan and it really felt to us that it was a good time to take a step back and examine it. And, you know, the people in the UK are pretty smart. They're essentially facing the same problem that we're facing, except they're ahead of us in terms of the variance. So they're racing against a foe that is faster that the one that we are racing against today. And they did embrace this plan and with the same facts that we have. I have not heard anyone say, and don't know if Paul would say that delaying the second dose a little bit would increase its efficacy in terms of getting you to 95% and getting you to more durable immunity. In fact, there are some people who say that it might even be a smidgen better, but I haven't heard anybody say it's worse. I haven't really heard a ton of people say that it's likely. And I'd love Paul to weigh in on this. It's likely that your immunity after the first dose is going to degrade a lot over the next month or so. But that may be an uncertainty and certainly is a possibility that there will be some degradation in the immunity. But I think Paul's argument -- I hate to argue against myself -- Paul's argument is perfectly reasonable argument. And I sort of think you need to model this and maybe get sociologists involved and other people who study such things. If, in fact, people heard this and said, "Oh what I am hearing, what I'm taking away from this is I only need one dose." That would be bad and I would not support this as an idea because the implications of that really are quite bad. I sort of believe there would be a way of messaging this so that you get more people vaccinated quickly, people understand the reason that we're doing it and people still come back for their second dose. But it does introduce a level of uncertainty. But we're talking about an emergency and we're talking about sometimes you have to do a little bit of improve, you know, the defenses lined up in a different way and the quarterback, you know, calls a new play on the line. And so that was what we were reacting to, whether we really needed to think hard about shifting the strategy in a way to get more people vaccinated quickly because of the situation we find ourselves in.
>> Howard Bauchner: I think one of the points that you made, Bob, is interesting to me, is that when we've shifted messaging in the U.S. it hasn't worked very well. Masking is probably the most prominent, but there's been others about how much social distancing, schools opening, schools closing. It's not something we've done very well with. Now, there's a reason in part why that's happened. But I somehow think the populous knows one dose, a second dose three weeks later or four weeks later, and if we move off of that I don't know what the psychological impact would be. And I think everyone is committed to a second dose. And I don't know what would happen if that went out to six weeks or eight weeks. Paul, commenting, Bob had some other comments or points that he made and I just wanted to interject this notion of changing pretty much how we've educated the public.
>> Paul Offit: Right. No, I think when you sort of change your messaging regarding a vaccine strategy it's never good. You know, people get confused. I agree. Although, one thing about that that I think is certainly true is that is there is not a vaccine that is given in multi-doses where when there is a delay in that second dose, or third dose, you never need to start over again. I mean we just always pick up where we left off. So I don't think there's likely to be a degrading of immunity. What worries more is just that the first does induces a lesser immune response. And I think there are problems associated with lesser immune response. For the longer that you have that lesser immune response I think the worse off you are.
>> Howard Bauchner: Bob, do you know, let's say it did go out to six weeks or eight weeks and someone then got infected and died, would be there legal ramifications? Because currently Moderna, Pfizer, the EUA recommends a second dose very specifically. Do you know if there would be legal ramifications if we lengthen the time between the first and second dose and someone unfortunately became infected and then died?
>> Robert Wachter: I don't the answer to that. It's an important question and obviously would influence things. I think you would want the FDA to weight in and say, "This is a reasonable safe strategy." and endorse it. And I wouldn't recommend that people go out and do this on their own and choose to delay the dose on their own, and I wouldn't even recommend that states embrace this without a broader review by, you know, appropriate scientists who think through all of the moving pieces and come to decide that this is the right thing to do, as the U.K. has done.
>> Howard Bauchner: Bob, another question and then I'll turn to Paul, and we chatted at the beginning before we went live about this. We've made it complicated, Phase 1A, Phase 1B, Phase 2A, 2B, I related the story of one brother who could get vaccinated. The other brother couldn't get vaccinated. I haven't been vaccinated. Have we made it too complicated, Bob?
>> Robert Wachter: I think so. So, Ashish Jha had another editorial last week in the New York Times and this one was on the complexity of the rollout. And I think what we had was a lot of well meaning groups sit down and try to parse this around which groups should be prioritized. And they're using ethical principles and redressing healthcare disparities, all correct, all in a vacuum correct. But I don't believe there was a whole lot of discussion about the practical applications. And I would frame it this way. Someone stopping and saying, "How the hell is this going to work?" And I think what we've seen is the results of that. So I'll give you a couple of quick examples of how, you know, they say that OK, you know, people who are front line essential workers are going to go, should go earlier. I've been asking people for now months, tell me how Walgreens or CVS is going to figure out that you are a grocery store clerk? Or you are a preschool teacher. Is that a note from HR? Is that the honor system, you know, really? How is that going to work? Preexisting conditions. I had thyroid cancer when I was a medical student at the University of Pennsylvania 23-years-old. I'm 63. I'm pretty sure I'm cured. Is that a preexisting condition? I have a history of cancer. Who is going to figure that out? Is that going to be a note from the doctor? And the more we thought about it, we came to a general principle that I think is worth us reflecting on, which is systems. The more complex a system is the less equitable it is likely to be. Who is going to be able to figure out their way around the system? Who is going to game it? Or who is going to have the resource and wherewith all to get to the front of the line? It's going to be the well to do. It's going to be the privilege. Exhibit A is the tax code. And so what our fear was, was in a well meaning, perfectly well meaning effort to get the ethics right we had created a monster. An absolutely unworkable mess of a system that was going to be confusing and ultimately inequitable, you know, even though the goal was equity. So our recommendation in the Times was that we go back to the drawing board and say you start with the groups that we started with, healthcare workers and people in nursing homes. It makes all the sense in the world. And then go to age. And 75 and up, you're done with 75 and up, 65 to 75, you're done with that group, 55 to 65 very importantly because many of the deaths in communities of color occur in younger age groups. And so if you stop, if your age cutoff is too high you may miss a lot of people from disadvantaged groups and you may create inequities. The advantage of age is it's completely knowable. Stores know how to card people. Everybody has identification that shows their age. When you're done with 55 and above you go to a lottery. And the lottery is this week the number we pulled is a number three. If the last date, if the last number in the year of your birth is number three, it is your week. Congratulations. You go and get your shot. What we said in the article is the lottery is the worst system except for all the others. It's fair. It's doable. We're old enough to remember the gas, the oil crisis lottery in the 70's. And you could make the same arguments, Howard, you could have said, "Well, you know, I have more of a need for gas because my commute is longer, my family is bigger, I'm poor, my job is more essential." And we said, "Yeah, yeah, yeah, here's how we're going to do it. Last digit of your license is an even number you get gas on an even day, odd number an odd day." So it's a way of taking a very, very large pool and saying we're going to divide it up into groups of manageable size to prevent overloading the system. The alternative is what happened to my mother, 84 in Florida, yesterday, which is five hours in the car waiting in a huge parking lot for her vaccine. Or people waiting on hold for three hours. Or people trying to get onto the website and it crashing. And again, who is going to figure out their way around the system? Mostly the privileged. So that was our sense, it's just become an unyielding mess. And in a perfectly well meaning effort to get it right.
>> Howard Bauchner: Paul, when you hear that now, your obviously your expertise in the development of vaccines, but you are also smart enough to know if it doesn't make it to the patient all the extraordinary scientific advances over the last year are wasted. Do you think we need to try to make it simpler?
>> Paul Offit: Oh definitely. I just think it's -- you know, there's not a clear right way to do it. There is a Sophie's Choice element to this. I mean, you know, it's easy to say, for example, let's start with nursing home residents and staff, because you know, 40% of the deaths were in nursing homes. And clearly vaccinating staff does make a difference. That, in many ways, is an easy decision. And you can -- you know, but when you get to the different gradations say, for example, of physical health, it's, you know, it gets much more subtle and you're -- and a lot of great ideas, and interesting idea, because it's like a lottery for life. I mean, you know, the fact of the matter is, probably 100,000 and maybe 150,000 people are probably going to die over the next two months. What percentage of those had they gotten the vaccine would have their lives saved? Probably most. And yet, we don't have enough vaccines. So this lottery has that sort of Shirley Jackson "The Lottery" feel. Or when I was, you know, when I was coming into college and was part of the lottery for the Vietnam War. I mean I still remember my number. I mean these were like life and death lotteries, which is kind of what this is.
>> Howard Bauchner: So my lottery number for the Vietnam War was 363. I remember it to this day. You obviously remember yours.
>> Paul Offit: 265.
>> Robert Wachter: I'm much younger than you guys. So, I don't have to remember mine.
>> Howard Bauchner: If, now President elect Biden, President Biden as of tomorrow at 12:00, I think, Eastern Standard Time, said 100 million doses in 100 days. That obviously depends on supply. He didn't talk about whether that meant 50 million people vaccinated or 100 million people vaccinated. Let's assume it meant 50 million. There's been about 15 million people already vaccinated. Let's say we get another 15 million vaccinated. So that's 30 million and 50 million. That's 80 million over the next two and a half months. A hundred million people should cover everyone older than 65, I believe. I have to do the math a little more quickly. Where does that get us, Paul? A hundred million, say 50 million people plus the current 30 million. Say we have 80 million people vaccinated in the next two and half months.
>> Paul Offit: Well, ultimately the question you want to answer is percentage of the population needs to be vaccinated in order to stop the spread of this virus. There is a formula for this. It's in the Plotkin's Vaccines book under the Community Immunity.
>> Howard Bauchner: Yeah right, no doubt right.
>> Paul Offit: So without going into the details of it, when you have a highly effective vaccine like these first two mRNA vaccines of 95% efficacy, if you assume that's also close to the level of efficacy at preventing at least a lot of asymptomatic shedding, which I think is likely, although I think it may not prevent asymptomatic shedding. I think it will prevent the immunized person will shed virus less than would the non-immunized person asymptomatically. So let's assume that that 95% is close. And you assume that the 25 million people or so who have said to have been infected in the U.S. or those who have been tested and found to be infected, but when you do antibody surveillance studies, you realize that's off by at least a factor of three and possibly more. But so let's say the 25 million is 70 million. So 70 million people, you're already at 20% of the population. It's immune enough that when they get exposed to this virus they're not likely to get sick. So you're starting with a basic 20%. So then what percent above that would you need to be, to have immunized, or protected, in order to say that you're going to stop spread. If you don't do that formula, you need about 55% to 60% total. So, but remember, we're vaccinating people who have also been infected. So that's going to be 20% of those that are infected. So, I would think that if you can vaccinate say 60, 65 million people with two doses, that I think we can stop the spread of this. And to do that we need to be vaccinating at least a couple million people a day and probably closer to 3 million if we're going to try and stop spread of this virus by the summer.
>> Howard Bauchner: Bob, when you hear those numbers and I was particularly interested in your scheme of older than 75, older than 65, older than 55. And let's say the focus is that 50 or 60 million people, where's the light at the end of the tunnel when you hear the discussions? Is it April? Is it May? Is it June? Not for herd immunity, but where the number of patients at your two facilities will be minimal, or the number of hospitalizations in the U.S. won't be 180,000, but will be 10,00. Is that -- do you think that's May, or June, or July?
>> Robert Wachter: It all depends. It's a numbers game, Howard. So it completely depends on how fast we're getting people vaccinated. And, you know, if you look at the number of people vaccinated versus supply, that difference is beginning to close.
>> Howard Bauchner: Right.
>> Robert Wachter: So we always thought, in December we thought this was just going to be a supply problem. I don't think anybody dreamed -- maybe Paul did, but I did not dream that it was going to be a last mile problem to the degree that it's been. But if you have been tracking those numbers it's gone from about a week ago it was about 28% of the vaccine doses that were out there had been injected. That number is closing in on 50. So, I think we're pretty soon going to get to a point where it truly is a supply problem rather than a last mile getting it into arms problem. Then it's really a matter of, you know, what is the supply and I think probably the biggest factor, or two factors, on is the Biden administration comes in and really pushes on the manufacturing process for the two companies and you know, can they ramp it up at all by involving others to help? But the biggest one is there are going to be one or two more companies in the mix. And if there are one or two more companies in the mix, we could have a substantially increased supply of vaccine available, we may find ourselves then back in the last mile problem again of now trying to distribute four vaccines. And now you got to figure out how to keep it straight, which one you got, and you're going to have another prioritization problem that may be even more complex than the ones we face so far, you know, so I've been asked all the time, you know, "Should I get Moderna or Pfizer?" You know, the answer is you should get whichever one you can get tomorrow. But if now they approve a vaccine that 75% effective, not 95, you're going to see a lot of jockeying about who gets which vaccine and where I go to get the vaccine I really want. So that's a long answer to say it all depends on the numbers and when we can reach -- the reason the 55 cutoff is important is it's about 25% of the U.S. population.
>> Howard Bauchner: OK, I couldn't remember.
>> Robert Wachter: Fifty-five and then represent 92% of the deaths. So if we can get to that group and, you know, it is about 80-90 million people, you know, then plus the healthcare workers and nursing home folks in nursing homes. So it's not inconceivable that we get there by, you know, by April or May and you have decreased the deaths down to about 10%, not zero. But you see the curve, even though you have not reached herd immunity and there's still Covid in the community, you've seen those curves plateau and really begin to come down.
>> Howard Bauchner: Now, Paul, I had Arnold Moreno on last week and he had told me he had mentioned that both of the advisory panel meetings for January were cancelled, which I think meant that there was not yet another EUA application for the committee to consider. And I know, I believe there's two tentative meetings scheduled for February. Is there anything you can say about either of those meetings?
>> Paul Offit: Technically, no. But what I would say is this, I mean we're told, those dates are communicated to us, we're always told to keep them confidential. But I'll say this, we don't -- when we meet, when we are scheduled to meet, there has to be a 15-day advanced notice in the federal register. So, you'll know, a little more than two weeks in advance whenever, because it has to be advanced. Dr. Fauci said, and he's close to the data, he said that for the J&J and AstraZeneca vaccines, he feels that we're going to be hearing those stories in February. So with vaccines likely released then by no later than early March. I think Bob's point about, you know, what to do if there's different efficacy levels, I think the key thing though is efficacy against moderate [inaudible]. I think, what you're trying to do here is keep people out of the hospital and keep them from dying. That's the most important thing. To the degree to which one, one vaccine may not be as good at preventing mild disease, I don't see that as big of an issue. Plus Johnson & Johnson single dose vaccine, obviously that's an advantage. You know, we may be learning about some safety issues with mRNA vaccines that we don't know right now that we may learn over the next few months. So, I mean, so there's always a number of other factors to consider other than that just 95% efficacy. So we'll see.
>> Robert Wachter: Paul, don't you think there is if they come out and the answer is it's 70 efficacious in the trials, I mean how do you think that's going to play out? Because, yes there are nuanced arguments about whether that's still good enough because it actually is 95% effective against severe disease or it's an older technology, something we're more comfortable with. But what people are going to hear, talk about messaging. They're going to hear, "My friend got 95% protected and I'm getting this 70% protective vaccine and I, you know, I'm getting a class B vaccine." How do you think it's going to play out?
>> Paul Offit: Well, it depends on the messaging. I mean let's assume just for argument sake that Johnson & Johnson's vaccine is 85% to 90% effective against moderate to severe disease. I mean that would be part of the messaging. It's a single dose. That's part of the messaging. You can get it. That's a part of the messaging. And it's certainly much easier to transport. You know, when you look, for example, the Pfizer -- especially the Pfizer efficacy trial, I mean that was an efficacy trial right under highly controlled conditions. Now it's out in the real world, this vaccine that has to be shipped on dry ice that has basically a five-day life in the refrigerator and a six-hour life once the rubber stopper is violated. I mean, I'd like to see whether the effectiveness is the same as the efficacy in the real world. So all those things factor in. But we'll see.
>> Howard Bauchner: Yeah. Paul, two quick questions, we mentioned it earlier and it has come in. Moderna adverse reactions in a single facility, if you just can briefly comment on that.
>> Paul Offit: Right, so you're missing the critical piece of information. You know that there were 330,000 doses part of this lot. You know that in one of the many facilities in which it's been -- this vaccine has been distributed there was a problem. The problem is that within 24 hours people had come back with a medical problem. At least it's not clear to me from what I've read and maybe you have more information or Bob has more information on this than I do, that what specifically were those problems? Why was it just one facility? What ended up happening though, the messaging here since that seems to be the theme of this was to withdraw the lot. So the messaging was the hot lot. I mean there has not been a hot lot of vaccines since the Cutter Incident in 1955. I mean that was the birth of consistency lots. I mean these lots are consistent from one lot -- that's what the FDA does best really is to make sure that those productions are consistent. So the notion that this is a bad lot is a bad one. Also, you know, when they withdrew it in a time when we need vaccines and they said we're exercising an abundance of caution, it's not a risk-free choice. I mean over the next six weeks or eight weeks a lot of people are going to die. No doubt some of them who could have gotten this vaccine and we don't even know what these medical problems were. It was just in one facility. I think that was a bad decision, frankly, to take that essentially that off the market.
>> Howard Bauchner: The story in Israel in fascinating. They've reached a much larger percent of their population, I believe, than any country in the world. I mean we're hovering at 3% or 4%, I think as of this morning they're somewhere between 25% and 30%. But now there's been some early reports that they're concerned about how effective the Pfizer vaccine is in their population. And in fact, Paul, this may go to the point you just made. There's a difference in a randomized clinical trial where everything is so closely controlled versus shipping it, de-thawing it, administering it. Do either of you have any sense of what we will learn from Israel?
>> Robert Wachter: I'll let Paul take that, I think.
>> Paul Offit: Right. I think because they're so far ahead of us they're much better organized at getting manufacturing, distributing, getting it out there. I think we will learn a lot. I think that that country will probably be the first to teach us about efficacy both for what the efficacy is with a single dose and then what the efficacy is with the second dose. I think that that's probably the country that's going to teach us the most about what it means to have some delay between that first and second dose. And we'll learn about the effectiveness of a two-dose vaccine in the real world. And that will be valuable information. And we'll learn also about safety, which we constantly have to keep our eyes open to. I mean this is the remember any technology is a novel technology. I think we have to be humble at making sure, at knowing that there may be things we don't know that we're going to learn.
>> Robert Wachter: Yeah, and I'd add that, you know, the most important thing we can learn is logistics. I mean they have figured out how to get vaccines into people's arms, you know, much, much, much faster and better than we have. And I think it's a little too fast, I'll just say, it's just because they're small, because in many ways, you know, we are a big complex country, but much of the allocation is to local jurisdictions. It's to the city and county of San Francisco or to the state of Arkansas. You know, these are relatively small units that in some cases are no bigger than Israel and we are massively behind them. So, you know, I hope the Biden Administration is watching because there's something that they have done in terms of logistics, the messaging, the support that they have given to local districts and regions and hospitals and pharmacies to have the right systems, the right computer systems. This is something we just didn't do. You know, we put a huge amount of energy and resources into developing the vaccine and we just kind of spaced on the last mile problem. And the point Paul has made many, many times is that until it's in people's arms its not doing any good. So I hope we learn lessons not only from Israel, but if you look at the vaccine distribution in the United States, my state, California, has given out about 35% of the vaccines that are currently in freezers. Texas is close to 60%, West Virginia is 70% or 75%. So we should be learning from each other. You know, for better or worse, mostly worse, we're doing 50 natural experiments. We should be learning about what works.
>> Howard Bauchner: Yeah, it's interesting that rural states have generally done better than so-called urban states. Las question to you, Bob, and then I have one last question to you, Paul. Bob, you chair a major Department of Medicine. How has the rollout of vaccines gone at UCSF and then, in the surrounding healthcare facilities in which you provide care, particularly skilled nursing homes?
>> Robert Wachter: I think it's gone extraordinarily well at UCSF and part of my argument with Ashish for a lottery was because we did a version of that. The first thing we did was we divided up our population of our people of people who face, have patient-facing work into four big groups in terms of the amount of potential COVID exposure. And that was a little bit contentious, because the HR systems were not designed to do this. So we had to go in and parch the list. And the buckets were pretty big, 6,000 people in group one, 10,000 people in group two. Once we did that, the allocation then was by a lottery. It was essentially by random choice. So once I was in group one because I was starting on the wards at the hospital less than a few weeks. And once I knew I was in group one I would go to my email everyday and wait for the magic email and I waited about six days. The first person who got his vaccine at UCSF was one of the members of our custodial staff. And I thought that was spectacular. Our CEO of our medical center, our chancellor still had not been vaccinated because they did not come up because they are not doing patient-facing work. So there was a lot of attention to equity. There was a lot of attention to who really needs it. We were religious about, you know, the donors, the VIPs do not get a place in line, do not cut the line. And I think, you know, the quality of the rollout shows a lot about the values of an organization. There were a lot of reports of rollouts in big academic medical centers that went poorly. You probably read about the problems at Stanford where the residents were cut out because of the way the algorithm played out. There were problems at Mass General because it was a first come first serve system and the computer system crashed. There was a big article in the Times about some of the problems in some of the New York hospitals where there was some line cutting. And I don't want to be critical of any of those systems because it turns out to be hard, but what they demonstrated to me is if multi-billion dollar hospitals and health systems trying to vaccinate their own people who have -- they have a robust HR system, robust computer systems and it's this hard, how are we going to make this work when we're trying to vaccinate 300 million people in pharmacies. So it just demonstrates how incredibly complex this is, but I think we did pretty well.
>> Howard Bauchner: Yeah, no, it made me reflect your comment about if we can make at least a criteria simpler, the likelihood of success becomes greater. Paul, the last question to you, the variants. There's now been a number reported. Rochelle asked me not to refer to them by the name of the country, because she worries that it's stigmatizing. I, of course, could never think of the long numbers, but do you just want to comment on the variance and then the variance visa vie the vaccine? And then we'll stop.
>> Paul Offit: All right.
>> Howard Bauchner: And if you know the numbers you can use the numbers. I can't remember the numbers.
>> Paul Offit: All right, so there right now are three variants. One of them was from a country that gave us a T-. I don't know if you remember that.
>> Howard Bauchner: That's good, OK, we can go with that.
>> Paul Offit: We became independent of that country eventually. We won't mention its name. The variant is B117.
>> Howard Bauchner: Thank you.
>> Paul Offit: But the key question, what you want to do is you want to identify these variants as quickly as possible. Well, I think as Bob alluded to earlier, we need to be much better at sequencing these viruses in this country, in our country, and try and duplicate what's happening in the UK where they are much better at sequencing, so that we can identify these variants when they come. But when they come up, what we need to do initially is to see whether or not the sera that are obtained from people who are immunized with these mRNA vaccines neutralize that virus. That's what you need to know. So with that UK variant, what you have is you have, Phil Dormitzer from Pfizer stepping forward and saying we have looked at sera that we obtained from people who were immunized with two doses of Pfizer vaccine. It neutralizes that virus. Good. Now, that should be reassuring. We don't yet really have a clear immunological correlate for protection against disease, but that is reassuring. Then there's this South African variant. And you're going to be hearing about this a lot in the next few days, because I just saw the preprint of this. And so this is what you're going to hear. When they took sera, South Africans took sera and then from people who were convalescing from the infection to see whether or not it neutralized this particular variant, which is different than the UK variant. What they found was that half of the sera didn't neutralize it. So of the 44 sera, or so, that they tested, 22 did not neutralize that virus. Now, there were a handful of sera that did neutralize it completely. Those were the sera that were obtained from people who had more severe disease and had higher titers of neutralizing antibodies in convalescents. So but that's not the critical question. The critical question is does the people who were vaccinated --
>> Howard Bauchner: Vaccinated, right.
>> Paul Offit: Develop it, because the vaccine may induce higher, longer-lasting titers than people who have a convalescent -- who are convalescent, which can have, I think, a broader range, frankly, of neutralizing titers just because they have different levels of disease. So at least the vaccination is always the same, right, 30 micrograms, 30 micrograms, with Pfizer 100 micrograms, 100 micrograms for Moderna. So that's the critical question. That's what you want to see. And I don't understand why it takes us so long to do this. I mean the South African and Brazilian variance were isolated a while ago. Just maybe it's the companies have not been great at either allowing people to look at those sera or testing them themselves. But that's what you want to hear immediately from these companies. Do those sera. polyclonal sera neutralize those variants. Because, what people tend to do is they use monoclonal antibodies because they're available and, you know, then it's more fun, I think for the researcher to see exactly where is that variant, you know, where has it drifted away from the non-variant strain. But what you really want to know is do the neutralizing antibodies generated by vaccination neutralize these viruses. That's what you want to know and we don't know that yet, frankly, for either of these two other variants, the South African or Brazilian. But we will know that. I think we'll know that soon. And then if that's a problem, if it really does just completely escape neutralization by the vaccine, then what you want to see is whether or not vaccinated people are infected with these viruses, because that's really where the -- that's where the proof is in the pudding, because right now we're assuming that the neutralization titers are predictive of whether or not you're protected, but it may be T-helper cells or cytotoxic T-cells. You know, Shane Crotty when he did his work looking at how people recovered from natural infection found that really all three of those neutralizing antibodies, T helper cells, cytotoxic T cells were all important. So that's the ultimate thing. I mean and if that's true, if people who are vaccinated with these mRNA vaccines who are then exposed to these variant viruses get sick, then we're going to have to have essentially a multivalent vaccine strategy where it's not just, for example, one mRNA in there, but it's the mRNA from not the non-variant strains, but also the variant strains. And that's going to be a nightmare.
>> Howard Bauchner: This is Howard Bauchner Editor in Chief of JAMA. What a pleasure. I have been joined by Paul Offit and Paul is a Maurice Hilleman Professor of Vaccinology at Perelman. And Bob Wachter. Bob is a Holly Smith Distinguished Professor in Science and Medicine and the a Benioff Endowed Chair in Hospital Medicine and is often referred to as the "Father of Hospital Medicine." Not the grandfather, Bob. I won't make you that old. Thanks to the two of you for joining me today. It's always a wide ranging and enjoyable conversation. And say healthy, both of you, please.
>> Paul Offit. Thank you. You too, Howard.
>> Robert Wachter: You too, Howard.
>> Howard Bauchner: Bye-bye.
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