Pushkin from Pushkin Industries. This is Deep Background, the show where we explore the stories behind the stories in the news. I'm Noah Feldman. In recent weeks, three new variants on COVID nineteen have been occupying a lot of attention in the news. There's a variant in the UK that is apparently more contagious and possibly more harmful. Then there is a variant in South Africa and one in Brazil, at least one of which and possibly both of which do appear to be less responsive to existing vaccines, or two antibodies created by people who've already had COVID. How alarmed should we be about these developments, How will they affect the interaction between the rollout of the vaccine and the progress of the disease, and what will it all mean for when we can begin to get back to conditions resembling normal. Here to talk us through these challenging questions is Mark Lipsitch. Mark now qualifies as a friend of a Deep Background for his regular appearances on the show to help explain the coronavirus pandemic to us, stretching all the way back to February of twenty twenty, when he was one of the first epidemiologists to sound the alarm about the coming pandemic. Mark is Professor of epidemiology at the Harvard chan School of Public Health, and he's also the director of the Center for Communicable Disease Dynamics. There, he has spent years creating and analyzing models that study pathogen spread in a population, and he's also studied how to effectively communicate this information to decision makers and the wider public. All of that study has turned into practical reality over the last eleven months. We're very lucky to have back to talk about this mutation and its consequences and the lessons we've learned from living with COVID now for nearly a year, Mark, welcome back today. I want to start with the South African variant, which has been getting a lot of attention because of the question of the extent to which it is or is not susceptible to the vaccines that have been created. So I want to begin by asking you, how worried are you about the South African variant and what are the consequences of that worry for your picture in the big sense of where we're headed. Well, I think most observers, including me, are seriously worried that this will complicate efforts to protect people by vaccination and reduce the quality of immunity from natural infection. Because there's evidence that for the South African variant that both of those things are likely true, the extent of the concern is still really matter ulation. Most likely is that there will be some degree of immunity, maybe more immunity to severe infection than to getting infected at all, but it really remains to be seen. It's not a good sign. It will certainly make things harder, but I think the degree of that is really a matter of complete speculation right now, and is the reason. The underlying reason for why both vaccine efficacy might be reduced as well as why natural immunity might be reduced the same, namely, that the variant has some sort of evolutionary shift in the spike protein that makes it less of a good match for what's been designed for the antibodies created in response to the pre existing version of the virus. That's right, So the existing vaccines narrowly target a very specific part of the spike protein, but also are natural antibodies that we respond that we make in response to natural infection. Also, in most people heavily target that region of the virus, and so in both cases the antibuddies do their job less well. Both Fiser and Maderna have released highly preliminary in vitro studies where they had a sort of good news bad news formulation in their In their pr there the good news was supposed to be well. They do say that their vaccines are still working on the South African variant, but the bad news is that it's not working as well as they would have liked it to work. I mean, I'm over simplifying that a little bit. And Maderna in fact said, just out of an abundance of caution, we're going to try to rejigger our version of the vaccine, so we'll address the South African varenton. We think we should be able to pull that off. Tell me about what should one think about those public statements. Yeah, I think those are accurate. And of course, where it falls on the good news bad news spectrum is the part that I said a minute ago is a matter of speculation. I mean, this is the general picture. When we have a vaccine or we have an immune response, we can measure many of its properties, and very often the degree to which it works in a test tube or in a cell culture correlates with how well it works in people, but not usually perfectly, and so translating it's in between nothing and very effective into where it is on the spectrum of epidemiological effectiveness is the part that we just don't know yet but should be able to learn more about as we see the variant spread and infect people in places with more vaccine coverage. All of this is happening in this extremely complicated dynamic game. I mean, for most of us who don't do what you do for a living, we're just slowly gradually beginning to appreciate just how complicated it is to keep track of all the moving parts. So we already have this very complicated phenomenon of vaccines being introduced, social distancing continuing in some places, and then the ongoing spread of the virus. And now, in addition to those three factors that were already in play, we also have an evolutionary twist that may change the game as well. So I want to ask you a few questions about the interaction of those four factors. And since there's so many moving parts, I'm going to go slowly so that you can explain it to me in slower terms. Start with which vaccines are in play here? So is there a reason to think that, even if Fiser and Maderna vaccines work all right on the South African variant, that other of the vaccines that are out there in the world that are more available, let's say, in less developed countries where it's harder to get the refrigeration and so forth, is there a reason to think that those would be even less efficacious than the mr Anda vaccines. I think, first of all, it's not just people who don't do this for a living who find it hard to keep track of the moving parts. It's really hard if you do. In answering your question about the other vaccines, a recurring theme in this pandemic, as in a lot of science, is there's what we have reason to think based on scientific precedent, and then there's what we have data about the specifically answers the question. We don't have data yet as far as I'm aware, on the effectiveness of the other vaccines against this. What we have reason to think is that the story will be probably quite similar. I think all of the vaccines that are far along in clinical trials, and virtually all of the vaccines that are being developed, a significant part or all of their immune response that they're generating is to the spike into this particular these particular parts of spike, and even natural infection, which is the whole virus that we can respond to, is the response is compromised for the South African variant. So I think it would be likely that the story will be similar across the board, but there could be some variations in the types of immune responses that are favored by different vaccines in some subtle way that would make it better or worse. Is it right? As I've gleaned in a lay person's way, that the mRNA vaccines might be more tweakable in the lab and in real time than the other vaccines. I mean, that's certainly how again, the public relations suggests it to be. Yeah, I think the public relations suggests that, and I think it is the most straightforward because you're simply generating a sequence of RNA, and the sequence can change a little bit, and it's those same process as making it the first time was. I think a lot of the technologies that are used for vaccines have this feature that they take a piece of the virus and generate the immune response. So I think to a large degree all of the vaccine technologies are pretty flexible. I don't know whether mRNA will be a whole lot faster. It may be somewhat faster. So let's turn then to the first step, as it were, of the interaction question. So, even before the South African variant was emerging, you've been thinking and writing and speaking about the interaction between the rollout of vaccines and the question of the trajectory of the pandemic. Would you give us, let's say, your prevariant analysis in a nutshell of what that interaction looks like, and then we can layer in the variant change. If we put aside the variance for the moment, then it's clear that for most of the world the vaccine is still not a serious factor. For the rich countries it is becoming a serious factor, and sort of low single digits of percents of people. But in most of the developed world it's still a minor factor, but is ramping up and the level of coverage is likely to be meaningful in a few months well in certain rich countries. So you think sort of April May and rich countries, it will be meaningful by April May, but not necessarily high. I mean, the Biden administration came into office saying one hundred million doses in one hundred days. The pace has been nearly a million doses a day already, and it's been quite quiet from the Biden administration when that was reported that this was just a modest increase. There was not a statement, Okay, we're going to make a two hundred million And I think I don't have any particular information, but my sense is there just aren't the capacities in the companies to make more doses than they're making. And it's not just a matter of saying please do it or you must do it. It's just that they are at capacity for manufacturing. And one hundred million doses means fifty million people vaccinated in a country of over three hundreds, so that is still modest prior to the variants, and even still, I was saying, I don't know when we're going to get to hurt immunity, if at all, because we don't know how well the vaccines protect against transmission. But at least we can protect the most vulnerable people if we can identify them and persuade them to be vaccinated. A few tens of millions of doses will not quite cover that, but will be a very big step towards covering the most vulnerable if they're prioritized. Sensibly, can I go back and ask you a question about something you just said? Mark, You were making the point that we don't know when we'll hit hurt immunity with vaccines because we don't know how well the vaccines do against transmission. So I guess my first question is why don't we know that? It's not just a function of the design study that was used in testing these vaccines. Yeah, the easiest way to find out if someone has gotten the virus is to wait for people to get sick from the potentially from the virus, and then test them. And so that was the centerpiece of the design of all the clinical trials, which for very good reasons, were designed to be fast and not answer every question, but answer the most important question as quickly as possible. Two of the three major vaccine Western vaccines, the Maderna one and the astrosenica one, had aspects of the trial that gave us a bit of a hint about transmission. The Astrosenica trial looked at people in the UK part of the trial who were not sick and asked them to come in any way and get swabbed so they could compare vaccine to posebo and the Maderna trial when they had people come in for their second shot, swabbed their noses and so we're able to estimate the impact of the shot on whether you get infected, even if you weren't sick. So each of those gave some data, not very much data, but a little bit of data that suggests that both of those vaccines do have some impact on transmission, which is really good. Question is how much, And that's the part where we just don't have enough data or enough high quality data to really say. In light of that, and again leaving out the variance, which will come back to in a moment, do you read the situation presently as in the rich countries we're headed for a kind of endemic pandemic that never goes away fully and is more like the flu, or do you read it as again leaving out for a moment the variance as something where at least in the rich countries eventually maybe it's not going to be in April or May, but maybe it's in June or July and August, or when more doses become available in a higher percentage of the population has been vaccinated, where we might actually be able to say COVID is not really a danger in these rich countries anymore. I think that would be quite surprising to get to the point where we have essentially no transmission. I think it's not out of the realm of possibility, but I think other scenarios are more likely. There was a paper in Science by a group from Memory that suggested that it would over time evolve into a situation more like a common cold, maybe up to influence a severity, but not pose the same danger, and I do think that that is the most likely. I think vaccines will accelerate that insofar as they protect the most vulnerable. But I think when a virus is this widespread in most of the world, and when the capacity to vaccinate heavily will remain limited for several years at least at a global scale, that the right things are going. And also, given that the first generation of vaccines probably are not super effective against transmission, they probably are quite effective if I had to bet on a number, I would say they probably reduce it by about two thirds, but I could be off maybe maybe eighty percent, which would be a lot, but would not be enough to get rid of the virus from circulation. And in those numbers, even with a very high percentage of the population vaccinated, you think there would still be enough transmission going on that we're looking at something that fits that that paper you were talking about, something more like the common cold. Yeah, I mean eighty percent effectiveness and one hundred percent coverage might just eliminate it, or nearly eliminate it, but but maybe not in all the most densely populated places, which could then recede other places. And maybe not. Maybe it won't be eighty percent effective, and probably there won't be total coverage because everywhere it's been tried so far, there's significant vaccine has been so that combination of things makes me think a lot of uncertainties would have to go our way for elimination to be a realistic possibility. Presumably, it's also the case that even in this best case scenario, the very small probability one that you're describing, it would take years because it would require something like a global spread of the vaccine unless you had isolation of the rich countries, and you're probably not going to get total isolation of those countries. It is not realistic, right right, And it wouldn't be justifiable, even for someone like me who's been an advocate of control measures for a long time. Once we have high vaccination coverage in the most vulnerable groups, it would not be economically or otherwise justifiable to say we're going to try to keep the economy hobbled for months or years just to stop this one virus. I'm glad you brought up the control measures because that was going to be my next question. Again, once more with the caveat of that we don't know enough yet about the variants, but again, assuming the variants are relatively controllable using the vaccine, where do you think is the right inflection point on the control measures? Where in the inflection point, what percentage of people need to be vaccinated in a country or a region for control measures to be substantially pulled back. Well, I think, that's of course a very hard question. I think that the first indicator that I'd be looking to, or indicators would be in places with high vaccine coverage, is there a substantial drop in the mortality rate and in the hospitalization or hospital capacity use, because those are the two things that are most damaging about this virus. It kills people, and it overwhelms healthcare indirectly harms people's health. It's going to be hard but necessary for us as epidemiologists to try to disentangle how much of that is directly protecting the most vulnerable, how much of that is reducing transmission through the vaccine, and how much of that is reducing transmission through control measures. And we'll all be working hard at that, and it will be a challenging thing to separate out. But I think the scenario that I imagine unfolding and I hope is correct, is that as vaccine gets rolled out to the people over sixty five and over seventy five, people on nursing homes, and people in other of the highest risk groups, you'll see still a lot of cases, but not nearly so much damage from those cases. You'll have a lot of continuing diagnoses, but a dropping ratio of hospitalizations and deaths cases. And that would be a sign to me that we're doing what we are trying to do that, which is to defang the virus by protecting the people whom it is most likely to harm. Exactly where you then draw the line. You know, it's very hard to say, well, we can tolerate this many deaths, but we can't tolerate that many deaths. But we tolerate deaths from influenza, and we tolerate deaths from a lot of other infections. And at some point we will draw that line. We'll be back in a moment. Mark, I want to ask you a kind of big picture what will the world look like question? And let's fast forward to September twenty twenty one, when at least in the United States, Canada, maybe Mexico, schools are supposed to be back in session. And again, let's assume relatively good uptake of the vaccine and relatively good efficacy of the vaccine, not against transmission but against serious illness. First of all, do people go back to school? Our schools open pretty much everywhere. And second of all, what does ordinary life look like with respect to different control measures ranging from masks to social distancing, to closings or openings of retail and restaurants. It's just having this exact conversation with people at our common University to try to think through all of these contingencies. I think under that relatively optimistic scenario of high vaccine uptake, particularly among teachers, would be an important qualification there for the reopening of schools and continued high vaccine efficacy at least again severe disease. I think the amount of damage done by the closing those schools to kids education is going to be something people won't continue to tolerate, and that there will be very very much social pressure, societal pressure to reopen schools, and that if teachers have access to vaccination in a fairly universal way, that will be the likely outcome. For the same reasons, I think other things will start to open up under such a scenario. And I think if we really have if we go a million doses a day for that amount of time, all the way through September, we're still going to have very low overall vaccine coverage. But if other vaccines come on and are highly effective, and or if we get more manufacturing capacity for the existing vaccines, then we will start to have some reasonable level of coverage and the population and with it, I would expect some reduction and transmission. I think the one caveat to that is that the seasonal changes that we saw last summer will probably happen again this summer, So everything will look better in the summer as it did last summer, because people will be outside more, the virus will transmit less well, and we may have a sense of security as we did last summer. That's partially due to the vaccine and partially due to seasonal factors, and so I think we're going to have to try to again separate out that contribution and make sure that as things reopen, which there will be great pressure to do, and we're not setting up for another bad winter like the one we've had here. But I think if we continue with continued high coverage and continued high efficacy in the most at risk groups, it should be a very different winter next year. You mentioned vaccinating teachers before us potential fall reopening. I know that in the debate about whether teachers should come first, or whether professions should really be our basis for vaccination as opposed to the people most vulnerable and most at risk, you have been more unvaccinate the vulnerable rather than identify a professional class like teachers. But it sounds like maybe as we get more vaccine out to the population, you think it would make sense to target teachers in order to achieve the social goal of reopening schools, or at least an acknowledgement of the fact that people are going to want it anyway. I have been very much in favor of trying to vaccinate first those who would be most likely to die. I do think that of all the professions, apart from healthcare workers, teachers play a truly fundamental role in our society for a whole variety of complicated reasons. But one of them is that they, through their childcare role, they make it possible for other adults to work. And another one, which we think of as the primary one, and it is, but it's not the only one, is that they create human capital and they and they educate our children to move on with their lives. And those are two really, really fundamental roles that are different from those of many other important occupations. And I think there will be appropriate demand to vaccinate teachers at least in time for fall reopening, which in practice means starting probably in the late spring. Mark you describe that scenario, that September scenario as optimistic. I grant you that it's optimistic. How optimistic I mean, does it seem to you when you really check your gut pretty darn unlikely that by September again in the United States will have enough vaccine uptake, declining mortality among the most vulnerable, and be able to begin the process of really getting back to normal. Or when you think in singularly, you say, yeah, that could be, but we have to be honest. Things are more things, things are changing, and it might will come out of different ways, so we should be prepared for something different. I think if I had to put my that's on the most probable scenario, it would be of a September that we would all be reasonably happy with in terms of our lives being something like what we want them to be. I think people will still be wearing masks in places where they have been and I think, you know, air filters will continue to do a brisk business and people will continue to be cautious, but that that there will be My best guess is that we will have a school year that is recognizable as a normal school year. But I think there are, as you say, ways that could that that could go wrong that are just hard to predict until we have more data on the variants and their consequences for immunity and on any other surprises that lion store Mark, what am I not asking you that I should be asking you? Here? We didn't get to talk about the variants actually all that much. We talked more about if they don't become a big problem. But well, let's talk a little bit for a moment then about what you know, what you think would be the case if they do become a big problem. Yeah, well, I think in the period between now and when the vaccine is protecting the vulnerable, there could be a period where we have a really hard time controlling the virus. We also haven't talked about the UK variant, which almost certainly is more contagious. Conflicting data about whether the vaccines are less effective. Nothing that shows suggests that they're wildly less effective, but some suggestions that they're somewhat less effective depending on whose data you read, and some hints but from very preliminary studies, that the UK variant is more lethal. Mark, was there a moment as the data began to come out about the UK variant where you started to buy the view that it was in fact substantially more transmissible, because the very earliest data was pretty loosely associational. So what was the thing that pushed you to say, yes, it's almost certainly, I think, which is your formulation a moment or two ago. Almost certainly more transmissible? Yeah, I think the fact that it's been seen to spread more effectively than the prior variants in multiple places in the UK. And it's not just that people are moving around so fast that every place is connected perfectly to every place else. It's that in multiple parts of the country the frequency was going up at a rapid rate. Okay, so the UK variant reason for serious concern there? What about the other variants Brazilian or South African? What are the other big warriors we should have about those? Well? I think the big worries with those or we don't know how much the escape from immunity in the lab will translate into escape from immunity in populations of people, but that means to be seen. And if the thing that we're worried about were to transpire, we would be signing up then for a longer period of time, slower progress because the vaccines would be less efficacious more social distancing sort of more of what we're dealing with, more mortality, presumably more risk to vulnerable populations. Yeah, I think that's the worst case, and I don't think that's the likely case. Now we're really in the realm of speculation because we've just never watched this process happen with a coronavirus, But with influenza, we know that it involves to escape our immunity. It does so every few years it makes a substantial bit of progress against our immune system, and we don't have a flu pandemic and lockdowns every three or four years. Even though it's we're racing it with our immune systems, we keep up to some degree, and we don't have huge tolls of mortality and hospital use in almost any season outside of pandemics. So by that analogy, it's not perfect because it's a different type of virus, but by that analogy, we can certainly imagine a similar thing happening with this coronavirus. It would really be unprecedented to have two or three or four years of really bad circulation of the same virus causing the same amount of destruction, especially with good vaccines. I think it's irresponsible to totally rule it out, but it's also irresponsible or it's inappropriate to describe that as a likely outcome at this point. Well, that's a relatively cautiously optimistic note on which to add. And I hope that by the next time we speak again, Mark, that there will be good progress on some of these things. Thank you so much. Thank you. Speaking with Mark is always bracing and clarifying, and it always provides some central takeaways. Here's the first. Mark is seriously concerned about the new variants that are coming, especially from South Africa. He says it's too soon to make determinative statements because the data is not there yet, but he wants us to watch this very closely, and in particular, he's concerned to make sure that vaccines as they currently exist, are able to function as effectively as possible against these variants. Second, Mark continues to sound serious concerns about our goal of reaching the most vulnerable population with vaccines. That remains his priority, and to achieve that goal, we need more vaccine, faster, producing just enough doses to provide one million a day. Mark points out, even in a rish country like the United States, is not going to get us there. Because two doses of the vaccine are required per person, and we have three hundred million plus people in the United States. Another important and perhaps more optimistic takeaway from Mark is that all else being equal, it should, in principle be possible by September of twenty twenty one to begin to open schools and return to something very much more closely resembling normal than anything we've seen in the last year. Mark says there will still be masks in lots of public places, but ultimately, if things go well, and if it turns out that the vaccines do work at least basically against the emerging variance of the virus, he thinks we will be able to get back to normal. He does add a caveat, which is that if seasonally we begin to see declines in the spread of the virus in the summer of twenty twenty one, we need to remember that there is a seasonal variation. We saw it last summer, and we should be very careful to be sure that what we're seeing is a reduction that is caused by vaccination, not simply a seasonal reduction, so serious concerns, but a guarded optimism for the future that's what Mark has to say, and I think we should be very grateful to him for his always cogent analysis. Until the next time I speak to you, all, be careful, be safe, and be well. Deep Background is brought to you by Pushkin Industries. Our producer is Mo laboord, our engineer is Martin Gonzalez, and our shore runner is Sophie Crane mckibbon. Editorial support from noahm Osband. Theme music by Luis Guerra at Pushkin. Thanks to Mia Lobell, Julia Barton, Lydia Jean Cott, Heather Faine, Carl Vigliori, Maggie Taylor, Eric Xander, and Jacob Weisberg. You can find me on Twitter at Noah R. Feldman. I also write a column for 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 the stories behind the stories in the news. I'm Noah Feldman. In recent weeks, three new variants on COVID nineteen have been occupying a lot of attention in the news. There's a variant in the UK that is apparently more contagious and possibly more harmful. Then there is a variant in South Africa and one in Brazil, at least one of which and possibly both of which do appear to be less responsive to existing vaccines, or two antibodies created by people who've already had COVID. How alarmed should we be about these developments, How will they affect the interaction between the rollout of the vaccine and the progress of the disease, and what will it all mean for when we can begin to get back to conditions resembling normal. Here to talk us through these challenging questions is Mark Lipsitch. Mark now qualifies as a friend of a Deep Background for his regular appearances on the show to help explain the coronavirus pandemic to us, stretching all the way back to February of twenty twenty, when he was one of the first epidemiologists to sound the alarm about the coming pandemic. Mark is Professor of epidemiology at the Harvard chan School of Public Health, and he's also the director of the Center for Communicable Disease Dynamics. There, he has spent years creating and analyzing models that study pathogen spread in a population, and he's also studied how to effectively communicate this information to decision makers and the wider public. All of that study has turned into practical reality over the last eleven months. We're very lucky to have back to talk about this mutation and its consequences and the lessons we've learned from living with COVID now for nearly a year, Mark, welcome back today. I want to start with the South African variant, which has been getting a lot of attention because of the question of the extent to which it is or is not susceptible to the vaccines that have been created. So I want to begin by asking you, how worried are you about the South African variant and what are the consequences of that worry for your picture in the big sense of where we're headed. Well, I think most observers, including me, are seriously worried that this will complicate efforts to protect people by vaccination and reduce the quality of immunity from natural infection. Because there's evidence that for the South African variant that both of those things are likely true, the extent of the concern is still really matter ulation. Most likely is that there will be some degree of immunity, maybe more immunity to severe infection than to getting infected at all, but it really remains to be seen. It's not a good sign. It will certainly make things harder, but I think the degree of that is really a matter of complete speculation right now, and is the reason. The underlying reason for why both vaccine efficacy might be reduced as well as why natural immunity might be reduced the same, namely, that the variant has some sort of evolutionary shift in the spike protein that makes it less of a good match for what's been designed for the antibodies created in response to the pre existing version of the virus. That's right, So the existing vaccines narrowly target a very specific part of the spike protein, but also are natural antibodies that we respond that we make in response to natural infection. Also, in most people heavily target that region of the virus, and so in both cases the antibuddies do their job less well. Both Fiser and Maderna have released highly preliminary in vitro studies where they had a sort of good news bad news formulation in their In their pr there the good news was supposed to be well. They do say that their vaccines are still working on the South African variant, but the bad news is that it's not working as well as they would have liked it to work. I mean, I'm over simplifying that a little bit. And Maderna in fact said, just out of an abundance of caution, we're going to try to rejigger our version of the vaccine, so we'll address the South African varenton. We think we should be able to pull that off. Tell me about what should one think about those public statements. Yeah, I think those are accurate. And of course, where it falls on the good news bad news spectrum is the part that I said a minute ago is a matter of speculation. I mean, this is the general picture. When we have a vaccine or we have an immune response, we can measure many of its properties, and very often the degree to which it works in a test tube or in a cell culture correlates with how well it works in people, but not usually perfectly, and so translating it's in between nothing and very effective into where it is on the spectrum of epidemiological effectiveness is the part that we just don't know yet but should be able to learn more about as we see the variant spread and infect people in places with more vaccine coverage. All of this is happening in this extremely complicated dynamic game. I mean, for most of us who don't do what you do for a living, we're just slowly gradually beginning to appreciate just how complicated it is to keep track of all the moving parts. So we already have this very complicated phenomenon of vaccines being introduced, social distancing continuing in some places, and then the ongoing spread of the virus. And now, in addition to those three factors that were already in play, we also have an evolutionary twist that may change the game as well. So I want to ask you a few questions about the interaction of those four factors. And since there's so many moving parts, I'm going to go slowly so that you can explain it to me in slower terms. Start with which vaccines are in play here? So is there a reason to think that, even if Fiser and Maderna vaccines work all right on the South African variant, that other of the vaccines that are out there in the world that are more available, let's say, in less developed countries where it's harder to get the refrigeration and so forth, is there a reason to think that those would be even less efficacious than the mr Anda vaccines. I think, first of all, it's not just people who don't do this for a living who find it hard to keep track of the moving parts. It's really hard if you do. In answering your question about the other vaccines, a recurring theme in this pandemic, as in a lot of science, is there's what we have reason to think based on scientific precedent, and then there's what we have data about the specifically answers the question. We don't have data yet as far as I'm aware, on the effectiveness of the other vaccines against this. What we have reason to think is that the story will be probably quite similar. I think all of the vaccines that are far along in clinical trials, and virtually all of the vaccines that are being developed, a significant part or all of their immune response that they're generating is to the spike into this particular these particular parts of spike, and even natural infection, which is the whole virus that we can respond to, is the response is compromised for the South African variant. So I think it would be likely that the story will be similar across the board, but there could be some variations in the types of immune responses that are favored by different vaccines in some subtle way that would make it better or worse. Is it right? As I've gleaned in a lay person's way, that the mRNA vaccines might be more tweakable in the lab and in real time than the other vaccines. I mean, that's certainly how again, the public relations suggests it to be. Yeah, I think the public relations suggests that, and I think it is the most straightforward because you're simply generating a sequence of RNA, and the sequence can change a little bit, and it's those same process as making it the first time was. I think a lot of the technologies that are used for vaccines have this feature that they take a piece of the virus and generate the immune response. So I think to a large degree all of the vaccine technologies are pretty flexible. I don't know whether mRNA will be a whole lot faster. It may be somewhat faster. So let's turn then to the first step, as it were, of the interaction question. So, even before the South African variant was emerging, you've been thinking and writing and speaking about the interaction between the rollout of vaccines and the question of the trajectory of the pandemic. Would you give us, let's say, your prevariant analysis in a nutshell of what that interaction looks like, and then we can layer in the variant change. If we put aside the variance for the moment, then it's clear that for most of the world the vaccine is still not a serious factor. For the rich countries it is becoming a serious factor, and sort of low single digits of percents of people. But in most of the developed world it's still a minor factor, but is ramping up and the level of coverage is likely to be meaningful in a few months well in certain rich countries. So you think sort of April May and rich countries, it will be meaningful by April May, but not necessarily high. I mean, the Biden administration came into office saying one hundred million doses in one hundred days. The pace has been nearly a million doses a day already, and it's been quite quiet from the Biden administration when that was reported that this was just a modest increase. There was not a statement, Okay, we're going to make a two hundred million And I think I don't have any particular information, but my sense is there just aren't the capacities in the companies to make more doses than they're making. And it's not just a matter of saying please do it or you must do it. It's just that they are at capacity for manufacturing. And one hundred million doses means fifty million people vaccinated in a country of over three hundreds, so that is still modest prior to the variants, and even still, I was saying, I don't know when we're going to get to hurt immunity, if at all, because we don't know how well the vaccines protect against transmission. But at least we can protect the most vulnerable people if we can identify them and persuade them to be vaccinated. A few tens of millions of doses will not quite cover that, but will be a very big step towards covering the most vulnerable if they're prioritized. Sensibly, can I go back and ask you a question about something you just said? Mark, You were making the point that we don't know when we'll hit hurt immunity with vaccines because we don't know how well the vaccines do against transmission. So I guess my first question is why don't we know that? It's not just a function of the design study that was used in testing these vaccines. Yeah, the easiest way to find out if someone has gotten the virus is to wait for people to get sick from the potentially from the virus, and then test them. And so that was the centerpiece of the design of all the clinical trials, which for very good reasons, were designed to be fast and not answer every question, but answer the most important question as quickly as possible. Two of the three major vaccine Western vaccines, the Maderna one and the astrosenica one, had aspects of the trial that gave us a bit of a hint about transmission. The Astrosenica trial looked at people in the UK part of the trial who were not sick and asked them to come in any way and get swabbed so they could compare vaccine to posebo and the Maderna trial when they had people come in for their second shot, swabbed their noses and so we're able to estimate the impact of the shot on whether you get infected, even if you weren't sick. So each of those gave some data, not very much data, but a little bit of data that suggests that both of those vaccines do have some impact on transmission, which is really good. Question is how much, And that's the part where we just don't have enough data or enough high quality data to really say. In light of that, and again leaving out the variance, which will come back to in a moment, do you read the situation presently as in the rich countries we're headed for a kind of endemic pandemic that never goes away fully and is more like the flu, or do you read it as again leaving out for a moment the variance as something where at least in the rich countries eventually maybe it's not going to be in April or May, but maybe it's in June or July and August, or when more doses become available in a higher percentage of the population has been vaccinated, where we might actually be able to say COVID is not really a danger in these rich countries anymore. I think that would be quite surprising to get to the point where we have essentially no transmission. I think it's not out of the realm of possibility, but I think other scenarios are more likely. There was a paper in Science by a group from Memory that suggested that it would over time evolve into a situation more like a common cold, maybe up to influence a severity, but not pose the same danger, and I do think that that is the most likely. I think vaccines will accelerate that insofar as they protect the most vulnerable. But I think when a virus is this widespread in most of the world, and when the capacity to vaccinate heavily will remain limited for several years at least at a global scale, that the right things are going. And also, given that the first generation of vaccines probably are not super effective against transmission, they probably are quite effective if I had to bet on a number, I would say they probably reduce it by about two thirds, but I could be off maybe maybe eighty percent, which would be a lot, but would not be enough to get rid of the virus from circulation. And in those numbers, even with a very high percentage of the population vaccinated, you think there would still be enough transmission going on that we're looking at something that fits that that paper you were talking about, something more like the common cold. Yeah, I mean eighty percent effectiveness and one hundred percent coverage might just eliminate it, or nearly eliminate it, but but maybe not in all the most densely populated places, which could then recede other places. And maybe not. Maybe it won't be eighty percent effective, and probably there won't be total coverage because everywhere it's been tried so far, there's significant vaccine has been so that combination of things makes me think a lot of uncertainties would have to go our way for elimination to be a realistic possibility. Presumably, it's also the case that even in this best case scenario, the very small probability one that you're describing, it would take years because it would require something like a global spread of the vaccine unless you had isolation of the rich countries, and you're probably not going to get total isolation of those countries. It is not realistic, right right, And it wouldn't be justifiable, even for someone like me who's been an advocate of control measures for a long time. Once we have high vaccination coverage in the most vulnerable groups, it would not be economically or otherwise justifiable to say we're going to try to keep the economy hobbled for months or years just to stop this one virus. I'm glad you brought up the control measures because that was going to be my next question. Again, once more with the caveat of that we don't know enough yet about the variants, but again, assuming the variants are relatively controllable using the vaccine, where do you think is the right inflection point on the control measures? Where in the inflection point, what percentage of people need to be vaccinated in a country or a region for control measures to be substantially pulled back. Well, I think, that's of course a very hard question. I think that the first indicator that I'd be looking to, or indicators would be in places with high vaccine coverage, is there a substantial drop in the mortality rate and in the hospitalization or hospital capacity use, because those are the two things that are most damaging about this virus. It kills people, and it overwhelms healthcare indirectly harms people's health. It's going to be hard but necessary for us as epidemiologists to try to disentangle how much of that is directly protecting the most vulnerable, how much of that is reducing transmission through the vaccine, and how much of that is reducing transmission through control measures. And we'll all be working hard at that, and it will be a challenging thing to separate out. But I think the scenario that I imagine unfolding and I hope is correct, is that as vaccine gets rolled out to the people over sixty five and over seventy five, people on nursing homes, and people in other of the highest risk groups, you'll see still a lot of cases, but not nearly so much damage from those cases. You'll have a lot of continuing diagnoses, but a dropping ratio of hospitalizations and deaths cases. And that would be a sign to me that we're doing what we are trying to do that, which is to defang the virus by protecting the people whom it is most likely to harm. Exactly where you then draw the line. You know, it's very hard to say, well, we can tolerate this many deaths, but we can't tolerate that many deaths. But we tolerate deaths from influenza, and we tolerate deaths from a lot of other infections. And at some point we will draw that line. We'll be back in a moment. Mark, I want to ask you a kind of big picture what will the world look like question? And let's fast forward to September twenty twenty one, when at least in the United States, Canada, maybe Mexico, schools are supposed to be back in session. And again, let's assume relatively good uptake of the vaccine and relatively good efficacy of the vaccine, not against transmission but against serious illness. First of all, do people go back to school? Our schools open pretty much everywhere. And second of all, what does ordinary life look like with respect to different control measures ranging from masks to social distancing, to closings or openings of retail and restaurants. It's just having this exact conversation with people at our common University to try to think through all of these contingencies. I think under that relatively optimistic scenario of high vaccine uptake, particularly among teachers, would be an important qualification there for the reopening of schools and continued high vaccine efficacy at least again severe disease. I think the amount of damage done by the closing those schools to kids education is going to be something people won't continue to tolerate, and that there will be very very much social pressure, societal pressure to reopen schools, and that if teachers have access to vaccination in a fairly universal way, that will be the likely outcome. For the same reasons, I think other things will start to open up under such a scenario. And I think if we really have if we go a million doses a day for that amount of time, all the way through September, we're still going to have very low overall vaccine coverage. But if other vaccines come on and are highly effective, and or if we get more manufacturing capacity for the existing vaccines, then we will start to have some reasonable level of coverage and the population and with it, I would expect some reduction and transmission. I think the one caveat to that is that the seasonal changes that we saw last summer will probably happen again this summer, So everything will look better in the summer as it did last summer, because people will be outside more, the virus will transmit less well, and we may have a sense of security as we did last summer. That's partially due to the vaccine and partially due to seasonal factors, and so I think we're going to have to try to again separate out that contribution and make sure that as things reopen, which there will be great pressure to do, and we're not setting up for another bad winter like the one we've had here. But I think if we continue with continued high coverage and continued high efficacy in the most at risk groups, it should be a very different winter next year. You mentioned vaccinating teachers before us potential fall reopening. I know that in the debate about whether teachers should come first, or whether professions should really be our basis for vaccination as opposed to the people most vulnerable and most at risk, you have been more unvaccinate the vulnerable rather than identify a professional class like teachers. But it sounds like maybe as we get more vaccine out to the population, you think it would make sense to target teachers in order to achieve the social goal of reopening schools, or at least an acknowledgement of the fact that people are going to want it anyway. I have been very much in favor of trying to vaccinate first those who would be most likely to die. I do think that of all the professions, apart from healthcare workers, teachers play a truly fundamental role in our society for a whole variety of complicated reasons. But one of them is that they, through their childcare role, they make it possible for other adults to work. And another one, which we think of as the primary one, and it is, but it's not the only one, is that they create human capital and they and they educate our children to move on with their lives. And those are two really, really fundamental roles that are different from those of many other important occupations. And I think there will be appropriate demand to vaccinate teachers at least in time for fall reopening, which in practice means starting probably in the late spring. Mark you describe that scenario, that September scenario as optimistic. I grant you that it's optimistic. How optimistic I mean, does it seem to you when you really check your gut pretty darn unlikely that by September again in the United States will have enough vaccine uptake, declining mortality among the most vulnerable, and be able to begin the process of really getting back to normal. Or when you think in singularly, you say, yeah, that could be, but we have to be honest. Things are more things, things are changing, and it might will come out of different ways, so we should be prepared for something different. I think if I had to put my that's on the most probable scenario, it would be of a September that we would all be reasonably happy with in terms of our lives being something like what we want them to be. I think people will still be wearing masks in places where they have been and I think, you know, air filters will continue to do a brisk business and people will continue to be cautious, but that that there will be My best guess is that we will have a school year that is recognizable as a normal school year. But I think there are, as you say, ways that could that that could go wrong that are just hard to predict until we have more data on the variants and their consequences for immunity and on any other surprises that lion store Mark, what am I not asking you that I should be asking you? Here? We didn't get to talk about the variants actually all that much. We talked more about if they don't become a big problem. But well, let's talk a little bit for a moment then about what you know, what you think would be the case if they do become a big problem. Yeah, well, I think in the period between now and when the vaccine is protecting the vulnerable, there could be a period where we have a really hard time controlling the virus. We also haven't talked about the UK variant, which almost certainly is more contagious. Conflicting data about whether the vaccines are less effective. Nothing that shows suggests that they're wildly less effective, but some suggestions that they're somewhat less effective depending on whose data you read, and some hints but from very preliminary studies, that the UK variant is more lethal. Mark, was there a moment as the data began to come out about the UK variant where you started to buy the view that it was in fact substantially more transmissible, because the very earliest data was pretty loosely associational. So what was the thing that pushed you to say, yes, it's almost certainly, I think, which is your formulation a moment or two ago. Almost certainly more transmissible? Yeah, I think the fact that it's been seen to spread more effectively than the prior variants in multiple places in the UK. And it's not just that people are moving around so fast that every place is connected perfectly to every place else. It's that in multiple parts of the country the frequency was going up at a rapid rate. Okay, so the UK variant reason for serious concern there? What about the other variants Brazilian or South African? What are the other big warriors we should have about those? Well? I think the big worries with those or we don't know how much the escape from immunity in the lab will translate into escape from immunity in populations of people, but that means to be seen. And if the thing that we're worried about were to transpire, we would be signing up then for a longer period of time, slower progress because the vaccines would be less efficacious more social distancing sort of more of what we're dealing with, more mortality, presumably more risk to vulnerable populations. Yeah, I think that's the worst case, and I don't think that's the likely case. Now we're really in the realm of speculation because we've just never watched this process happen with a coronavirus, But with influenza, we know that it involves to escape our immunity. It does so every few years it makes a substantial bit of progress against our immune system, and we don't have a flu pandemic and lockdowns every three or four years. Even though it's we're racing it with our immune systems, we keep up to some degree, and we don't have huge tolls of mortality and hospital use in almost any season outside of pandemics. So by that analogy, it's not perfect because it's a different type of virus, but by that analogy, we can certainly imagine a similar thing happening with this coronavirus. It would really be unprecedented to have two or three or four years of really bad circulation of the same virus causing the same amount of destruction, especially with good vaccines. I think it's irresponsible to totally rule it out, but it's also irresponsible or it's inappropriate to describe that as a likely outcome at this point. Well, that's a relatively cautiously optimistic note on which to add. And I hope that by the next time we speak again, Mark, that there will be good progress on some of these things. Thank you so much. Thank you. Speaking with Mark is always bracing and clarifying, and it always provides some central takeaways. Here's the first. Mark is seriously concerned about the new variants that are coming, especially from South Africa. He says it's too soon to make determinative statements because the data is not there yet, but he wants us to watch this very closely, and in particular, he's concerned to make sure that vaccines as they currently exist, are able to function as effectively as possible against these variants. Second, Mark continues to sound serious concerns about our goal of reaching the most vulnerable population with vaccines. That remains his priority, and to achieve that goal, we need more vaccine, faster, producing just enough doses to provide one million a day. Mark points out, even in a rish country like the United States, is not going to get us there. Because two doses of the vaccine are required per person, and we have three hundred million plus people in the United States. Another important and perhaps more optimistic takeaway from Mark is that all else being equal, it should, in principle be possible by September of twenty twenty one to begin to open schools and return to something very much more closely resembling normal than anything we've seen in the last year. Mark says there will still be masks in lots of public places, but ultimately, if things go well, and if it turns out that the vaccines do work at least basically against the emerging variance of the virus, he thinks we will be able to get back to normal. He does add a caveat, which is that if seasonally we begin to see declines in the spread of the virus in the summer of twenty twenty one, we need to remember that there is a seasonal variation. We saw it last summer, and we should be very careful to be sure that what we're seeing is a reduction that is caused by vaccination, not simply a seasonal reduction, so serious concerns, but a guarded optimism for the future that's what Mark has to say, and I think we should be very grateful to him for his always cogent analysis. Until the next time I speak to you, all, be careful, be safe, and be well. Deep Background is brought to you by Pushkin Industries. Our producer is Mo laboord, our engineer is Martin Gonzalez, and our shore runner is Sophie Crane mckibbon. Editorial support from noahm Osband. Theme music by Luis Guerra at Pushkin. Thanks to Mia Lobell, Julia Barton, Lydia Jean Cott, Heather Faine, Carl Vigliori, Maggie Taylor, Eric Xander, and Jacob Weisberg. You can find me on Twitter at Noah R. Feldman. I also write a column for Bloomberg Opinion, which you can find at Bloomberg dot com slash Feldman. 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