COVID-19 Immunity With Professor Shane Crotty

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    Shane Crotty, PhD is a renowned virologist and immunologist whose research on immunological memory published in the prestigious journal, Science, was cited in a recent heated discussion between Dr. Anthony Fauci and Senator Rand Paul. He returns to MedCram to answer and explore the complexities of questions surrounding natural immunity, vaccination, COVID-19, and more.


    Professor Crotty is a Professor at the La Jolla Institute for Immunology, Center for Infectious Disease and Vaccine Research. In this video, he talks about levels of protection and immunity for the three main categories of individuals:

              A. Those  have had COVID-19 and recovered,

              B. Those who have been vaccinated, and

              C. Those who have had neither A nor B. 


    Dr. Crotty explains important nuances of this type of research — laboratory measurements and population-based studies — as well as likelihood of reinfection, transmission, and hospitalization, current public health recommendations, and what the future could look like for vaccines and variants. 


    Watch the full interview here, or read through the transcript below. 


    For more information on these subjects, revisit Professor Crotty’s previous MedCram discussions on a vaccine deep dive and coronavirus mutations and COVID-19 vaccine implications.


    Lastly, you can read more about Professor Crotty’s work here, and follow him on Twitter here




    How Long Does Immunity Last for Those Who’ve Had COVID-19?


    Kyle Allred, MedCram Co-Founder & Producer: Professor Crotty, thank you for coming back to the show to address some of the most important and frequently asked questions about COVID-19. In previous discussions, you talked a lot about immune memory, how well your body remembers viruses that we’ve been exposed to. And anyone watching this video essentially falls under one of three categories: you already had COVID-19, been fully vaccinated, or you’ve had neither. 


    So I’m looking forward to hearing your interpretation of the current data and what we know about each of these categories. How long will immunity last? Will it hold up to the variants? And perhaps, most important, what do answers mean for policy decisions and prevention strategies, like physical distancing, opening businesses, and mask-wearing, which was highlighted in a recent heated exchange between Senator Rand Paul and Dr. Fauci, both of whom cited your work, Professor, that was recently published in the journal, Science. We’ll try to cover all of those things, but I want to start with this graphic. So, group A, people who’ve had and recovered from COVID-19, what do we know about their immunity to the virus?


    Professor Shane Crotty: The executive summary is we know that those people have measurable immunity and there are essentially two categories of studies for measuring that. One is the type of study that we do, which is laboratory measurements, and the other type of study is population based studies of trying to measure who gets sick again. And so, there’s data from both of those types of measurements that there’s substantial immunity for at least six months after somebody’s had COVID-19 on average. And we can get into that “on average” caveat. 


    There’s no simple measurement of immunity that works for all viruses. The immune system’s complicated; the immune system has to control different viruses in different ways, and so we’re still learning how the immune system protects you against this disease, and so what we and others have done have collected data in, again, two different categories. So the one that we did was laboratory measurement, so saying OK, let’s take our group and Alex Sette’s group upstairs and Daniela Weiskopf’s, so the three of us who are faculty at LJI, we said, “alright, let’s take a group of people who have recovered from COVID-19 and ask, ‘do they have immune memory,’ right?” And so, immune memory is a lot like brain memory; it’s something your body does to remember something it’s experienced in the past, and we were starting from a perspective of people being worried, “is there memory at all against this virus, right?” And so context matters, so we said OK, we’ll gather together about 200 people who have had this disease and ask if their immune system did in fact remember it. And we did that over an eight-month period of time, because time matters. 


    How Antibody Levels and T Cells Drop Over Time


    So, for lots of infections, people’s memory of the infection fades some over time. So whether we measured antibodies or other parts of the immune system, the memory details and the various details, on average, people had, what we considered, a significant amount of memory to this virus. And what we could do is measure over time what happened to that memory, right? And so, the memory does drop over time, but it was a relatively slow drop over time. So between the time of infection and eight months, we considered it a reasonable drop, pretty normal compared to other infections. And so, all together, from those data — those are laboratory measurements, which Tony Fauci brought up in that discussion.


    Dr. Fauci: Difference Between In Vitro and Real-World Studies


    [Clip of Dr. Fauci] 


    Dr. Fauci: OK, the studies that you quote from Crotty and Sette look at in vitro examination of memory immunity, which in their paper they specifically say “this study does not necessarily pertain to the actual protection. It’s in vitro.”


    [Back to MedCram Interview with Kyle Allred and Professor Crotty]


    Professor Crotty: What we can do with those laboratory measurements is make some inferences, but they don’t directly show protection. But they provide us some other useful things, right, about which parts of the immune system and sort of the change over time. 


    Population-Based Studies About COVID-19 Immunity Against Reinfection


    The complementary set of studies are population-based studies and say, OK, let’s take a large group of people who have had COVID-19 and ask, “do they get infected with the virus again?” And if they do get infected with the virus again, do they get symptomatic infection, or is it just a small asymptomatic infection? And there have now been a number of good studies like that. One that was in the discussion was a UK study that was published in the New England Journal of Medicine, a very good study, that showed very little reinfection after six months. 


    There was a much larger UK study of nurses that saw somewhere between, I think, like 83 percent and 90-something percent protection from reinfection, depending on the exact definition. There was a big study in Qatar and a recent study in Denmark. That’s the largest study involving millions of recorded events and, again, over something like a six-month period of time, which also showed substantial protection against reinfection, but not perfect protection from reinfection. And I think the most interesting thing, the Denmark study now adds, in the past two weeks, is that people over 65 were at greater risk of reinfection than people under the age of 65, and so that’s the other kind of thing you can only see if you have very large numbers of people that you can look at the data for. And so that’s truly where we are now with our understanding of protection generated by having been infected with COVID-19. 


    Huge Variability From Person to Person for Post-Coronavirus Immunity


    The nuance to that is that actually people who have been infected with COVID-19, their immune memory is very heterogeneous. There’s a lot of differences from person to person. And so we noted that; other studies noted that, where if you look at the data in our paper, whether you look at the antibody measure or the B cells or the different kinds of T cells, there’s about a hundred-fold range between any two people at, sort of, opposite ends of the scale. So, that’s a big difference, right? 


    So we can say, yes, overall, the vast majority of people have measurable memory, and it looks like decent memory. But if you look at specific individuals, there are big differences and a hundred-fold differences, and as I said, we don’t know what exactly is needed to protect against this virus. But certainly, a hundred-fold difference is big, right. If you were playing a basketball game, right, and one team scored one point and the other team scored a hundred points, that’s not very close. There’s a difference there that you should pay attention to. 


    Immunology’s not a basketball game, but still that’s a large difference, and we don’t know how to interpret those details. And so, in fact, we said it’s plausible that people at the low end of that are more susceptible to reinfection, because it looks like they might have a lot less immunity than some other people. And, unfortunately, there’s no simple way to predict which person is which. So we can say, at a population level, yeah, most people have measurable immune memory. But some people — something like five percent of people — are really at the low end. So are those people at greatest risk? 


    Policy Decision: Individual vs. Community Goals During a Pandemic


    And so that’s where the immunology is. If you put on your hat as an individual, or if you put on your hat as a public health professional, right, you’re gonna view those data in some different way, right? So, at an individual level, one end of the spectrum would be, “I myself am comfortable getting infected; I don’t mind if I get infected, I don’t mind if I get sick, but I really don’t want to end up in the hospital.” That would be maybe one end of the spectrum of a person’s level of comfort. 


    Very Rare for Hospitalization From COVID-19 Reinfection


    You know, how protected can I expect that I am having already had COVID-19? It’s quite rare for somebody who has previously had COVID-19 to end up hospitalized. The numbers are so low, we can’t even get good numbers still at this point, I think, is what it is. But that, you probably want to warn that person that even a non-hospitalized infection can be pretty serious, right? Long COVID issues have been present in people who don’t get hospitalized. 


    Avoiding COVID-19 Infection and Transmission Potential


    And I’d say, another end of the spectrum would be somebody saying, “no, I don’t want to get sick at all,” either because of the age category that they’re in, right, or underlying conditions, or just that they don’t want to get infected and be passing it on to other people,” right? Whether or not they themselves will be healthy, they don’t want to risk their parent or grandparent or neighbor, right, getting infected by them. So they really want — don’t want to change their behavior, unless they have a very high level of protection. 


    Should Mask-Wearing Continue for Those Who’ve Had COVID-19?


    Would people who have previously had COVID-19 get infected enough to transmit to other people? There just haven’t been studies that would measure that. And so, continuing to where a mask and do social distancing is very much what we would recommend to that one person. But, of course, the United States has 350 million people, so you can’t go and make 350 million individual recommendations, right? So if you put on your public health hat, what’s the recommendation that you give? And given that there is such heterogeneity from person to person who’s had COVID-19, some of them have a lot of immunity and some of them don’t have much immunity, so some of them — there’s definitely data that some of them can get infected again. Again, almost all of them are asymptomatic, but can get infected again. 


    And can some of those people transmit? Well, yeah, there’s at least some concern of that, so that’s why the public health recommendations have generally been, people who’ve had COVID should continue to behave as if they haven’t, as well as they should get the vaccine, and maybe we can come back to the vaccine after we talk about the vaccine in general. I will also say, obviously public health officials — which I am not, right? I’m a scientist and immunologist; I measure the immune responses to vaccines and interpret them, but if you are a public health official, you also have to deal with the realities of implementing a policy, right? And one of the problems with policies surrounding people who have had COVID-19 is that there’s no stamp that says “I’ve had COVID-19 and you haven’t.” There’s no consistent definition of that.


    If I’ve Had COVID-19, Shouldn’t My Vaccine Dose Go to Someone Else?


    Kyle: A question a lot of people have at this point is if I’ve already had COVID-19 and there’s data that shows that I have likely strong immunity for 6-8 months to it, why would we waste a precious vaccine dose with a limited supply at this time on someone who’s had an infection. Shouldn’t we spread those vaccines around to people that haven’t had COVID-19 and then maybe consider coming back later to the people who have had COVID-19 and get them vaccinated at a later time? Yeah, what do you think about those questions that people have?


    Professor Crotty: Yeah, those are great questions. The quick answer is most people who’ve had COVID-19 have immunity or for a significant period of time, but there’s a lot of variation between people and that’s that hundred-fold range I was talking about, right? Because of that, some of those people don’t have much immunity, and so that’s point one. And point number two is, if you take a look at the vaccines, the vaccines are eliciting even more immunity than natural infection, OK? And so if you put those two things together, those two pieces of immunological data, as well as the protective immunity data, that’s generally led to this public health recommendation of you should still get vaccinated. We can go into the details of that. 


    Is Natural Immunity Better Than a Vaccine?


    And a backdrop to some of that is the argument that “well, natural immunity is always better, right, than vaccines, so let’s go with natural immunity” and that’s incorrect. There are definitely a range of infections that natural immunity isn’t very good and vaccines can do better. Papilloma virus is the most dramatic example where people really don’t develop immunity to HPV, which can lead to that virus causing fatal cancers in people. And instead, the vaccine gives 99.9 percent protective immunity very quickly. There’s a night and day difference between natural immunity and the vaccine with the vaccine being dramatically better. 


    And in fact, the reference point for this novel coronavirus was: well wait, do people develop immunity at all? Do people develop immune memory at all, right? And that’s the way we approached the problem when we were measuring immune memory in people and from that context, we said actually people make a substantial amount of immune memory; there’s definitely a real response there. It’s not a fantastic response, OK? People who’ve had COVID-19 don’t have an amazing immune response to the virus. It’s not super high in neutralizing antibodies; it’s not super high in anything. But it’s decent, and also that this virus doesn’t generally — it’s not that hard of a virus to stop. So for some things, you just have to have a huge amount of immunity, a huge amount of antibody and T cells to be able to stop a virus. 


    This virus generally doesn’t take that much to stop, and so in that context, people who have had COVID-19 have a decent amount of immunity, is the way that we would really phrase that, and I think that’s the way we’ve phrased it at the time. And I think, thankfully, that’s been enough immunity, right. To provide a significant amount of protection to those people for a substantial period of time. But, you know, compare that to the vaccines and both the Pfizer and Moderna vaccine elicit higher neutralizing antibody titers than the natural infection and they elicit decent T cell responses and the Novavax vaccine elicits far higher neutralizing antibody titers than the natural immunity normally does. And so all the other vaccines fit in that mix as well. 


    And then, what you combine with that is this variability issue, right, that I mentioned. With natural infection, you’ve got people with this hundred-fold range between people of different immune responses and you don’t know who is low and who is high. Really, one of the wonderful things about vaccines is everybody gets the same dose in a vaccine, right. And people tend to make quite a consistent immune response to the vaccine, and so we know from the early clinical trial data and from the information coming from the phase three clinical trials that people who get these vaccines, everybody’s making an antibody response — and a consistent antibody response, right — and so that’s where you want to be that you know everybody’s in the same range of protective immunity and you’re basically not leaving people behind. 


    And so, from a public health perspective, it’s both the magnitude of immunity that the vaccines get and the consistency of immunity that the vaccines get that leads the recommendation that even if you’ve had COVID before, you should still get vaccinated, so that we know that, again, if it was sort of a green-yellow-red range, then we go “OK, everybody who gets vaccinated is in the green range, but some of the people who’ve had COVID-19 are in the yellow or red range, so we want to bring everybody up to be in that green range.” That’s the public health perspective, looking at people as a population, right, the whole group of people and trying to make sure that nobody’s left behind. 


    Well, shouldn’t you still kind of vaccinate everybody else first? You know, if you do a risk stratification of everybody in the United States, shouldn’t the people who’ve had COVID-19 before, shouldn’t they be at the back of the line? And there’s a totally reasonable argument for that, and if that was public health policy, I would have no qualms with that decision. I think that largely comes into the problem of being realistic, right, about what you can implement and what you can’t. So that goes into that initial topic of, well, how do you define who’s had COVID and who hasn’t? Does asymptomatic count? Right? 


    So instead of getting into all the complexity of that, the decision has been to treat them like everybody else, which is a reasonable decision, I think. I think a lot of the places that have done pretty well with their vaccine rollouts have been to be relatively inclusive about their definition of who should be vaccinated, so that you’re just making sure that you’re vaccinating people as quickly as possible. So, from a public health perspective, you’re not putting too many barriers between people getting that appointment and showing up. 


    If You’ve Had COVID-19, Should You Get Vaccinated? Both doses?


    If you’ve had COVID before, when should you get vaccinated? And how many doses should you get? And that remains an active topic of conversation. Scientifically, there are, I think, five studies out now specifically looking at vaccinating people who’ve had COVID before, and after one dose of an RNA vaccine — Pfizer or Moderna — people who have had COVID before make a fantastic immune response. Their antibody titers are way, way, way above everybody else’s and their T cell responses jump a lot as well. 


    And so, actually, if I had had COVID-19 before, I would definitely be going to get the vaccine, because that’s probably a level of immunity that’s gonna be really good for quite a while. It’s literally, like, 50 times higher antibody levels than other people. And it also looks like those antibodies work against variants better than otherwise, which we can come back to as well. So, it looks like there’s very good reason for people to get at least one dose of vaccine, and exactly when to get it is, I think, something to talk to your own doctor about. Because I think there are variables there depending on your age and your underlying conditions and how serious was your first infection and how long has it been since your first infection? The simple recommendation that’s being made is to get vaccinated three months after you’ve had COVID-19.


    Kyle: So you mentioned that if you’ve had COVID-19 and you get at least one dose of a vaccine that it’s almost like getting a super booster in a way, that your protective antibody levels really jump high. T cell levels jump. 


    And I want to show a chart that you sketched and posted to your Twitter account. I’m a very visual person, so it helped me conceptualize how these variants can change the game, to some degree with what we know about protective immunity. This chart shows a certain level of protective antibodies and immunity, and how it just naturally declines over time. A couple things, if you could kind of explain this chart and what it is. And secondly, you mentioned getting one dose of a vaccine if you’ve already had COVID-19. Do we have any data about two doses boosting those levels even further? And what’s your recommendation there?


    Professor Crotty: Scientifically, between the several studies that are out, it doesn’t look like there’s a big difference between the one dose and the two dose, for people who’ve already had COVID-19. And some of those individuals have reported larger side effects after the one dose, which is probably related to the fact that they’re making a really big immune response. 


    So that’s where some of the discussion is, is “OK, the current recommendation is that people still get the two doses,” and people are discussing — or there have been comments in some of these scientific papers — that perhaps one dose would make more sense, since people are already, after one dose, they make such a big immune response and they are having side effects from that. You know, just like fever and feeling really lousy for a day or two. That one dose could suffice. And I’d say right now there are difference of opinions there. Essentially that you’d really have to do a clinical trial to directly show that to actually change the public health information. So that’s what the information is. Like a lot of information we have, it’s partial and it can point a couple different directions depending on your comfort levels. 


    If I’ve Had COVID-19, Can I Stop Wearing a Mask?


    For the variants, the variants do have a lot of implications for thinking about immunity and protection and going back to these big picture questions that we asked at the beginning and saying, “well, I’ve had COVID-19, I’m immune now, right?” “Well, I’ve been vaccinated, I’m immune now, right?” “Why don’t I just totally change my behavior?” And one of Fauci’s primary comments there was “variants, we have to worry about variants.”


    [Clip of Sen. Rand Paul and Dr. Fauci] 


    Sen. Paul: And what study can you point to that shows significant reinfection? There are no studies that show significant reinfection.


    Dr. Fauci: Just let me finish the response to your question, if you please. The other thing is that when you talk about reinfection and you don’t keep in the concept of variants, that’s an entirely different ballgame. That’s a good reason for a mask. In the South African study conducted by J&J, they found that people who are infected with the wild typed and were exposed to the variant in South Africa, the 351, it was as if they had never been infected before. They had no protection. So when you talk about reinfection, you’ve got to make sure you’re talking about wild type. I agree with you that you very likely would have protection from wild type for at least six months if you’re infected, but we in our country now have variants…


    [Back to MedCram Interview with Kyle Allred and Professor Crotty]


    Professor Crotty: And I think that’s right, and a lot of us are thinking along the same lines, which is for a lot of variants, there’s no problem at all. You look at the laboratory measurements of immunity or you look at the way the variants are behaving in a population to get the real world data, and a lot of the variants aren’t a concern. The vaccines are gonna work fine against those. 


    Variants of Concern and How the Vaccines Fare Against Them


    But, there are several variants that have come along that are of concern, and I tend to put them in two categories. One is the UK variant, the B.1.1.7, and the variant first identified in South Africa, B.1.351, or variants similar to that immunologically, because they do kind of fall into those two different banks. 


    For the UK variant, the quick answer is, the RNA vaccines work completely fine against that variant, and the expectation is — speaking specifically to the US population — the J&J vaccine will be fine against that variant. And we know the Novavax vaccine is good against that variant, because it got tested in the UK. And so, that variant is a concern because it spreads so much better than the original virus. It looks like it probably replicates faster and replicates more in your upper respiratory tract, and it transmits a lot more efficiently to other people than the original virus. 


    So that’s a problem, because you want to talk about surges. When that variant starts spreading in the UK, there was an incredible surge. And then it got going in Ireland, and it was an incredible surge. And in several other countries, that’s occurred. It spreads like wildfire, right. So it’s a much tougher virus to stop. And obviously, simply by having more cases, you then have more deaths. It is a virus that is at least as virulent as the original virus, so by having more cases, you do have more hospitalizations and deaths. 


    Again, we know from both lab experiments and real-world data that the vaccines work against that variant at preventing disease and at preventing most cases, so having a very reliable impact on transmissions. And so in the US, that variant is the immediate concern to a lot of us, because it’s proven that it can spread like wildfire through a population. And it’s definitely in the US and it’s been increasing in frequency in many states in the US. And so a lot of what’s been going on between January and now has been a race between how many people can you vaccinate and how fast is that UK variant spreading in the US, and then the changing of the seasons. And trying to get people to follow the public health recommendations of wearing masks and having social distancing to reduce the spread. If you have a virus like that, that is more transmissible, it becomes all the more important to wear the mask to minimize the amount of that virus that gets spread. 


    That’s also pretty specifically the virus that led to the recommendations about double masking, to say “well yeah, that virus is so much more transmissible, it really is hard to stop in a population. What are the public health measures you can do?” And really, wearing a mask is one of the simplest ones. Wearing masks is very effective at preventing transmission, particularly, if you are infected, keeping it from spreading to other people. And again, that particular variant, it’s very good at spreading That’s its superpower, you know. That’s what you really have to worry about with that one. Longer term, a lot of us are worried about the other variants more — the South Africa variant and one similar to it — because, immunologically, those variants are definitely escaping immunity to some measurable degree. And how much they’re escaping immunity depends on the study and depends on what you’re looking at. 


    But, to look specifically at vaccines, the clearest data was that with the AstraZeneca adenoviral vaccine, that vaccine worked really well in the UK at stopping the regular strain of this novel coronavirus, somewhere between 75% and 85% efficacy. And it also worked in South Africa. But then, as this new variant emerged in South Africa — this South Africa variant — it actually emerged in the same window of time that the vaccine trial was going on for the AstraZeneca vaccine, and so they could look at how protective the vaccine was against the main strain and against this variant. And it essentially lost — it didn’t protect against cases. So it’s possible it still protects against severe disease, but the basic measurement of stopping cases of COVID, it no longer worked. 


    And when, really quite good labs in South Africa measured the neutralizing antibody responses, they saw that the vaccine elicited good neutralizing antibodies against the original strain, but very poor neutralizing antibodies against the variant, OK? Against the South Africa variant. And so, that’s what’s really set off a lot of alarm bells. So some people have taken the perspective of saying “well look, isn’t it all about hospitalizations and deaths, right? We really want to prevent those things from happening. And then, well, then everything can go back to normal.” 


    This is one perspective some people have, and it’s absolutely true that the top level concern for vaccine success is preventing deaths and hospitalization. It’s hard to get those numbers, because it takes really big trials to get those numbers. But, additionally, it’s important to layer onto that transmission. Most of these vaccines are doing a fantastic job, not only at preventing hospitalizations and death, but also just preventing cases, period. And preventing asymptomatic cases. 


    So, those vaccines against the regular strain are going to be doing a great job at preventing total cases and preventing transmission. So they’re going to reduce spread of the virus in the community, and that’s what you really want, to try and shut down the pandemic or the spread in individual states. And we know that vaccines against this virus can be good enough to do that. So it looks like for that vaccine and for that variant, right, for the AstrzZeneca vaccine and the South Africa variant, it’s not doing that any more. So then, what do you do about that? 


    We don’t know for sure how the RNA vaccines are doing against that variant. There are reasons to think that the Moderna and Pfizer vaccines will do better against that variant than the AstraZeneca, but there’s no data, there’s no real world data to show that. And so, as a result, then to really have to behave with caution in this area, which is that “OK, we know that that variant, the South Africa variant, is in the United States now, and we know that it’s worrisome for immunity, because again, with the AstraZeneca vaccine in South Africa, immunity was completely lost against getting infected at all and presumably transmission. 


    So then what you really want to do is do your best to minimize the spread of that variant. At the moment, there are very few people in the US who have that variant. You want to keep it that way as much as possible, right, while finding out along the way, how do other vaccines do against that variant? 


    Will We Need Updated Coronavirus Vaccines?


    And, essentially, your worst case scenario that you need to be preparing for is that other vaccines will have the same experience — well, several of the other vaccines — will have the same experience as the AstraZeneca vaccine and have a loss of efficacy. And so, then you need an updated vaccine to be able to protect against that variant. OK, so if you’re running that hypothetical scenario, that means you have to buy yourself time for that vaccine to be developed. 


    And we know that the South African variant is in the US right now, so yeah, it very much makes sense to recommend that even if people have been vaccinated with Pfizer and Moderna vaccines, we don’t know how well they protect against that variant or prevent transmission of it, so yes, please continue to wear a mask and continue to have public health measures so we don’t have a surge or explosion of these more problematic variants. The somewhat flipside of that is to say, “OK, the J&J vaccine, the one-dose J&J adeno[virus] vaccine was tested in the US, the UK, and in South Africa. 


    And between the US and South Africa, it only had a drop in efficacy of 72% to 64% for cases. That’s actually a very small drop, so that vaccine seems to be doing pretty well against the South African variant. So, it’s not that there’s something impossible about that variant. Your immune system can recognize it, you can get protective immunity against it, so that’s a good sign. We have data that that happens, and in fact the Novavax vaccine was tested in the UK and South Africa and it still had 60% efficacy in South Africa, so that’s a second vaccine that has at least some efficacy against that virus. 


    But we don’t know how well they do against spread, and as I said, we know that vaccines can be really good against novel coronavirus, and so that’s the bar to try and reach for and to save as many lives as possible, right? Keep us from ending up on a merry-go-round as well of variants. One of the other things people have pointed out, right, is obviously, the fewer the cases you have — variants occur, essentially, stochastically because of the number of cases — so the fewer cases you have, the less likely it is that some new variant can come up that is even more problematic. 


    So we’d all love for this to be over as quickly as possible and get back to normal as quickly as possible, and yeah, the best chance for that to happen is to minimize, is to keep minimizing spread and certainly minimize spread of the variants we know about to give the vaccines the best chance to control them. 


    Coronavirus Antibodies vs T Cells and Other Parts of the Immune System


    The scenario that I sketched — and I said, think of this as written in crayon, because we really don’t have as much data as we would like — is that antibodies are really good at preventing infections. So if you have a high level of neutralizing antibodies, you can probably stop the infection from ever even starting in your nose, right. So the virus affects your nose, your upper respiratory tract, but if the antibodies don’t recognize the variant any more or recognize it quite poorly, you still get infected as a simple model. 


    So now that you’re infected, now what happens? Are there other things your immune system can do to stop this virus? And I think it’s really helpful to think of this viral infection as occurring in two stages, and one is the replication in the nose, in the nasal passages, and and the other is the pneumonia, the replication in your lungs. And it’s really that replication in your lungs that’s the big worry. And that’s the big health problem. It’s that pneumonia that can lead to serious breathing problems and requirement for hospitalization. 


    And one of the things about this particular virus is that it replicates really fast in your nose. And that’s one of the big problems with this virus in terms of controlling it is that there’s a lot of pre-symptomatic spread before they even know they’re infected. Well, they don’t know they’re infected because they’re not showing any symptoms, and that’s happening because the virus is replicating so fast in people and so secretly — it’s hiding from the immune system well enough that there are no symptoms. 


    So it’s very hard to stop that replication in your nasal passages because it does happen very quickly and can result in spread quite quickly, like say within four days of the infection. But the serious part of the disease in the lungs happens much more slowly, and in fact, the median time to death is probably something like 25 days post-infection. Even one day is a lot of time for the immune system to make a response. So there’s actually a lot of time for your immune system — even if your immune system can’t control the virus in your nose quickly — it still has a lot of chances to control the virus, prevent the virus from getting into your lungs or control it pretty quickly in the lungs, so that you have a mild case or you end up with a non hospitalized case of the disease. Even if you don’t have enough antibodies to stop the infection, so you still have enough T cell and memory B cells and antibodies to still respond within a few days to control the infection. 


    I think the data indicates that’s probably happening and is probably a good explanation for why some vaccines work even if the antibodies aren’t very good any more. But we do still really need data on that, which is why it’s in crayon. So that’s talking about the vaccine. To shift from that to talking about people who have natural immunity, it’s a similar story: it depends on what neutralizing antibody assay you look at and what data you look at. 


    But if you look at the data from the labs in South Africa, which is where they could really see comparisons of biological relevance, right. They could see, well these people are getting infected or not getting infected. A substantial fraction of people who have had COVID have neutralizing antibodies that really fail to recognize the South Africa variant. If you start from the perspective of saying, “OK I’ve had COVID, I have natural immunity, I have nothing to worry about any more.” Well, the lesson from South Africa has been, no, at least for that variant, there is reason for concern. There’s a decent chance that your antibodies aren’t good enough to stop that variant. 


    Vaccine Incentives and Senator Rand Paul’s Perspective


    And I do think it’s an interesting thing to talk about, to raise the issue of incentivizing people to get vaccines.


    [Clip of Sen. Rand Paul and Dr. Fauci]


    Sen. Paul: You want to get rid of vaccine hesitancy? Tell ’em they can quit wearing their mask after the vaccine. You want people to get the vaccine? Give them a reward, instead of telling them that the “nanny” state’s gonna be there for three more years and you gotta wear a mask forever. People don’t want to hear it. 


    [Back to MedCram Interview with Kyle Allred and Professor Crotty]


    Professor Crotty: Most anything you do in life, right, your best outcomes are if you can get an alignment of incentives, right? The incentive of something and the outcome you want are aligned and pointing in the same direction. So for vaccines, you know, as you’re trying to communicate to get as many people as possible to get vaccinated, because the more people who get vaccinated, the more protected the US population is as a whole. So, that’s definitely a huge priority, and getting vaccination rates up to now three million people a day is fantastic and it’s still going up. Those are really good things. 


    But to keep those occurring, you have to keep getting more people getting vaccinated. And so I do think public health officials are taking that into account, and I think you can hear that in the CDC recommendations in the past couple weeks, right. Coming out with a specific recommendation saying, “yes, if you’ve been vaccinated, you can gather in small groups with other vaccinated people, and have your masks off.” So if you’ve got one pair of grandparents and another pair of grandparents and they’re both vaccinated, they can totally hang out and have meals together and some things like that. And I think you’ll keep seeing progressions of that as more data are available. 


    I do think there are significant pieces of data now that public public health officials worry about transmission, right, as we’ve talked about, that you really want to knock down as many cases as possible. Well, if somebody doesn’t get infected at all, they’re not going to transmit. So the data that are coming out about a number of these vaccines, at least against the main coronavirus strains, is that they’re very good at preventing even asymptomatic infections. Some of them are in the 80% range for that, so that’s a very good sign for reduction of transmission, which I think feeds into the CDC recommendations and other recommendations.


    Looking Ahead, SARS-CoV-2 vs Influenza, Will We Need Annual Vaccinations?


    Kyle: So you mentioned earlier how our situation right now, in some ways, is a race between how many people can we get vaccinated and how many people have immunity versus how much time does the SARS-CoV-2 virus have to replicate, to infect more people, and potentially mutate into variants that can potentially escape immunity, whether it’s from the vaccine or from a natural infection. So one of the viruses, of course, that we’re all very familiar with and — to some degree, for better or for worse — comfortable with, is influenza. 


    And we are aware that we can potentially get influenza every year, and that’s one of the things that I thought a lot about. Is this gonna be a like-influenza scenario with this novel coronavirus. So from your perspective as a virologist and immunologist, how likely is that? Obviously, influenza is a completely different family of viruses. Coronaviruses are different. So, when you look at these two viruses, what comes to mind for you as you look ahead to the future?


    Professor Crotty: A simple answer is if you really get the case numbers way down and there are very few people infected and you get lots of people vaccinated, there are very few opportunities for variants to show up, and so it becomes less of an issue. The more direct answer is we don’t know. 


    There are definitely a wide range of opinions right now amongst virologists and immunologists about where the future of this pandemic lies. I’d say definitely one end of the spectrum is people with the perspective that this will become like another influenza virus and there will be new variants every year. Annual vaccinations will be the norm to try to deal with the variants. 


    I’d say, essentially, the other end of the spectrum would be SARS-CoV-2 variants do exist, but the fact that there’s been a lot of convergence evolution between the variants in different parts of the world, variants coming up with the same mutations, may indicate that there aren’t actually many mutations that the virus can do that escape immune responses, which may indicate that you need one more vaccine improvement, for example, a vaccine booster immunization that’s really to the South Africa variant. Because a lot of the other variants in concern look fairly similar to that variant immunologically, so using that one as a stereotypic variant that’s escaped significant amount of antibody responses. You may need one more booster vaccine against that, and then after that the virus may be mostly out of tricks. It may have basically played its best cards. 


    And I do think I lean more towards that second end of the spectrum. I do think in looking at the human antibody response and human T cell response to this virus, they’re both pretty broad responses and so if it was a really narrow response, it’s much easier for a virus to escape a narrow response than a broad response. 


    And so the breadth of the response is a good sign. Plus data that people who have been infected with the South Africa variant are actually making very good antibodies both against the South Africa variant and the parental strain, again suggesting that there’s not something magical about that variant. It’s not that the immune system can’t see that variant. It just hadn’t before. And in fact, there’s data that people who have natural immunity to COVID-19 and get one dose of mRNA vaccine actually make really good antibodies to the South Africa variant, even though they’ve never seen the South Africa variant, which is consistent with the immune system being pretty sophisticated about making antibodies that can recognize a virus in multiple different ways. 


    So even if one solution doesn’t work, it’s got multiple other solutions at the same time, as well as those people, as I mentioned before, those people getting a big bump overall in their immune response. So, where they’re having natural immunity or vaccination generates a decent amount of immunity, but then a booster vaccine on top of general immunity definitely generates a big bump in overall immunity, and that will probably also occur when people get booster doses after a vaccination, though we don’t have the data for that now. 


    So from an immunological perspective, I think there’s decent chance that we have to deal with one big round of variants, and then it becomes less of a problem in the future. Maybe the virus has like one additional escape that requires one additional round of coming up with a better booster vaccine. And I think the virology largely supports that as well, that the viral evolution experts look at the mutation rates of this virus, and people, like Jesse Bloom, who have looked at mutation rates of common cold coronaviruses and how they’ve interacted with human antibody responses over time, suggest that a relatively slow evolution of that virus, which I think is consistent with if you’ve got a good vaccine, it’s likely to be able to protect. 


    Current Research and Goals for Prof. Shane Crotty


    Kyle: Professor Crotty, thank you as always for your time and clarification of these important questions. And just to wrap things up, I know you and your team there at the Crotty Lab at La Jolla Institute of Immunology are always busy and continue to look at these questions. So, what are you and your team looking at now, and are you working on any other publications at the moment?


    Professor Crotty: Yeah, we’re — so one of the questions about variants has been even if the antibodies don’t work, can T cells provide some protection, or do the variants escape T cells? And so Alex Sette’s lab upstairs is leading really great efforts on that, and we’re helping out with that. And then continuing to ask and answer questions about immune memory after getting vaccinated, after getting infection. You know, how long do those last? 


    The immune system’s complicated, so there are a lot of different parts of that memory to measure and track over time, and how does that relate to variants? And then, trying to get answers about these questions, in particular, populations of interest, right? People over the age of 65 or people who maybe struggle to make good immune responses normally. Obviously, these are — you want to have good answers for populations at risk. So things like that are high on our list, as well as doing our day jobs of the non-COVID research at the same time. 


    Kyle: Well, we look forward to seeing those publications when they come out and speaking with you again in the future. Really appreciate your time today. 


    Professor Crotty: Thanks, Kyle. Great stuff. Thanks for having me.

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