In the Bubble with Andy Slavitt: Our Shot

How Is SARS-CoV-2 Going to Evolve, and What Does It Mean for Our Future? (with Jesse Bloom)

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Andy tries to get a glimpse into SARS-CoV-2’s future with Fred Hutchinson molecular biologist Jesse Bloom. Jesse is studying the ways the virus could continue to evolve and he gives us a sense of what may be on the horizon and how our immunity could hold up to those changes. Plus, they go back to the basics and talk about how and why this virus is evolving so much faster than other known viruses.

Keep up with Andy on Twitter @ASlavitt and Instagram @andyslavitt.

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Andy Slavitt, Jesse Bloom

Andy Slavitt  00:18

Welcome to IN THE BUBBLE. It’s February 28, last day of February. This is your host, Andy Slavitt lot going on in the world. Let’s catalog a little bit of it. Coronavirus is subsiding in most parts of the world, including the US only in parts of Asia Pacific and Hong Kong area. Are we seeing continued case growth, hospitalizations are down, deaths are down. We have a war in Europe, the largest invasion of another country since Hitler, and an unprovoked attack from President Putin, to the Ukrainian people. And we are going to be watching that very closely in touch. As we are with State Department, we will be bringing you news on that and updates, it is just an incredible thing to think about. So far away for many of us, yet, the idea of a democracy being attacked with troops, it’s almost like being attacked by a pathogen, it’s a bit of a different thing to get your mind around. As a result, I think things in COVID land are impacted and are a little bit up in the air in the White House, there is a new plan being rolled out to be introduced around the State of the Union this week, which is tomorrow. And that’s seen some delay given current events in Russia, etc. But the flavor of what I think we’re hearing, then we’re going to hear with that speech. And the flavor of what you’re starting to hear around the country is politicians essentially, trying to figure out how to move the country on to a less urgent and emergent stage and phase of this, I did an event with Governor Gavin Newsom, last week, rolling out their plan. And we’d have a little clip of it here.

Andy Slavitt  02:22

You know, I think the role of the state’s person in this kind of climate is to find some balance. And understand that while we have a declining case count, it is actually a good time for government to invest in making sure that we are on top of preventing the next flare up, there will be another flare up. And we should not be living in fear that flare up. We should be expecting our public health agencies or scientists and others to be focusing on those things I spent some of the weekend at fascinating weekend won’t tell you about all of it on this show. But I spent a bunch of it with David Ho, who’s the man who really is an AIDS researcher was one of the people that was part of the cure AIDS in 1990s. And Albert Bourla, who’s been on the show before from Pfizer, and one of the things that we talked about was that, at least as you go back to the flu in 1919, pandemics are over when people decide they’re over, not when the pandemic actually ends. But in fact, the year after the flu pandemic, quote unquote, officially ended. There were just as many deaths in that third year as they were in the second year. According to David, who knows a lot about these things. And he said what changed was the country basically decided it was going to move on. And you know, we live in a world where the majority of people no longer want to abide by a customer rule that just happens, it just ends. And you know, that will leave people on the margins, who are still going to be struggling with and facing the scope of the pandemic, much more on their own. Now, they’re not without tools. And I think that’s part of the justification. But I can’t emphasize enough that the empathy we need to have is got to make its way into how we do things.

Andy Slavitt  05:28

Whether you’re talking about the people of Ukraine, whether you’re talking about people who are still going to be dying from COVID, and quite frankly, having their lives altered by COVID, we have to understand that even if the pandemic feels over for you, it is not over for everybody. And that’s an unsettling feeling, as is not knowing what’s going to happen in the future. Nevertheless, showing some solidarity with people around the world who are dealing with a really hard time who are suffering or dealing with some trauma. It’s kind of what makes us good people, makes us the people that we are, when we’re doing it right. This show today is about trying to take some of the mystery out of what will happen next with the virus. And I’m going to be talking with someone who studies analytically, mathematically how SARS-CoV-2, two will evolve next. And so while we may have some people who may predict this is what’s likely to happen, and we may have others who don’t want to predict, Jesse is someone who studies it analytically, mathematically, and actually has a point of view based upon how he models things. So I find it very interesting. And I think this is in the mode of in the bubble interviews where we go and get at some really deep expertise. And try to make that poor expert talk to someone as simple minded as me in a way that helps us all understand this. And so it is very interesting, it is fascinating, I find, I find talking to sparring people to be one of the most enjoyable and enduring things that I love about doing this show. And I hope that if that’s why you listen, you’re gonna get that itch, scratched, big time. Jesse is a molecular biologist. He studies the evolution of viruses and viral proteins. He is the principal investigator of the Bloom lab and a professor at The Hutch, Fred Hutchinson Cancer Center. He’s affiliated with the University of Washington; I think you’re really going to enjoy this. Let’s dive in.

Andy Slavitt 

Hey, Jesse.

Jesse Bloom

Hi, Andy.

Andy Slavitt 

Thanks for coming in the bubble.

Jesse Bloom 

Thanks for inviting me.

Andy Slavitt 

So what are we dealing with here? One day, it looks like pear one day, it looks like an orange one day it looks like an apple. How much can this virus mutate.

Jesse Bloom  08:05

So SARS-CoV-2 has obviously evolved a lot over the last two years. And I expect it’s going to continue to evolve, you know, into the future for the rest of our lives. You know, many human RNA respiratory viruses, including other human coronaviruses do evolve in a way that allows them to eventually evade, you know, immunity from prior infection. So I expect that’s going to be what goes on with SARS-CoV-2 as well. That said, I think there’s a lot of reasons to be optimistic that art, although starts coming through is probably going to remain a significant human pathogen. Hopefully, as time goes forward, it will be, you know, more of something that we can manage and live with than it has been so far.

Andy Slavitt 

Well, let’s try to understand it. First. I guess, in the scheme of human respiratory viruses. This feels like it has more. I don’t know whether the right term is fitness or evolutionary capacity, then then we’re used to, and is that true or is that just a perception?

Jesse Bloom 

So the primary human respiratory virus that evolves rapidly that had been studied before SARS-CoV-2was influenza virus, because influenza virus, this is a fairly significant human pathogen, and it’s known that influenza virus does undergo rapid evolution, you know, that’s why the vaccine is updated, you know, most years and that’s why the typical person gets infected with influenza virus about every five years prior to the emergence of SARS-CoV-2 people had not really looked that much at the evolution of other human coronaviruses the so called common cold causing Corona viruses simply because they didn’t cause sufficiently severe disease that people paid attention, but it is known that people are typically in infected with these common cold Coronavirus is probably about every three years and we now know that they do undergo pretty rapid antigenic evolution to escape immunity. That said the rate of evolution of SARS-CoV-2 so far has been really extraordinary, even when calibrated to these common cold coronaviruses and influenza virus. And I think part of the reason for that is SARS-CoV-2 is currently evolving both to increase its transmissibility and to reduce its susceptibility to immunity. And we do expect that eventually, the transmissibility of the virus will sort of plateau and increase further over time, although it’s hard to say when we will get to that point.

Andy Slavitt  10:41

Yeah, I think, well, what are the limits is one of the questions I think, yeah, well, I just thought something would show that BA2, which is an iteration of Omicron that first appeared at least We first noticed it in Denmark is 30%. More transmissible. Now, I don’t know whether that’s because it’s 30% better at evading fire immunity or whether it’s actually 30% more transmissible, but, you know, are there are there limits that we see being reached? I remember alpha, we consider it to be you know, pretty much as transmissible as we could have imagined then delta, even more so and Omicron even more so.

Jesse Bloom

Yeah, it’s a great question. So I mean, clearly there are limits. It’s hard to say what those limits are. So at this point, the most transmissible human respiratory virus that’s known, still remains measles virus, which is an extraordinarily transmissible virus much more transmissible than things like influenza virus, and still even more transmissible than SARS-CoV-2 you know, even measles virus is not intimately transmissible, I mean, you know, a respiratory virus in the end transmits do the airborne route, you know, I’m not going to give it to you right now talking to you over the internet. And, you know, there’s, there’s going to be someone that you know, at some point, someone has to breathe out the virus and it has to land in someone else’s airways to cause an infection, and that’s a physical process. So there’s going to be a limit to that and then the virus is not going to be infinitely transmissible, but what that limit is, is hard to know. And many of our intuitions, including my intuition, had sort of been honed on influenza virus, which is the respiratory virus that’s caused the pandemics we sort of know about in modern history, respiratory virus pandemics, and influenza virus isn’t thought to have gotten dramatically more transmissible from the beginning to the end of pandemics maybe a little bit more transmissible, but not the sort of dramatic thing to see with SARS-CoV-2, but then as you describe, you know, original source COVID, who is already fairly transmissible, Alpha was more transmissible than that. Delta was more transmissible than that. Omicron BA1, it’s probably been more transmissible than Delta, and Omicron BA.2 is more transmissible than Omicron BA.1. So clearly, the virus is still acquiring mutations that are making it better at the various processes involved by sort of essentially being exhaled by an infected person and ended up in the airways of another person.

Andy Slavitt 

It is that it’s more transmissible? Or is it that it’s better, it’s infecting more people because it prior immunity doesn’t work as well.

Jesse Bloom 

Yeah, that’s a difficult question to totally deconvolve. Certainly early on, there was good evidence that Alpha for instance, was just more transmissible even not worrying about immunity. And certainly I think everybody thinks that Omicron is more transmissible than early SARS-CoV-2 even not worrying about immunity, it also seems like BA.2 most likely is inherently more transmissible than BA.1, even in the absence of immunity, because they don’t differ that much. And their ability to be recognized by the immunity from current vaccines, BA.2 seems to be spreading faster. That said, when we compare something like Omicron to Delta, it’s hard to be certain with the data at this point, whether Omicron is inherently more transmissible, it could well be […], or whether Omicron is mostly getting into advantage over Delta from the fact that Omicron has more immune escape. And in a way, it’s a little bit of a, although it’s interesting questions, a little bit of a moot point, because at this point, the majority of the population has immunity. So transmissibility at this point really becomes a combination of how good is viruses inherently transmitting, and how it can escape the immunity that’s out there.

Andy Slavitt  14:30

Maybe step back, can you step back and give a lay person like me a bit of a science lesson in, you know, how a virus goes about mutating, we understand that it replicates. But, you know, I think the things that I think we’re all becoming curious about is, you know, to what degree you know, when we see something like Omicron, the scientific community seemed surprised at the number of mutations. And it caused people to conclude that it probably been mutating inside someone potentially immunocompromised. There’s other theories as well. And we’re very interested to hear your theories. But you know, how does this happen? And how does it help us understand what’s likely to happen next, or quite frankly, it’s happening already with viruses, it’s mutating, because it’s still replicating in so many places so quickly.

Jesse Bloom 

Yeah, so most viruses, including SARS-CoV-2 have a high mutation rate, you know, so when the virus infects someone, it’s making copies of itself. And at a pretty reasonable rate, those copies of the virus have a mutation. Now, the vast majority of those mutations are bad for the virus, or don’t do anything at all to the virus. So most of them are deleterious. But in some nonzero rate, the virus will get a mutation, which allows it to still be good at infecting cells, and potentially better at transmitting or better escaping antibodies. So there’s a big filter where most of the mutations are bad, but there’s enough mutations arising that good ones happen sometimes, importantly, in a typical short of infection. So you know, most people, fortunately have sort of relatively short self-limiting SARS-CoV-2 infections where they’re sick for a while, and they get better. In most cases, you know, you have a very large number of viruses, replicating your body. But most of the time, even if that virus gets a beneficial mutation, it just doesn’t have a chance, because you’re only breathing out a very small fraction of all the viruses in your body. And then those only have a very small chance just sort of land in the airways of someone else. So most of the time, even if the virus gets a beneficial mutation, just by sort of bad luck for the virus anyway, that mutation doesn’t end up getting transmitted to anybody.

Jesse Bloom  16:51

But occasionally, a beneficial mutation will get transmitted to someone. And typically, that’ll just be one change. And I’ll take the virus one step further along, you know, sort of its evolutionary path to adaptation. So typically, we think of evolution as sort of a gradual path where if we could watch it well enough, each transmission event there’d be at most one or two mutations. What’s really striking about Omicron is, Omicron sort of appeared without any knowledge on our part that existed with a very large number of mutations. So for instance, in the spike, which is the key part of the viruses, about 30 mutations, and there’s also mutations in the rest of the virus. And one hypothesis, which I think is the most likely, although by no means certain to be the case hypothesis is that this happened during a chronic infection, which can occur, for instance, in immunocompromised individuals. And the reason you can get so much virus evolution in a chronic infection is normally you know, even if the virus gets mutation, it’s got to get through this transmission bottleneck, this sort of random transmission bottleneck to someone else before your immune system clears your infection. In a chronic infection, the virus can just keep replicating in this unfortunate individual for a long time. So that beneficial mutation that arises can then spread, become dominant in that individual and then there could be another mutation, and this can potentially go on for months. And so that’s probably how Omicron acquired many of the mutations that has although we don’t know for sure.

Andy Slavitt 

Any particular reason why we think SARS-CoV-2 is more fit and is evolving so much faster than other viruses?

Jesse Bloom 

So certainly all viruses are sort of evolving, you know, to become as transmissible as possible in the sense that that’s what’s benefits the virus but there’s just sort of, you know, limits that how well they can do that. I mean, each of these viruses sort of has, you know, different strategies. You know, measles virus has particular receptors that uses and particular ways that infect cells. Flu has particular receptors that uses in particular ways that infect cells. And so does SARS-CoV-2 and it appears that particular ways that SARS-CoV-2, you know, infect cells is sort of given it a lot and spreads has given it a lot of room to acquire mutations to just make it really transmissible you know, why that is, is like is a, you know, sort of hard to predict. But I tend to think of evolution as something that at least over the timescales we’re watching it can sort of modify something that’s existing, you know, if you do have a car, you know, evolution sort of a process that can end up making the car better, but it’s not going to turn the car into airplane or something right and At least over a short or over the timeframe we’re looking at. And it just seems that the way that SARS-CoV-2 infect cells has given it a lot more latent potential to become more transmissible.

Andy Slavitt  20:12

So what does this tell you about what future variants are likely to look like?

Jesse Bloom 

I mean, I think that future variants are going to continue to have mutations that are eroding the effectiveness of human immunity. So I think, you know, whether we’ll see more big jumps like Omicron, it’s hard to say, but I would suspect, you know, in a year, there’s going to be even six months, there’s going to be other variants that have more mutations, they’re getting away from immunity a little bit more. And for that reason, I think that we’re going to be in a situation where probably just like with the common cold, Human coronaviruses, the typical person is infected, you know, about every two to three years. Ah, that’s in the absence of any sort of vaccination. So the reason that the common cold Coronavirus is, the reason that people aren’t infected, on average, you know, every month is that because after they’re infected, their body makes an immune response. And that’s able to reduce their chance of getting infected again, until either that immune response wanes, or the viruses evolved to get away from that immune response. And for common cold coronaviruses. This on average takes about three years, although you know, sometimes a person might get infected twice in the same year, and sometimes a person might not get infected for many years. And so for SARS-CoV-2, my guess is we’ll see the same dynamic, the difference could obviously be, you know, people can get that immunity, that reduces their risk of being infected, either from getting infected, which gives you immunity, or from getting vaccinated, which gives you immunity. And as long as the disease burden of SARS-CoV-2 remains high, it’s making people really sick. It’s obviously, probably an advisable thing to get your knee from being vaccinated rather than from being infected. And then obviously, how the impact of all this sort of public health level is going to critically depend on how sick people are getting right. You know, these common Poltrona viruses are infecting the average person every three years or so. But people traditionally don’t worry about it that much, usually at most they get a common cold off. You know, influenza virus infects a typical person and maybe every five years people worry about that a lot as people get pretty sick. And right now, the average disease from SARS-CoV-2 is even higher than influenza virus. So the higher that disease burden is the more sort of public health bonus there is to try to get people that immunity by vaccination, rather than by infection. An open question is as we get further into the future, and more and more people have more and more create system in immunity, will the severity of SARS-CoV-2 remain high, or will the severity become lower? And I don’t think we’ve answered that yet.

Andy Slavitt 

What’s your view based on what you see the things behave.

Jesse Bloom 

I mean, I certainly think that the typical person who gets infected with SARS-CoV-2 and has some preexisting immunity, let’s say from a vaccine, or in some cases from a prior infection is on average going to get less sick than the typical person who gets infected and doesn’t have any immunity. And I think we’ve already seen that off, you know, with good data, right? Like people who’ve been vaccinated, even if they have breakthrough infections, on average, they get less sick than people who weren’t vaccinated in primary infections. That said, sometimes they still get really sick. It doesn’t seem like SARS-CoV-2 even in the presence of prior immunity, has become a common cold at this point, you know, it still remains a significant disease. And that could happen forever. Right? As we discussed, human influenza virus is something that, you know, everybody except for really young children have immunity to at some level, but it still sometimes makes people pretty sick and sick enough that we worry about it as a public health issue. It’s possible SARS-CoV-2 will end up being worse than influenza virus. In that sense, it’s possible or end up being similar. Or, you know, maybe it will end up being milder, but I don’t think we know that answer is fine.

Andy Slavitt  24:02

Well, it’s it seems like from the data I’ve seen most recently, that there’s a possibility that it could actually be worse for people who haven’t been vaccinated and slightly better, or even materially better for people who have been vaccinated.

Jesse Bloom 

Yeah, probably, although I think we still have to be a, you know, cautious about making those sorts of comparisons too much. And the biggest thing being that the population of people who are in general most susceptible to getting really sick from respiratory viruses, which in general are older people at this point, you know, anybody who’s, you know, my age, certainly older than my age has had a lot of prior influenza exposures through vaccinations and infections, you don’t probably, you know, more than 10, you know, if you’re, you know, even if you’ve never gotten the influenza vaccine, if you’re 50 years old, you probably had at least 10 influenza exposures up and so you know, most people haven’t had nearly that many SARS-CoV-2 exposures. So I don’t think we’ve necessarily reached the state of immunity yet. So I think it’s hard to know exactly where that will settle.

Andy Slavitt 

So it makes it, it makes you wonder if there’s a point in time when either the body or science will get ahead, can get ahead of the virus to the point where, you know, this does become something that is at least more predictable, and, you know, more predictable. To be clear, as you’re saying, isn’t necessarily a home run. Right? If we could be in a situation where, you know, once or twice a year, most people are getting SARS-CoV-2, we could be in a situation where 200,000 people in the US every year are dying, and which is a multiple of how many people die from the flu. So, you know, we look at a scenario like that. First of all, does that seem right to you? Does it seem like we are going to have some sort of steady state like that? And if so, you know, there’s both an upside and a downside scenario. From there. The downside scenario from there is that we occasionally get variants, which could do a lot more damage. And of course, the upside from there is that we could have some sort of annual booster regime, or more frequent regime that keeps the keeps that number down, or antivirals or other things like that.

Jesse Bloom  26:31

Yeah, so I certainly think it should be technically feasible. I think it is both this point to make updated SARS-CoV-2 vaccines as new variants arise, and the SARS-CoV-2 vaccines we have now like the current mRNA vaccines, particularly prior to the emergence of Omicron. These were quite effective vaccines. I mean, they weren’t, you know, almost perfect vaccines, I mean, something like the measles vaccine is exceptionally effective. And also measles virus doesn’t really evolve, get away from the immunity. So I mean, that’s sort of like a gold standard, right? If you get the measles vaccine, you’re exceedingly unlikely to ever get measles. You know, the SARS-CoV-2 vaccine wasn’t that good. But it was certainly a lot better than something like the influenza vaccine, in terms of its efficacy, in terms of presenting infection, severe disease. And so I think those vaccines are quite good. And I’m optimistic that if there’s an intelligent process for sort of updating these vaccines as new variants arise, and if there’s sort of good uptake of people taking the new variant vaccines, that it could cut the disease burden a lot, and although it’s always treacherous, to guess numbers, probably since treacherous enough that I shouldn’t even try. I mean, I would be optimistic that this works well, in the sense of both good vaccine updates and good uptake of those vaccines by the public, that the annual disease burden could be, you know, less than numbers like 200,000 that you’re throwing out there. But it’s hard to say for sure, because it’s hard to predict.

Andy Slavitt  28:05

Sure, sure, sure. And I appreciate you even venturing that. Your brave man. So I spent the weekend with Albert Bourla, the CEO of Pfizer, and, you know, they’re about to get data back on the Omicron specific booster that they’re that they’re targeting. You know, one of the things that he said to me was, his concern is that if they find something that’s effective on Omicron, will it likely remain effective against delta? And what I think I understood from talking to him and from David Ho, the famous AIDS researcher, is that prior Omicron infection is not very effective against preventing delta, which we don’t have a ton of experience with our data with. But he’s, he’s pretty certain of that. So that would have been a good fact. Right? If Omicron exposure would protect you also against a variant. So similar, like Delta. But the suggestions that I was hearing were that, you know, you kind of you may be in a situation where you have to pick one or the other or mess around with some sort of by Vaillant. Is that consistent with what you’re hearing or observing?

Jesse Bloom 

Yeah, I mean, so obviously, I don’t think any data on sort of controlled human vaccine trials with […] boosters, if that data exists, it hasn’t been made available yet. But there are data on people who have been infected with Omicron either after having been vaccinated or having Omicron be their primary infection. And essentially to roughly summarize a large number of studies, if you receive the current vaccine, you have pretty good neutralizing antibody titers against Delta. Because delta is somewhat but not dramatically different than the strength of the vaccine. If you’ve just received the current vaccine, your titers against Omicron are not nearly as good as they are against Delta or the strain of the vaccine. You know, if you’ve gotten a booster, they’re still okay. But they’re not nearly as good against Omicron. Because I’m a console app different. Similarly, if you’ve only been infected with Omicron, so you had a primary infection with Omicron, you will have pretty good antibody titers against Omicron, but not so very good neutralizing antibody titers against Delta and the earlier strains. The data that’s out there so far on people who’ve got the current vaccine, and then got a breakthrough infection with Omicron sort of indicates that those individuals, in many cases end up with pretty good neutralizing antibody titers both against the older strain and against Omicron. So certainly, I agree it’s a concern, and that, as long as we’re not sure what’s going to be there in the future, and maybe it’ll be delta rather than Omicron. It wouldn’t be advisable to only have people having been vaccinated with an Omicron vaccine. That said, my guess is at least in the US, if an omen crime specific vaccine is made available, probably most of the people who would take that vaccine are people who have already taken the earlier SARS-CoV-2 vaccine, which gave pretty good antibody titers against Delta. I mean, there’s certainly people who unfortunately haven’t taken the current SARS-CoV-2 vaccines, but I doubt they’re that likely to come take the homographs. So in that sense, I think potentially an Omicron specific booster could make a lot of sense, I certainly also think cocktail, there are reasons that cocktail vaccines could work really well or less. Well, I don’t think there’s the empirical data on that yet. But having a cocktail that consists of something like delta, and Omicron, OT, could also be a good idea to explore. And then obviously, in a, you know, another six months, we’ll probably know, Delta actually go extinct. You know, if Omicron is actually driven Delta to extinction, then an Omicron vaccine clearly makes a lot of sense. But as you’re pointing out, right now, we’re in this uncertainty area where we, we know that Omicron is dominant right now, but we don’t know what’s going to be dominant in six months. So you don’t want to take a strategy, which is going to, you know, you want to take a shot at we’re just going to try to encompass the range of possibilities as much as possible.

Andy Slavitt  32:38

What do you think about that? Is it possible that Delta was wiped out? Or because of what you said earlier about someone with a chronic infection, someone who is immunocompromised? Is it? Is it and because of animal reservoirs, I guess is it is it virtually impossible, that delta is eliminated, and that therefore, delta, you know, we’ll have pockets where it’ll rev up, where it won’t get crushed by Omicron.

Jesse Bloom 

So Delta certainly has not been wiped out. At this point, there’s still Delta infections ongoing. I mean, there are incidence is much lower than Omicron. But there’s still Delta infections ongoing, I think more of the question is what will be the status of Delta and, you know, six months or a year from now, and that’s hard to say so often with other respiratory viruses like flu. You know, in some cases, when a new variant comes through, it will drive the older variants to extinction. Not always, but in some cases. And the reason for that is that there’s enough cross immunity between the strains, that after people get one, they’re also less likely to get the other. So one sort of pushes the other one down. Ah, yeah, that said, I mean, the fact that how Omicron sort of came out of left field thought, which totally I didn’t think anybody really shows that we should be a little bit circumspect about being overly confident about what’s going to happen in the future.

Andy Slavitt 

So the ability to understand how we react to the virus, to some degree, you know, you’ve talked about the antibody titers, and how they react. But to another degree, we’ve all learned about our cellular reaction, which is sort of it to some extent, I think lay people might think of as a failsafe, if you do get infected, that you still have some memory in your in your T-cells. That is what’s responsible for perhaps keeping these future iterations of the virus more mild, that even if you get infected, if you get a bad infection, you’re less likely to end up in the hospital. Because of the T-cell response, does that work the same way against from moving from a Delta to an Omicron and back from an Omicron to a Delta? I mean, if you imagine there’s all these different types of people out there, people have been infected with thermochromic, but that delta people interact with Delta and Omicron. You know, will that do them justice when the next variant comes up? Even if it doesn’t protect them from getting infected? Will it potentially help on the severity?

Jesse Bloom

Yeah, that’s a good and very complicated question.

Andy Slavitt 

I couldn’t even ask it again, if I tried.

Jesse Bloom

I don’t remember the question, but I’ll just give a complex answer here. First, as you were pointing out, there’s, you know, a number of different aspects of the immune response, either vaccination or infection. And those include neutralizing antibodies, which are antibodies that directly block viral infection. They include other antibodies, which might not be neutralizing, but can bind to the virus in certain cases, and help control our replication in various ways. They also include things like T cells, which don’t block infection, but can sort of control infection when it’s ongoing. So something that we as scientists wonder a lot about are, which of these things really sort of protect humans from either getting infected or diseases. And there’s, we often refer to what’s called the correlative protection, which means that like when you make this measurement in the lab, it does a good job of predicting whether someone’s going to get infected or how sick they’re going to get. The reason we call them correlates of protection is it’s hard to know exactly what’s causing the protection. And one of the reasons is, you know, if you get a SARS-CoV-2 vaccine, you make neutralizing antibodies, you make non-neutralizing antibodies, and you make T-cells, right, so you have all of those now, and we can see that the vaccine is reducing your chance of getting infected, and especially reducing your chances of your disease. But it’s hard to figure out which of those three things are causing the protection.

Jesse Bloom  36:36

So for a variety of reasons, some of which are rigorous, some of which are more circumstantial, most scientists think, or at least I think, and probably it’s a fairly widely shared view that in terms of just keeping you from getting infected at all, neutralizing antibodies are probably the most important thing. And certainly, we can see in the evolution of the virus, it’s evolving, especially to escape from neutralizing antibodies, it’s especially getting mutations that help it get away from neutralizing antibodies. But some of these other immune mechanisms are particular the CDA T-cells, but also not neutralizing antibodies. The virus may be getting indications that escape them a little bit, but it’s a much slower process. And part of the reason is that, for instance, CDA T-cells just target lots and lots and lots and lots of different parts of the virus. So unlike for escaping antibodies, where the virus can get, you know, a dozen mutations and escape a lot of the neutralizing antibodies, it’s gonna need an astronomical number of mutations to fully escape all the T cells. And so, probably having things like CDA T cells and non-neutralizing antibodies will reduce disease severity, even people, you know, who are still able to get infected, even viruses mostly escaped into the antibodies. And certainly we’ve seen, you know, empirically, that even when there are breakthrough infections after vaccination, or even infection after a prior infection, on average, the disease severity is lower. And probably T cells are one of the things that contribute to that, although it’s hard to know what all the underlying mechanisms are. But certainly this is one of the reasons that I’m at least optimistic that, you know, as time continues to go forward, SARS-CoV-2 remain, I think most likely a significant human pathogens going to remain a significant threat to public health. But probably, the overall disease burden is going to at least be lower than it was like last year, because you’re going to have many of these immune mechanisms, including things like T-cells, that the virus is not going to totally escape in any short timeframe.

Andy Slavitt  38:36

So you’re saying things probably continue to trend in the right direction although I think we don’t have your personal guarantee. Recognizing that you’re not willing to bet your house on it, which would make people more comfortable, if you were, that situation, I think lends itself to one where, you know, I think, for many, many people, this becomes, you know, a part of the fabric of life, that there’s a very severe virus that they may get occasionally, that they can take steps to protect themselves. They’ll have antivirals available, eventually in a scalable basis. And so the implications are, you know, life goes on life’s events go on. There’s another, there’s another factor out there. But there’s another group of people that I want to ask you about, which are people whose lives might be severely impacted going forward by this presence, people who are frail, elderly, of course, people who have diabetes, or have comorbidities like obesity, people are to whom vaccines don’t work very well because they’re taking drugs that suppress their immune system, people to whom, you know, this is a game changer. This is a more of a social commentary than scientific commentary. And I’m probably not qualified to make either of those things. But you know the population, the majority of the population seems to decide when it’s time to move on from this pandemic, and it’s when most of the people, the majority feel safe. And that it’s time to stop depriving themselves as some fundamental things, including, you know, wearing well-fitting masks and so forth. Where does that sort of leave everybody else? And does that? Does that haunt you to an extent that says that we’re taking people who are on the margins and had to be careful already, and really, just accepting a bad fate for them? And I know, that’s a very different type of question. But I think the implication of this sort of depends on where you sit and what your circumstances are.

Jesse Bloom  40:56

Yeah. I mean, I think that’s a great question, a great point. And I mean, I think one of the things that’s, you know, difficult, but it’s some of the reality of this is that, you know, although we’ve made a lot of progress, compared to, you know, 100 or 200 years ago to controlling infectious diseases, we still can’t control them. I mean, so when you, I mean, and like you pointed out, people in the end, are going to live their lives. I mean, if you look back, 200 years ago, there was smallpox, which killed, you know, more like 10% of the people who got it. And, you know, a lot of people die, you know, a lot of children died from smallpox and other diseases like that. And, you know, fortunately, something like smallpox was able to be eradicated, and many of these other diseases, we got more of a handle on, but I mean, people, you know, live different lives. But in the end, you know, in the end, society was sort of molded around the reality of the diseases that were there. So, when it comes to something like SARS-CoV-2, you know, I think we know, scientifically, the main thing that can, you know, mitigate the effects of the virus is vaccines, and then as you play it out to some degree therapeutics, once people get infected, the other thing that, of course, can mitigate things that is measures to keep people from getting infected in the first place. So, you know, I think we then come to this larger, you know, I mean, so, certainly, a year and a half ago, when vaccines were still being developed, you know, it was clear that there would be this better tool available in, you know, six or nine months, you know, and we had this better tool available at the beginning of 2021, which is vaccines, you know, unfortunately, not everybody availed themselves to the tool, but at least a lot of people avail themselves of the tool. And, you know, at least for people who were had healthy immune systems, were able to at least reduce their personal risk. You know, as you point out, you know, people are and are already, you know, sort of, you know, deciding where they want to calibrate their lives, you know, now that we’re sort of in the stage where these vaccines are fillable. And I think that’s a very difficult question, right, there’s lots of competing, you know, interests. I mean, there’s obviously, you know, he was difficult for, you know, children who were in remote school, and things like that.

Jesse Bloom  43:05

And so that was obviously a real, you know, burden on society. But it’s also very difficult for, you know, people who obviously have, you know, underlying medical conditions that make them especially susceptible to respiratory viruses, and also, people who don’t have any underlying medical conditions and think that they’re fine, not really risk and happen to be unlucky want to get really sick. So all of those are, like really important, or spreads into someone who does. And all of those are like, really difficult situations. And I don’t know the answer to that. I mean, I think it’s unfortunately clear that unlike something like smallpox, where by a coordinated public health effort, it was actually able to be eradicated, or something like measles, where, although unfortunately, hasn’t been eradicated, if there’s a global effect of public health measures that can basically be permanently suppressed by immunity. You know, it doesn’t seem like we’re going to be able to permanently suppress SARS-CoV-2 circulation. And I do think, you know, I think in the end, this is sort of a societal question that has to be asked, but I certainly think there’s some easy measures that can be taken, you know, the easiest one being things like improving ventilation, you know, which is, you know, something that, you know, I mean, there’s plenty of studies that show that if you have, that people are in well ventilated areas, they’re a lot less likely to get infected than or they’re in poorly ventilated areas, and, you know, providing options for people who want to work from home and avoid risks when that is what their jobs but I think it’s a very difficult question, I think. Yeah, I don’t know the answer to that. But I think, unfortunately, the scientific reality of how this virus works and how we have vaccines and therapeutics that help but in the end are not going to be sufficient to eradicate the virus like what happened with smallpox means that it’s going to be have to be answered as a long-term societal question. There’s not going to be a scientific answer. You know, in the way that smallpox vaccine was basically answered scientifically for smallpox.

Andy Slavitt  44:00

At a basic level, I just want people to know that if you think it’s over for you, it’s just over for you. It doesn’t mean it’s over for everybody else. I want to talk a little bit about the work of your lab, Jesse. What types of mutations are you looking out for? What types of mutations are you most worried about that would provide the greatest threat?

Jesse Bloom 

Yeah, so I think, you know, when we study mutations to the virus, we focus on really studying mutations that help the virus escape from antibodies, obviously, as we’ve discussed, there can also be mutations that make the virus more transmissible and Omicron and Delta have had some of those mutations, that’s really hard to understand and predict whether a mutation is going to make the virus more transmissible. So we aren’t even really trying to do that. But what we’re focused on doing is taking a sort of the immunity of given state in times like these are the antibodies that people have now and identify what are the mutations to the virus that will allow it to escape those antibodies, and those are the mutations we have to watch out for in the future. So we don’t think it’s possible to really predict how the virus is going to evolve in a precise way, simply because there’s some inherent randomness, you know, and what mutations happen, you know, if we went back to mid-2020, and played the process all over again, I expect that we would have variants, but they probably wouldn’t be exactly the same variants, because there’s multiple mutations that do the same thing. But we’re really focused on what are identifying those specific mutations that are likely to decrease antibody recognition, so that when mutations are observed, it’s easy to sort of prioritize what they might mean for variants and sort of think about, you know, figuring out whether new antibodies or new vaccines need to be developed. The other thing that we’re very interested in very optimistic about is their, you know, our approaches that are being developed, whether any of them will work, and it’s hard to say but there are certainly hopes of developing even better Coronavirus vaccines that might elicit somewhat broader immunity that would stand up a little bit better to this evolution and variants that we know is going on. So my lab is not personally sort of in the business of trying to make improve Coronavirus vaccines, but we are very interested in sort of evaluating how well these might work when they are developed. So one of the things we’ve been doing is taking serum and antibodies are elicited by different types of infections in vaccinations and really trying to see what are the mutations that escaped from these different types of antibodies. And hopefully, that can allow an informed choice of strategies that will induce antibody responses that it will be harder and slower for the virus to escape from.

Andy Slavitt 

So you guys have developed something I think, called an escape calculator. What is that?

Jesse Bloom 

really what we’ve mostly done is done something called a mutational scanner. So that’s just an experiment.

Andy Slavitt 

I do that at home, too, by the way, it’s one of my hobbies.

Jesse Bloom 

So the way that the mutational scanning works is we take a given viral strain, and we just asked that he made all the different mutations to it. How much would each of these mutations escape binding by individual antibodies. So we can measure that really precisely. Now, the challenges when it comes to applying this data is that when you get a new variant like Omicron, it doesn’t just have one mutation, a lot of mutations. And although we now have experimental approaches, we can look at the effects of all the individual mutations, the number of combinations mutations is just astronomical.

Andy Slavitt  48:29

Does the new iPhone have an app that you can just  plug it in and it just calculates all the different permutations for you?

Jesse Bloom

Yeah, well, you can calculate how many different permutations there are, but you’ll get a number that’s your iPhone can’t handle it. It’s actually kind of amazing. So when you think of something like the SARS-CoV-2 spite, there’s about 1000 amino acids there, you can mutate each one to 19 other things, there’s about 20,000, single amino acid mutations, you can make the spite. And so that’s sort of a manageable number. But once you make two mutations, it’s essentially 20,000 squared. Once you make three mutations, it’s 20,000 to the third, and these numbers quickly, just become astronomically large. So for that reason, you can’t look at all the combinations of mutations. So the escape calculator is basically a tool we came up with, which just says, given the effects of these individual mutations, how do we think they’re going to add up, and we can do that because we know which types of antibodies are escaped by each mutation. So there are certain mutations the SARS-CoV-2 spite, like a mutation at position 484 any mutation at position 490, which tend to escape the same types of antibodies. So the virus, from its perspective doesn’t really need both of those mutations, you know, gets one of them and escape those antibodies. But there’s other positions in the spine that say like 417, which are targeted by different antibodies than the ones that target 484. So if the virus has mutation at 484, and 417, which is the case for Omicron. It’s going to get away from more of these antibodies. And so the escape calculator is basically just taking these experimental data and that logic and trying to figure out what will be the effects of combinations of mutations.

Andy Slavitt 

Got it. So what does it tell you about the likelihood of just called a really significant variant of concern? The kinds of things like how frequently does the calculator tell us that there’s gonna be, there’s a really concerning combination?

Jesse Bloom  50:26

Yeah, no, that’s a great question. And, and again, I think this comes back to the limitation of what we can do, and that, I think the type of work that we and many other scientists in the field are doing is basically interpreting what the viruses evolution means. So what when the virus gets some combination of mutations, we can use various approaches, including this escape calculator, just sort of figure out what those mutations are going to do. We can’t use it to figure out what mutations the virus is actually got to make. And so that’s why I think it’s really important to understand that a lot of this in viral evolution are working on interpretation, then prediction.

Andy Slavitt 

So that when there is a variant, you’ll be able to do a quick analysis and say, this has the potential to increase immune escape that sort of thing.

Jesse Bloom

Yeah, exactly. And I also would hope that when people are updating vaccines, we could use this to sort of evaluate all of the variants out there, including the ones that are very low frequency, and figure out sort of how much immune escape they’re likely to have, because those are the ones to watch out for in the future. That said, we can’t really predict what exactly it’s going to actually rice in the future. But we can say, from the types of approaches we’ve done so far, you know, that there’s still a lot of mutations, and there’s probably always going to be a lot of mutations, you can make the spike, it’s going to reduce antibody recognition. And that’s why, you know, I think, unfortunately, the […] evolution is going to be an ongoing process that we sort of are going to have to deal with, ah, you know, for the rest of our lives on providing there’s not some substantial breakthrough in vaccine technology that you know, makes vaccines elicit, you know, much better antibodies we’re already getting, but I am very optimistic about some of the new vaccine platforms, particularly the mRNA vaccine platforms, because, you know, one of the things that, you know, is probably obvious to me and obvious to you, but may not be obvious to people who are just taking these vaccines, is the mRNA vaccine has really simplified the process of going from saying, This is what I would like to make a vaccine against, and making that vaccine, right, it’s really sped up that process. So I think to the extent that we can track the evolution of the virus, and identify potentially concerning new mutations, we have the potential to sort of get them in vaccines and update vaccines a lot faster. And in my view, an important thing to be thought about in a public health level, is how do we maximize the flexibility and potential for speed in the mRNA vaccine technology platform, which really exceeds that potential for, you know, anything we’ve seen, for current vaccines? We’re using it? So I think there’s probably going to need to be a lot of thought in, you know, what are the right regulatory and decision-making processes to, you know, to sort of maximize that potential of sort of responding rapidly to viral evolution with vaccines.

Andy Slavitt 

Right. Well, it’s funny, I was gonna ask you as a sort of final question. Is there any way that science as it understands the way this virus changes, can outsmart evolution? And I think that’s partially an answer is having a platform like mRNA, that allows you to very quickly evolve science? You know, doesn’t quite stay ahead, but at least it responds rapidly. But are there other any other things you see that the discovery of how this evolves, and would tell you that there are scientific areas we should be, could be hunting in, that will allow us to create something whether it’s a vaccine or antiviral, or some other breakthrough that really mitigates the potential or power of this kind of ever evolving, shapeshifting, enemy we have?

Jesse Bloom  54:20

So as far as antivirals, I think, those are really promising. I It’s not my core area of scientific expertise. So I’m not gonna try to comment on that.

Andy Slavitt 

It doesn’t stop everyone else from talking.

Jesse Bloom 

I think antivirals are important and promising, but I don’t feel like I’m the right expert to comment on that. As far as vaccines. The other thing that I think should really be pushed on is sort of cocktail vaccines. So that potential, you know, we talked about how it’s hard to predict what’s going to happen in the future. On the other hand, if you didn’t just need to make one guess you can make 10 or 20 guesses, you could maybe kind of cover the likely evolutionary space. From a basic science standpoint, there are theoretical reasons you can imagine that a cocktail vaccine just sort of mixed together, many variants could work really well, and also come with theoretical reasons why it might not work. So well. I think it’s just going to require testing to know exactly how well those approaches work. But I think in addition to speed of vaccine updates, the ability to sort of use new platforms, which include mRNA platforms, but also things like nanoparticle platforms to make sort of multivalent vaccines is something that should really be explored.

Andy Slavitt

Well, look, we really appreciate you coming in the bubble and educating all of us, Jesse, this is a world that I think people want to make sense of. It’s interesting, I happen to think that the deep, deepest burden that many people feel is the burden of uncertainty, the burden of not knowing what will come next, that does weigh on people. And I think it also causes some people to say, I’m out, I’m done, there’s too much uncertainty, I’m just going to not think about this thing any longer. All of which, by the way, are very human type of responses. But your work, I think, at predicting how this could evolve, will evolve, I think is going to be one of the critical tools to helping us understand what we’re dealing with. And even if that thing that we’re dealing with is something that evolves, if we’re able to bracket it into, sort of, it’s probably going to be between A and B and our tools are probably going to, you know, need to be able to evolve or the following types of people are going to really have to watch out for and be at risk and make sure science works for that I think is probably some part of the next step of what we’re going to be after here.

Jesse Bloom  56:34

I also think you’re playing a really important role and sort of bridging these two worlds here so I really appreciate that.

Andy Slavitt

On Wednesday, we’re going to talk with David Frum, about the war in the Ukraine, and the attack from Russia and our global response. Then, next week, we’re gonna be talking with Congressman Ro Khanna about things that are shaping society and about essentially the forces that are shaping our ability to live and prosper in an age of technology. With all the things going on. ROE is a congressman in the state of California. Very interesting, enjoyable guy. Okay. We’ll talk to you on Wednesday. Thank you for being with us today.


Thanks for listening to IN THE BUBBLE. Hope you rate us highly. We’re a production of Lemonada Media. Kryssy Pease and Alex McOwen produced the show. Our mix is by Ivan Kuraev and Veronica Rodriguez. Jessica Cordova Kramer and Stephanie Wittels Wachs are the executive producers of the show, we love them dearly. Our theme was composed by Dan Molad and Oliver Hill, and additional music by Ivan Kuraev. You can find out more about our show on social media at @LemonadaMedia. And you can find me at @ASlavitt on Twitter or at @AndySlavitt on Instagram. If you like what you heard today, please tell your friends and please stay safe, share some joy and we will definitely get through this together.

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