Pushkin from Pushkin Industries. This is Deep Background, the show where we explore at the stories behind the stories in the news. I'm Noah Feldman. Regular listeners of this podcast know that we view one of our chief jobs as keeping you updated on the twists and turns of developments relating to COVID, in particular when we seem to be at a confusing or complex juncture point in the process. We are at one of those points now, particularly with respect to the question of boosters. Back in August, the Biden administration announced that by September twentieth they plan to be giving out boosters on a broad scale in the United States. Almost immediately, this announcement met with pushback from senior career scientists, and then from scientists outside the government, and then ultimately from the politically appointed leaders of Scientific Agencias events seem to come to a head in the last week or so, they were dueling articles in different medical journals, the Lancet out of the United Kingdom and the New England Journal of Medicine advising, roughly speaking, different approaches or paths on the booster question. Then an advisory committee of scientists and physicians to the FDA focusing on vaccines, had a public meeting last week to discuss these matters. Meanwhile, this week, a separate advisory committee, also of independent scientists and physicians, that advises the CDC is also expected to weigh in. The upshot is a lot of confusion, certainly for me, but I think also for many people who like me, have been trying to figure out what's going on. To help us walk through this confusion and give us some clear understanding the process and of the opinions, we're turning today to doctor Genevieve Cantor, who is a Research Assistant Professor at the Perilman School of Medicine at the University of Pennsylvania. Doctor Cantor is trained as an economist, which means her central expertise is on the modeling and the measuring of causation, precisely the issues at hand today. Furthermore, her substantive area of expertise includes regulatory policy and the regulation of biomedical technologies, including vaccines, and the relationship between industry, government, politicians, and regulators. In short, doctor Cantor is the perfect person with whom to get some clarity in these very complex waters. Doctor Cantor thank you so much for joining me. Let's start with the underlying fascinating challenge of the science here. Just in the last week, two studies in highly respected places with roughly speaking at least in Layman's terms, contradictory messages about boosters, with the Lancet article suggesting that it's too soon to recommend boosters for people other than the oldest and the most infirm, and then the new England Journal study relying on Israel data suggesting that boosters had a substantially helpful effect for the part of the population that was studied. There. What is a reasonable person to think, right, So, the way it would interpret these two new papers is that the Journal article reports on one particular case, which certainly compelling case in Israel, where Israel launched its third vaccination campaign involving boosters, and in that study they staggered their role out, initially targeting the sixty plus population, eventually reaching the younger population. They found that administering boosters to the oldest population did reduce infections as well as severe disease and hospitalizations. That's pretty compelling evidence. And although there are some critiques that can be made of that study, which I'm happy to go into in general. This was a study that was presented, as you may know, during last week's Friday's f Day Advisory Committee meeting, and on the whole, that committee found that study to be compelling. The Lancet paper, I would say it doesn't present new information, As you said, it's sort of a study of studies. I might actually even just say that it's more of a framework, a holistic framework how we might consider the various pieces of data that we're seeing to justify boosters. It addresses do we know whether there's a need at all, is it greater among certain populations? How can we interpret some of that observational data. It also talks about considerations in terms of what impact that booster shot would have on either severe disease and hospit realizations or on infections. Those are two very distinct and important things. So I would consider that less a summary of the existing knowledge, but more of here the considerations we need to take into account. And perhaps there are also some political purposes behind that article, which I'm happy to also get into. Well, we need to talk about the political purposes, but again I'm trying to the extent we can and it's always hard here, and that's one of the reasons this topic is so fascinating to differentiate the policy, the regulatory component, and the scientific component, and they're intertwined. In my reading of the Lancet it sounded to me as though they were making a pretty substantive policy point, namely, do not jump from the Israeli data, which they had seen preliminary versions of, to concluding that we should go out in the United States and approve boosters for a wide swath of the population, which the Biden administration had already done weeks ago, now saying by September twentieth they hoped to start approving boosters. And so that's a huge practical difference. And just another piece of detail there that seems salient to me is that the Lancet study also questioned the israel data, not the version that was published a couple of days later, but their preliminary version, by pointing to some potential methodological flaws in that Israel's study, not that they were flaws in the way the study was done, but just in the data that was available at the time, namely that it was a relatively short period of time that was being studied after vaccination, and the fact that they bothered to do that in the Lancet study sent to me the message that this is really about two approaches to boosters, one approach saying full steam ahead, the one that the Biden administration had originally taken and now seems to be backpedeling from, and the other the more cautious Let's wait and see. Let's not acclimate the public to thinking that it needs boosters all the time the public lose faith in the phenomenology, in the phenomenon of boosters, Let's be sure that the data really bear it out. And let's not forget that if we have extra doses for boosters, maybe we should be using those to send them all around the world rather than using them in the US on third doses. So I guess I want to ask, am I overreading this? I mean, is it unfair to say, as I am basically saying from a late person's perspective that it seems like they're two pretty opposed of viewpoints here. I might take the view that it is possible for those who want to push forward to see more evidence that might convince them otherwise. You know, one of the really surprising things that came out of that statement that was issued by those political appointees and including the Acting Commissioner of the FDA, CDC director, US Surgeon General and IH and so on, is that it's not clear that they had all the information that say, you know, the FDA Advisory Committee in its review process did and I guess I'm up the view that what the Lansward article was doing was trying to present additional information that might inform you, if you want to characterize it, Oh, here's an opposing view of full speed ahead, sort of saying, hey, here are some additional considerations you might not have thought about. I think one of the most interesting things that came out of the Advisory Committee on Friday, in case you didn't have the time to watch all eight hours of it, was to highlight that one of the pieces of evidence that Fiser presented as justifying the need for boosters, they had not made that data available to the FDA to review. This was one concern that was highlighted in the lanswerd article, and it is a concern that maybe those who made the political pointies that made the decision to have a plan to set a date and to go ahead with it may not have fully taken into account. That was very helpful. I think it would be helpful for me and possibly for listeners to march through for a moment all of the different actors who have been involved in this, because in preparation for our conversation, I made myself a little chart, and I was myself kind of mind blown by just how many actors are involved right now. So let's take a half step back. First of all, you've got the White House, which has the authority to say what it plans to do, but not in every case the full authority to order the FDA or the CDC to dirt and do certain things, because there's a complex regulatory procedure a law that they would have to follow. So when they say they're going to do something, what they mean is we hope this will happen, not we can order even our political appointees at the FDA to approve things. If it were otherwise than Donald Trump, you could have ordered and probably would have ordered, the FDA and the CDC to do all sorts of things independent of the science. So there's the White House. Then there's the f which is in charge of formal approvals of new vaccines or new uses for vaccines, and is also authorized to issue emergency use authorizations. Then there are career scientists as opposed to political appointees within the FDA and the Centers for Disease Control. And then last, but not least, there is an Advisory Committee on vaccines that advises the FDA that's made up of outside physicians and scientists. And in the last week it seems like all of these actors have been doing things right. There was this meeting of the FDA Advisory Committee that's the committee of outsiders. But then there was a public statement from a whole bunch of political appointees that itself seemed to push a little bit against the Biden administration. And then the Biden administration itself, through a spokesperson, said well, we were always planning to follow the science and we will continue to follow the science. But they, of course had been criticized for being out ahead of the science on these things. So I guess let me start by asking have I left out any important actors here? And since you study this process for a living, how do you think about the different actors here? And they're different roles because this is one of those instances where the distribution of political authority and regulatory authority has huge practical implications for us on a day to day basis. It's going to determine whether we're going to get shots in our arms or not, and who's going to get them, you know. To add more fun to the mix, I would actually add two other entities that are parallel to what you mentioned with the FDA, So the CDC because we're talking about infectious diseases and vaccines in particular, as well as its advisory committee, the ACIP, which is the Advisory Committee on Immunization Practices. So yes, so they're all interacting. I have the feeling in China, where they've vaccinated a billion people, they don't have six different is pushing against each other. That's right. They either don't or they do, but it's all behind the scenes, and then they issue a single statement that everyone nods and agrees. In this case, and I think it is an unusual case of the interaction between the FDA and the CDC because a of the particular condition which is infectious, and secondly because of vaccines being the issue here as opposed to therapeutics, where then FDA would have full authorization for the regulation. And actually one thing we've one entity we've also forgotten are the drug companies or the manufacturers themselves issuing these vaccines. So boy, in terms of summarizing how they all fit together, you know, we have a vaccine manufacturer, in this case Viser. They have a product of vaccine that's been approved and so they submitted that application to the FDA. The FDA can make a decision on that application, with or without the Advisory Committee consultation. In this case, they've chosen to do that, and in general that's considered a good thing. It's generally more transparent. Probably perceived it correctly as being less political because these are outside experts, they're independent, and they can give the recommendation to the FDA. So I would say that's one part of this process that's a little unusual as well. The FDA doesn't always send applications to the Advisory Committee. In fact, you know, our study which covered about twenty years of vaccine licensure history, showed that about the half of all new vaccine applications are actually sent to the Advisory Committee. But Steve Hahn, you know, when he was Commissioner, made a commitment to say everything involving COVID would go to the Advisory Committee. So that's been a big and i think helpful change. So what happened last week the Advisory Committee for the FDA men, they gave their recommendations, which I'm sure we'll go into. The FDA then has to make a decision based on the recommendations of the Advisory Committee. Most of the time seventy five percent of the time they do follow those recommendations, but sometimes significantly they do not. They issue that recommendation for the conditions under which the vaccine is able to be administered. Advisor can market that product. After that, the Advisor Committee to the CDC, which is ACIP, convenes, uses its own information, which includes what the FDA saw but also actually includes other types of data issues its recommendation, and then the CDC can decide to follow it or not. Whatever the decides is generally considered vaccine policy for this particular vaccine. After that, then the White House comes in and to the extent that they can execute a plan for distribution help the states to do so. That's where their authority lies. So the statement was highly highly unusual. They statement they issued in August about we have a plan and by the way, we're going to execute at September twentieth. Yes, the White statement, that's right, and we have a plan. We're going to execute it on September twentieth, before the FDA Advisory Committee has reviewed it, before the FDA it's made its decision, before the CDC Advisory Committee has reviewed it, before the CDC has made its recommendation. That's highly unusual. And yes, so that is an anomaly in the typical process. That was wildly helpful. I feel like I know a lot more than when I started. Before we turn to the advisory committee's opinion. I actually now have to pause to ask you, is this process a good process? I mean that is to say, it may be a great process under ordinary circumstances where time is not of the essence, where time is of the essence. Is this very elaborate, complex, multi step process really value adding or is it primarily just about protecting us from an administration whether Biden's or Trumps that just says this is what we're doing and here's how we're doing it, without listening to the scientists. I do believe that process is important and that this particular process, which respects external expert independent advice through the formal process of advisory committees is almost indispensable, especially under these circumstances where public trust is important. Can I just pause there for one second, Jenny, because I totally agree the contradictory messages, or let's call them to be more polite messages in tension with each other, even though, as I just explained, I think their contradictory I think those are undercutting public trust. I think if you want public trust, you want the leading regulatory authorities and the scientists to speak publicly to the extent possible with one voice. It takes a very sophisticated public to say, well, there's real disagreement among epidemiologists and statisticians and scientists, and therefore I really trust this process because they're disagreeing with each other writing the public eye. I mean hard to imagine that in real life, very many actual people have such a worldly, sophisticated conception of the value of this kind of disagreement. So the alternative that you're proposing is, well, do it behind closed doors, you know, have the input, have a more streamlined process, or at least under emergency conditions have a more streamline process, so that what the public hears is the US government is recommending boosters, or the US government is not recommending boosters. I'm not recommending that. I'm raising that as an alternative. And you yourself mentioned that, you know, in the Chinese system, there of course is internal disagreement, but it's mostly behind closed doors. But then the government does speak with a single voice. It is interesting that you're saying that this chaotic process, the way it's played out in the public, at least in recent times, has ledged you or conjecture that public trust is diminishing. You know. My read of the issue is that really the tension is between the White House and it's political or partisan motives versus the scientists FDA, CDC, and IH and so on. And so I read the Lancet article as saying, especially since it was written by two career scientists who are resigning, as sort of a signal saying, you know, we had thought that this political risk that we experienced in the previous administration was over, and perhaps in its extreme form it is. But you know, there are also political risks here, and we'd like to raise this issue and also set out a framework for what we think should be driving the scientific decision as opposed to whatever is driving the White House action. We'll be right back. So now you've offered a kind of master interpretation of what's going on here for me and for listeners. So let me say it back to you, and to make sure that I'm hearing what you're saying correctly. What I think I hear you saying is actually, although there are lots of different actors here, what really matters is there two voices. There's the White House, which is elected politicians and the people who work for them, who said in August we're gonna get boosters out there on September twentieth, because we've heard some early reports from Israel that seemed like boosters are a good idea, so we're doing it. They wanted to get out ahead of it, and then fairly, unifically, fairly with one voice, the senior scientists within the government and the senior scientists outside the government who advised the government are saying in response, WHOA not the right move, don't do it right away, Maybe only do it for the oldest and potentially sickest people. We're going to have to follow a process here, and that's way these things should be done. And as you're adding, we thought we had to deal with this kind of thing from the Trump people, We never imagine we'd have to deal with it from the Biden people. And in that context, this Lancet article, which as you point out, was written by two senior career scientists who announced just before the article came out that they would be quote unquote retiring, which effectively means resigning, was a kind of way of saying to the White House, we can't work with you, guys. You know we're gonna We're willing to go down with the ship in order to stand up for the processes of science. And if that's the interpretation that you're saying, that's very clarifying. It's also reassuring. It basically suggests that is to say, at least, it's reassuring if you trust the scientists, that the scientists are saying, slow down, and they will probably win. I mean, we can talk about that in a moment too, but it seems like they will probably win. Since the public statement by the advisory body to the FDA did seem very much to be in line with the Lancet article written by among there's these two senior career scientists. It is my hope that the scientific process will work itself out. And it's even more compelling that these external career scientists, Marin Gruber and Phil Krause were at the FDA meeting, the Advisor Committee Meeting's what they said to tell us what they said. Sure, there are two aspects of the booster decision. One is to establish the claim that the protection from the initial series of two doses is diminishing, and the second is a booster shot of the same dose, the same vaccine six months later will be effective in increasing protection. So there are issues actually with both of those claims, and so that's why the Advisor Committee sort of, if you like, split the baby the way they did so. In terms of establishing the need for boosters, you would think this would be pretty straightforward, you know, the measures that we are most interested in, is the protection from severe disease and hospitalization and death diminishing over time, and is it losing its ability to protect against infection and to establish the need both basically, what we've what Feiser has appealed to, in general, what people supporting boosters have appealed to, are these observational studies that have tracked people who got the vaccine and compared them to people who didn't, and have we seen over time and increase in hospitalizations and severe disease, increase in infections. Now, as it happens, we did, you would think that, you know, you can do a straightforward inference, but it turns out there comes some complicating factors. The two big complicating factors are one, at the same time that you're seeing increase in hospitalizations in cases, you're also seeing the emergence of the delta variant. So you know, are we seeing these increase in hospitalizations because of the delta variant where the vaccine may not be as effective, or because the protection conferred by the vaccine is waning? But connection about So this is the part really, I think where you're getting to now, where the rubber really meets the road. There is this data that suggests inferentially that even against delta, you get reduced hospitalizations and reduced severity of illness, at least in the older population by adding the booster. So even though I hear you when you say that it might be delta that's doing it, I would have thought that it wouldn't and that sounds plausible. I would have thought that that wouldn't matter if we know that even under conditions of delta we get some reduction. So what's wrong with that straightforward inference? Why is it such an implausible inference to say, look, we've got this. It's only one study, but it's a relatively powerful study with highly statistically significant results. And if we know from that study that there were substantial reductions and hospitalization and severe illness in that older population, why wouldn't we just make the inference even knowing that the inference isn't absolutely perfect and that there could be some confounding elements and that delta may play a role. Why does that matter? If the efficacy seems to be improved even against delta, this is a great, great point we can make that inference. And the question is for whom can we make that inference? Is it for the older population where the evidence seems strongest. There does seem to be a lot of evidence for the older population seventy five plus sixty plus that it is protective against both non delta and delta variants. There are two additional factors here. One is, if we want to extend it to the sixteen to sixty five. They're the evidence is less clear in terms of the actual effect. The second thing, and this is where we get into the scientific weeds on this is when you get a vaccine, there are two immune responses that are elicited. One is more of a short term immune response that's mediated by antibodies, and then there may also be and one hopes there is a longer term immune response which is cell mediated, so not antibody mediated, but cellular mediated that tends to be later on. Takes a while for these cells to get going and to be generated, but it is much much more durable now when we see the evidence presented by fiz Or, which is actually depended a lot on this huge Kaiser population that they tracked, as well as their clinical trial which focus only on antibodies, not on the memory cells, which are more of a measure of the during protection, they saw antibodies declining. Now this is not at all surprising. After a month or so, your antibodies will decline, but it does not mean that the protection has actually decreased, because at the same time your cellular immunity is ramping up. And so that was also one of the issues is okay, the antibodies are declining, but that may not be what we really care about. We care about durable immunity, which is mediated by cells. Fiser did not present that information. The other reason cellular immunity is important is that that also varies. Going back to the original question, you know, to whom can we make these inferences about protection? And so it is entirely possible that we saw the boost response and that's based on antibody measures. We saw that, and that antibody response it's helpful in populations that don't have a particularly strong cellular response, and those particular populations are the immunocompromised. And that was the reason the FDA approved the use of the booster for immune compromise, you know, last month, and also sell you your immunity may be weakened in the elderly as well as those at risk of SEVERITYDS, those who have commor conditions, those who abies, and so on. So that's really the justification. And so you know, I think the median, at least the latest version of the study had a median follow up time of about two and a half months. So is it fair to say then that if that data, that two and a half month data were extended to say four months or five months, are we then going to see all of these scientists who were saying slow down, slow down. Are they just going to say, Okay, we asked you to slow down, Now you slow down. We're happy you slow down. Now the data extrapolates, now go ahead and approve boosters for I don't know, twenty five and up, thirty five and forty and up. Is that really what's going on here? Mean? Is this really just a question of speed, because there doesn't seem like there's any data actively suggest thing that it would be a bad idea to get the boosters. It's just that it seems like the scientists are saying, don't jump to the conclusion before we fully work through everything. So fair enough, I get the point. But in the future, if this data extrapolates, are we then going to have boosters a standard? So I would say no. I mean, on the one hand, that is a sentiment that is expressed that we just need more information. It's actually too premature to make a decision. I would say that there are a couple of additional considerations. So one is this is still the sixty plus population, we would have to keep an eye on the younger population. And there you know, the reason the age changes the calculus is that the older you are, the more benefit from protection against severe disease that you get from the vaccine. The younger you are, you know you're likely to have something mild asymptomatic, but the vaccine you may be at increased risk. And we saw this with young males increased risk of myocarditis. So that risk benefit calculation changes for the young population, so it's not simply an extension. The second factor is that people are still waiting to see what's happening with breakthrough infections. There are people who feel that some aspects of the Israeli situation actually don't really apply to the United States very well. And one aspect is that Israel, to its credit, has been amazing in its immunization coverage, you know, ninety five percent of sixty and older, and so the hospitalizations, the severe cases that they're seeing are actually primarily breakthrough infections of those who have been fully vaccinated. That is not the case in the US. In the US, most of the hospitalizations are from those who are unvaccinated. So we're seeing something very different, And so the question is are we better off just incrementally giving to dose people an additional boost in general if you wanted to expend it to the population where it will have sort of a marginal effect but some increased risk, versus targeting the unvaccinated, where you might have just a greater marginal return. Jenny, I want to just thank you for helping us walk through some very complicated waters, and your mastery, both of the science and of the complexity of the regulatory side is just it's a god send to us. So thank you very very much for your time and for your terrific work. Thank you so much for having me and for digging into these really important issues. We'll be right back. I am happiest here on deep background when I walk into an interview with a lot of confusion at a lot of questions, and I feel that the guests that we're talking to that week is able to guide me through the thicket and help me get much greater clarity. This conversation with doctor Genevieve Cantor was to me a model of that kind of improvement. Listening to Jenny, a clear narrative emerged of the way that the scientific community, both inside the government and outside, has been responding to the Biden administration's aggressive push to move in the direction of many boosters for many people very quickly. What I heard from Jenny is that the scientists think that this process is just going too quickly and is relying on a rapid mode inference from a relatively limited amount of data drawn from Israel on an older population to conclude prematurely that we all ought to be getting boosters as fast as possible. It's not only that the scientists think that the Biden administration moved too fast. It's also that they were frustrated that this administration, which pledges to follow the science, was actually out ahead of the science, substantially ahead of the science. As a consequence, the scientists are pushing or a slowdown for the gathering of more information and for the gathering of more data. The particular issue on which the focus seems to be most precisely is the question of whether the boosters are actually going to be very helpful in preventing serious disease and hospitalization in the population that isn't immunocompromised and isn't much older. That is to say, the population that is capable of having its body and its own immune system respond well in the wake of two shots and eventually be able to prevent disease in its more aggressive forms. Jenny also made the point that it may well be that none of the vaccines that we presently have are going to do a very good job against the possibility of passing along COVID. Rather, what they do a good job of, and they do a terrific job so far, is preventing serious illness and hospitalization. If that's the goal, then that is what we need to measure, and we need to measure it in a broader part of the population, not only among those who have weaker immune systems the way that older people statistically tend to do. It follows, says Jenny, that we should not assume that the data that exists will necessarily extrapolate to draw the conclusion that we should broadly have boosters for all that, truly, she says, remains to be seen. Will continue to watch this ongoing story here on deep background, will look for the CDC Advisory Committee's reports in the middle of this week, and I promise you that as this issue plays itself out and we get greater clarity on the Biden administration's overall policy and approach to boosters. We will revisit the issue for you here on Deep Background. Until the next time I speak to you. Breathe deep, think, deep thoughts, and booster or otherwise try to have a little fun. Deep Background is brought to you by Pushkin Industries. Our producer is Mola Board, our engineer is Ben Tolliday, and our showrunner is Sophie Crane mckibbon. Editorial support from noahm Osband. Theme music by Luis Gara at Pushkin. Thanks to Mia Lobell, Julia Barton, Lydia, Jean Coott, Heather Faine, Carlie Migliori, Maggie Taylor, Eric Sandler, and Jacob Weissberg. You can find me on Twitter at Noah R. Feldman. I also write a column from Bloomberg Opinion, which you can find at Bloomberg dot com slash Feldman. To discover Bloomberg's original slate of podcasts, go to Bloomberg dot com slash podcasts, and if you liked what you heard today, please write a review or tell a friend. This is Deep Background.

Pushkin from Pushkin Industries. This is Deep Background, the show where we explore at the stories behind the stories in the news. I'm Noah Feldman. Regular listeners of this podcast know that we view one of our chief jobs as keeping you updated on the twists and turns of developments relating to COVID, in particular when we seem to be at a confusing or complex juncture point in the process. We are at one of those points now, particularly with respect to the question of boosters. Back in August, the Biden administration announced that by September twentieth they plan to be giving out boosters on a broad scale in the United States. Almost immediately, this announcement met with pushback from senior career scientists, and then from scientists outside the government, and then ultimately from the politically appointed leaders of Scientific Agencias events seem to come to a head in the last week or so, they were dueling articles in different medical journals, the Lancet out of the United Kingdom and the New England Journal of Medicine advising, roughly speaking, different approaches or paths on the booster question. Then an advisory committee of scientists and physicians to the FDA focusing on vaccines, had a public meeting last week to discuss these matters. Meanwhile, this week, a separate advisory committee, also of independent scientists and physicians, that advises the CDC is also expected to weigh in. The upshot is a lot of confusion, certainly for me, but I think also for many people who like me, have been trying to figure out what's going on. To help us walk through this confusion and give us some clear understanding the process and of the opinions, we're turning today to doctor Genevieve Cantor, who is a Research Assistant Professor at the Perilman School of Medicine at the University of Pennsylvania. Doctor Cantor is trained as an economist, which means her central expertise is on the modeling and the measuring of causation, precisely the issues at hand today. Furthermore, her substantive area of expertise includes regulatory policy and the regulation of biomedical technologies, including vaccines, and the relationship between industry, government, politicians, and regulators. In short, doctor Cantor is the perfect person with whom to get some clarity in these very complex waters. Doctor Cantor thank you so much for joining me. Let's start with the underlying fascinating challenge of the science here. Just in the last week, two studies in highly respected places with roughly speaking at least in Layman's terms, contradictory messages about boosters, with the Lancet article suggesting that it's too soon to recommend boosters for people other than the oldest and the most infirm, and then the new England Journal study relying on Israel data suggesting that boosters had a substantially helpful effect for the part of the population that was studied. There. What is a reasonable person to think, right, So, the way it would interpret these two new papers is that the Journal article reports on one particular case, which certainly compelling case in Israel, where Israel launched its third vaccination campaign involving boosters, and in that study they staggered their role out, initially targeting the sixty plus population, eventually reaching the younger population. They found that administering boosters to the oldest population did reduce infections as well as severe disease and hospitalizations. That's pretty compelling evidence. And although there are some critiques that can be made of that study, which I'm happy to go into in general. This was a study that was presented, as you may know, during last week's Friday's f Day Advisory Committee meeting, and on the whole, that committee found that study to be compelling. The Lancet paper, I would say it doesn't present new information, As you said, it's sort of a study of studies. I might actually even just say that it's more of a framework, a holistic framework how we might consider the various pieces of data that we're seeing to justify boosters. It addresses do we know whether there's a need at all, is it greater among certain populations? How can we interpret some of that observational data. It also talks about considerations in terms of what impact that booster shot would have on either severe disease and hospit realizations or on infections. Those are two very distinct and important things. So I would consider that less a summary of the existing knowledge, but more of here the considerations we need to take into account. And perhaps there are also some political purposes behind that article, which I'm happy to also get into. Well, we need to talk about the political purposes, but again I'm trying to the extent we can and it's always hard here, and that's one of the reasons this topic is so fascinating to differentiate the policy, the regulatory component, and the scientific component, and they're intertwined. In my reading of the Lancet it sounded to me as though they were making a pretty substantive policy point, namely, do not jump from the Israeli data, which they had seen preliminary versions of, to concluding that we should go out in the United States and approve boosters for a wide swath of the population, which the Biden administration had already done weeks ago, now saying by September twentieth they hoped to start approving boosters. And so that's a huge practical difference. And just another piece of detail there that seems salient to me is that the Lancet study also questioned the israel data, not the version that was published a couple of days later, but their preliminary version, by pointing to some potential methodological flaws in that Israel's study, not that they were flaws in the way the study was done, but just in the data that was available at the time, namely that it was a relatively short period of time that was being studied after vaccination, and the fact that they bothered to do that in the Lancet study sent to me the message that this is really about two approaches to boosters, one approach saying full steam ahead, the one that the Biden administration had originally taken and now seems to be backpedeling from, and the other the more cautious Let's wait and see. Let's not acclimate the public to thinking that it needs boosters all the time the public lose faith in the phenomenology, in the phenomenon of boosters, Let's be sure that the data really bear it out. And let's not forget that if we have extra doses for boosters, maybe we should be using those to send them all around the world rather than using them in the US on third doses. So I guess I want to ask, am I overreading this? I mean, is it unfair to say, as I am basically saying from a late person's perspective that it seems like they're two pretty opposed of viewpoints here. I might take the view that it is possible for those who want to push forward to see more evidence that might convince them otherwise. You know, one of the really surprising things that came out of that statement that was issued by those political appointees and including the Acting Commissioner of the FDA, CDC director, US Surgeon General and IH and so on, is that it's not clear that they had all the information that say, you know, the FDA Advisory Committee in its review process did and I guess I'm up the view that what the Lansward article was doing was trying to present additional information that might inform you, if you want to characterize it, Oh, here's an opposing view of full speed ahead, sort of saying, hey, here are some additional considerations you might not have thought about. I think one of the most interesting things that came out of the Advisory Committee on Friday, in case you didn't have the time to watch all eight hours of it, was to highlight that one of the pieces of evidence that Fiser presented as justifying the need for boosters, they had not made that data available to the FDA to review. This was one concern that was highlighted in the lanswerd article, and it is a concern that maybe those who made the political pointies that made the decision to have a plan to set a date and to go ahead with it may not have fully taken into account. That was very helpful. I think it would be helpful for me and possibly for listeners to march through for a moment all of the different actors who have been involved in this, because in preparation for our conversation, I made myself a little chart, and I was myself kind of mind blown by just how many actors are involved right now. So let's take a half step back. First of all, you've got the White House, which has the authority to say what it plans to do, but not in every case the full authority to order the FDA or the CDC to dirt and do certain things, because there's a complex regulatory procedure a law that they would have to follow. So when they say they're going to do something, what they mean is we hope this will happen, not we can order even our political appointees at the FDA to approve things. If it were otherwise than Donald Trump, you could have ordered and probably would have ordered, the FDA and the CDC to do all sorts of things independent of the science. So there's the White House. Then there's the f which is in charge of formal approvals of new vaccines or new uses for vaccines, and is also authorized to issue emergency use authorizations. Then there are career scientists as opposed to political appointees within the FDA and the Centers for Disease Control. And then last, but not least, there is an Advisory Committee on vaccines that advises the FDA that's made up of outside physicians and scientists. And in the last week it seems like all of these actors have been doing things right. There was this meeting of the FDA Advisory Committee that's the committee of outsiders. But then there was a public statement from a whole bunch of political appointees that itself seemed to push a little bit against the Biden administration. And then the Biden administration itself, through a spokesperson, said well, we were always planning to follow the science and we will continue to follow the science. But they, of course had been criticized for being out ahead of the science on these things. So I guess let me start by asking have I left out any important actors here? And since you study this process for a living, how do you think about the different actors here? And they're different roles because this is one of those instances where the distribution of political authority and regulatory authority has huge practical implications for us on a day to day basis. It's going to determine whether we're going to get shots in our arms or not, and who's going to get them, you know. To add more fun to the mix, I would actually add two other entities that are parallel to what you mentioned with the FDA, So the CDC because we're talking about infectious diseases and vaccines in particular, as well as its advisory committee, the ACIP, which is the Advisory Committee on Immunization Practices. So yes, so they're all interacting. I have the feeling in China, where they've vaccinated a billion people, they don't have six different is pushing against each other. That's right. They either don't or they do, but it's all behind the scenes, and then they issue a single statement that everyone nods and agrees. In this case, and I think it is an unusual case of the interaction between the FDA and the CDC because a of the particular condition which is infectious, and secondly because of vaccines being the issue here as opposed to therapeutics, where then FDA would have full authorization for the regulation. And actually one thing we've one entity we've also forgotten are the drug companies or the manufacturers themselves issuing these vaccines. So boy, in terms of summarizing how they all fit together, you know, we have a vaccine manufacturer, in this case Viser. They have a product of vaccine that's been approved and so they submitted that application to the FDA. The FDA can make a decision on that application, with or without the Advisory Committee consultation. In this case, they've chosen to do that, and in general that's considered a good thing. It's generally more transparent. Probably perceived it correctly as being less political because these are outside experts, they're independent, and they can give the recommendation to the FDA. So I would say that's one part of this process that's a little unusual as well. The FDA doesn't always send applications to the Advisory Committee. In fact, you know, our study which covered about twenty years of vaccine licensure history, showed that about the half of all new vaccine applications are actually sent to the Advisory Committee. But Steve Hahn, you know, when he was Commissioner, made a commitment to say everything involving COVID would go to the Advisory Committee. So that's been a big and i think helpful change. So what happened last week the Advisory Committee for the FDA men, they gave their recommendations, which I'm sure we'll go into. The FDA then has to make a decision based on the recommendations of the Advisory Committee. Most of the time seventy five percent of the time they do follow those recommendations, but sometimes significantly they do not. They issue that recommendation for the conditions under which the vaccine is able to be administered. Advisor can market that product. After that, the Advisor Committee to the CDC, which is ACIP, convenes, uses its own information, which includes what the FDA saw but also actually includes other types of data issues its recommendation, and then the CDC can decide to follow it or not. Whatever the decides is generally considered vaccine policy for this particular vaccine. After that, then the White House comes in and to the extent that they can execute a plan for distribution help the states to do so. That's where their authority lies. So the statement was highly highly unusual. They statement they issued in August about we have a plan and by the way, we're going to execute at September twentieth. Yes, the White statement, that's right, and we have a plan. We're going to execute it on September twentieth, before the FDA Advisory Committee has reviewed it, before the FDA it's made its decision, before the CDC Advisory Committee has reviewed it, before the CDC has made its recommendation. That's highly unusual. And yes, so that is an anomaly in the typical process. That was wildly helpful. I feel like I know a lot more than when I started. Before we turn to the advisory committee's opinion. I actually now have to pause to ask you, is this process a good process? I mean that is to say, it may be a great process under ordinary circumstances where time is not of the essence, where time is of the essence. Is this very elaborate, complex, multi step process really value adding or is it primarily just about protecting us from an administration whether Biden's or Trumps that just says this is what we're doing and here's how we're doing it, without listening to the scientists. I do believe that process is important and that this particular process, which respects external expert independent advice through the formal process of advisory committees is almost indispensable, especially under these circumstances where public trust is important. Can I just pause there for one second, Jenny, because I totally agree the contradictory messages, or let's call them to be more polite messages in tension with each other, even though, as I just explained, I think their contradictory I think those are undercutting public trust. I think if you want public trust, you want the leading regulatory authorities and the scientists to speak publicly to the extent possible with one voice. It takes a very sophisticated public to say, well, there's real disagreement among epidemiologists and statisticians and scientists, and therefore I really trust this process because they're disagreeing with each other writing the public eye. I mean hard to imagine that in real life, very many actual people have such a worldly, sophisticated conception of the value of this kind of disagreement. So the alternative that you're proposing is, well, do it behind closed doors, you know, have the input, have a more streamlined process, or at least under emergency conditions have a more streamline process, so that what the public hears is the US government is recommending boosters, or the US government is not recommending boosters. I'm not recommending that. I'm raising that as an alternative. And you yourself mentioned that, you know, in the Chinese system, there of course is internal disagreement, but it's mostly behind closed doors. But then the government does speak with a single voice. It is interesting that you're saying that this chaotic process, the way it's played out in the public, at least in recent times, has ledged you or conjecture that public trust is diminishing. You know. My read of the issue is that really the tension is between the White House and it's political or partisan motives versus the scientists FDA, CDC, and IH and so on. And so I read the Lancet article as saying, especially since it was written by two career scientists who are resigning, as sort of a signal saying, you know, we had thought that this political risk that we experienced in the previous administration was over, and perhaps in its extreme form it is. But you know, there are also political risks here, and we'd like to raise this issue and also set out a framework for what we think should be driving the scientific decision as opposed to whatever is driving the White House action. We'll be right back. So now you've offered a kind of master interpretation of what's going on here for me and for listeners. So let me say it back to you, and to make sure that I'm hearing what you're saying correctly. What I think I hear you saying is actually, although there are lots of different actors here, what really matters is there two voices. There's the White House, which is elected politicians and the people who work for them, who said in August we're gonna get boosters out there on September twentieth, because we've heard some early reports from Israel that seemed like boosters are a good idea, so we're doing it. They wanted to get out ahead of it, and then fairly, unifically, fairly with one voice, the senior scientists within the government and the senior scientists outside the government who advised the government are saying in response, WHOA not the right move, don't do it right away, Maybe only do it for the oldest and potentially sickest people. We're going to have to follow a process here, and that's way these things should be done. And as you're adding, we thought we had to deal with this kind of thing from the Trump people, We never imagine we'd have to deal with it from the Biden people. And in that context, this Lancet article, which as you point out, was written by two senior career scientists who announced just before the article came out that they would be quote unquote retiring, which effectively means resigning, was a kind of way of saying to the White House, we can't work with you, guys. You know we're gonna We're willing to go down with the ship in order to stand up for the processes of science. And if that's the interpretation that you're saying, that's very clarifying. It's also reassuring. It basically suggests that is to say, at least, it's reassuring if you trust the scientists, that the scientists are saying, slow down, and they will probably win. I mean, we can talk about that in a moment too, but it seems like they will probably win. Since the public statement by the advisory body to the FDA did seem very much to be in line with the Lancet article written by among there's these two senior career scientists. It is my hope that the scientific process will work itself out. And it's even more compelling that these external career scientists, Marin Gruber and Phil Krause were at the FDA meeting, the Advisor Committee Meeting's what they said to tell us what they said. Sure, there are two aspects of the booster decision. One is to establish the claim that the protection from the initial series of two doses is diminishing, and the second is a booster shot of the same dose, the same vaccine six months later will be effective in increasing protection. So there are issues actually with both of those claims, and so that's why the Advisor Committee sort of, if you like, split the baby the way they did so. In terms of establishing the need for boosters, you would think this would be pretty straightforward, you know, the measures that we are most interested in, is the protection from severe disease and hospitalization and death diminishing over time, and is it losing its ability to protect against infection and to establish the need both basically, what we've what Feiser has appealed to, in general, what people supporting boosters have appealed to, are these observational studies that have tracked people who got the vaccine and compared them to people who didn't, and have we seen over time and increase in hospitalizations and severe disease, increase in infections. Now, as it happens, we did, you would think that, you know, you can do a straightforward inference, but it turns out there comes some complicating factors. The two big complicating factors are one, at the same time that you're seeing increase in hospitalizations in cases, you're also seeing the emergence of the delta variant. So you know, are we seeing these increase in hospitalizations because of the delta variant where the vaccine may not be as effective, or because the protection conferred by the vaccine is waning? But connection about So this is the part really, I think where you're getting to now, where the rubber really meets the road. There is this data that suggests inferentially that even against delta, you get reduced hospitalizations and reduced severity of illness, at least in the older population by adding the booster. So even though I hear you when you say that it might be delta that's doing it, I would have thought that it wouldn't and that sounds plausible. I would have thought that that wouldn't matter if we know that even under conditions of delta we get some reduction. So what's wrong with that straightforward inference? Why is it such an implausible inference to say, look, we've got this. It's only one study, but it's a relatively powerful study with highly statistically significant results. And if we know from that study that there were substantial reductions and hospitalization and severe illness in that older population, why wouldn't we just make the inference even knowing that the inference isn't absolutely perfect and that there could be some confounding elements and that delta may play a role. Why does that matter? If the efficacy seems to be improved even against delta, this is a great, great point we can make that inference. And the question is for whom can we make that inference? Is it for the older population where the evidence seems strongest. There does seem to be a lot of evidence for the older population seventy five plus sixty plus that it is protective against both non delta and delta variants. There are two additional factors here. One is, if we want to extend it to the sixteen to sixty five. They're the evidence is less clear in terms of the actual effect. The second thing, and this is where we get into the scientific weeds on this is when you get a vaccine, there are two immune responses that are elicited. One is more of a short term immune response that's mediated by antibodies, and then there may also be and one hopes there is a longer term immune response which is cell mediated, so not antibody mediated, but cellular mediated that tends to be later on. Takes a while for these cells to get going and to be generated, but it is much much more durable now when we see the evidence presented by fiz Or, which is actually depended a lot on this huge Kaiser population that they tracked, as well as their clinical trial which focus only on antibodies, not on the memory cells, which are more of a measure of the during protection, they saw antibodies declining. Now this is not at all surprising. After a month or so, your antibodies will decline, but it does not mean that the protection has actually decreased, because at the same time your cellular immunity is ramping up. And so that was also one of the issues is okay, the antibodies are declining, but that may not be what we really care about. We care about durable immunity, which is mediated by cells. Fiser did not present that information. The other reason cellular immunity is important is that that also varies. Going back to the original question, you know, to whom can we make these inferences about protection? And so it is entirely possible that we saw the boost response and that's based on antibody measures. We saw that, and that antibody response it's helpful in populations that don't have a particularly strong cellular response, and those particular populations are the immunocompromised. And that was the reason the FDA approved the use of the booster for immune compromise, you know, last month, and also sell you your immunity may be weakened in the elderly as well as those at risk of SEVERITYDS, those who have commor conditions, those who abies, and so on. So that's really the justification. And so you know, I think the median, at least the latest version of the study had a median follow up time of about two and a half months. So is it fair to say then that if that data, that two and a half month data were extended to say four months or five months, are we then going to see all of these scientists who were saying slow down, slow down. Are they just going to say, Okay, we asked you to slow down, Now you slow down. We're happy you slow down. Now the data extrapolates, now go ahead and approve boosters for I don't know, twenty five and up, thirty five and forty and up. Is that really what's going on here? Mean? Is this really just a question of speed, because there doesn't seem like there's any data actively suggest thing that it would be a bad idea to get the boosters. It's just that it seems like the scientists are saying, don't jump to the conclusion before we fully work through everything. So fair enough, I get the point. But in the future, if this data extrapolates, are we then going to have boosters a standard? So I would say no. I mean, on the one hand, that is a sentiment that is expressed that we just need more information. It's actually too premature to make a decision. I would say that there are a couple of additional considerations. So one is this is still the sixty plus population, we would have to keep an eye on the younger population. And there you know, the reason the age changes the calculus is that the older you are, the more benefit from protection against severe disease that you get from the vaccine. The younger you are, you know you're likely to have something mild asymptomatic, but the vaccine you may be at increased risk. And we saw this with young males increased risk of myocarditis. So that risk benefit calculation changes for the young population, so it's not simply an extension. The second factor is that people are still waiting to see what's happening with breakthrough infections. There are people who feel that some aspects of the Israeli situation actually don't really apply to the United States very well. And one aspect is that Israel, to its credit, has been amazing in its immunization coverage, you know, ninety five percent of sixty and older, and so the hospitalizations, the severe cases that they're seeing are actually primarily breakthrough infections of those who have been fully vaccinated. That is not the case in the US. In the US, most of the hospitalizations are from those who are unvaccinated. So we're seeing something very different, And so the question is are we better off just incrementally giving to dose people an additional boost in general if you wanted to expend it to the population where it will have sort of a marginal effect but some increased risk, versus targeting the unvaccinated, where you might have just a greater marginal return. Jenny, I want to just thank you for helping us walk through some very complicated waters, and your mastery, both of the science and of the complexity of the regulatory side is just it's a god send to us. So thank you very very much for your time and for your terrific work. Thank you so much for having me and for digging into these really important issues. We'll be right back. I am happiest here on deep background when I walk into an interview with a lot of confusion at a lot of questions, and I feel that the guests that we're talking to that week is able to guide me through the thicket and help me get much greater clarity. This conversation with doctor Genevieve Cantor was to me a model of that kind of improvement. Listening to Jenny, a clear narrative emerged of the way that the scientific community, both inside the government and outside, has been responding to the Biden administration's aggressive push to move in the direction of many boosters for many people very quickly. What I heard from Jenny is that the scientists think that this process is just going too quickly and is relying on a rapid mode inference from a relatively limited amount of data drawn from Israel on an older population to conclude prematurely that we all ought to be getting boosters as fast as possible. It's not only that the scientists think that the Biden administration moved too fast. It's also that they were frustrated that this administration, which pledges to follow the science, was actually out ahead of the science, substantially ahead of the science. As a consequence, the scientists are pushing or a slowdown for the gathering of more information and for the gathering of more data. The particular issue on which the focus seems to be most precisely is the question of whether the boosters are actually going to be very helpful in preventing serious disease and hospitalization in the population that isn't immunocompromised and isn't much older. That is to say, the population that is capable of having its body and its own immune system respond well in the wake of two shots and eventually be able to prevent disease in its more aggressive forms. Jenny also made the point that it may well be that none of the vaccines that we presently have are going to do a very good job against the possibility of passing along COVID. Rather, what they do a good job of, and they do a terrific job so far, is preventing serious illness and hospitalization. If that's the goal, then that is what we need to measure, and we need to measure it in a broader part of the population, not only among those who have weaker immune systems the way that older people statistically tend to do. It follows, says Jenny, that we should not assume that the data that exists will necessarily extrapolate to draw the conclusion that we should broadly have boosters for all that, truly, she says, remains to be seen. Will continue to watch this ongoing story here on deep background, will look for the CDC Advisory Committee's reports in the middle of this week, and I promise you that as this issue plays itself out and we get greater clarity on the Biden administration's overall policy and approach to boosters. We will revisit the issue for you here on Deep Background. Until the next time I speak to you. Breathe deep, think, deep thoughts, and booster or otherwise try to have a little fun. Deep Background is brought to you by Pushkin Industries. Our producer is Mola Board, our engineer is Ben Tolliday, and our showrunner is Sophie Crane mckibbon. Editorial support from noahm Osband. Theme music by Luis Gara at Pushkin. Thanks to Mia Lobell, Julia Barton, Lydia, Jean Coott, Heather Faine, Carlie Migliori, Maggie Taylor, Eric Sandler, and Jacob Weissberg. You can find me on Twitter at Noah R. Feldman. I also write a column from Bloomberg Opinion, which you can find at Bloomberg dot com slash Feldman. To discover Bloomberg's original slate of podcasts, go to Bloomberg dot com slash podcasts, and if you liked what you heard today, please write a review or tell a friend. This is Deep Background.