THE WASHINGTON FOREIGN PRESS CENTER, WASHINGTON, D.C. (Virtual)
MODERATOR: Good afternoon and welcome to the Washington Foreign Press Center briefing on COVID-19 vaccine immunity and the impact of variants. My name is Jen McAndrew, and I am today’s moderator.
As the Delta variant becomes the dominant strain of the COVID-19 pandemic, scientists are working to understand the role variants will play in future surges of COVID-19, the efficacy of current vaccines, and how long immunity will last. Our briefer today is Dr. Shane Crotty, virologist and professor in the Center for Infectious Disease and Vaccine Research at the La Jolla Institute for Immunology in California. As an expert on human immune responses to vaccines, he will provide insights on the progress of current COVID-19 vaccine immunity research for current U.S. COVID-19 vaccines, and critical emerging questions, such as the impact of the Delta variant on the efficacy of current COVID-19 vaccines.
And now for the ground rules: This briefing is on the record and the views expressed by briefers not affiliated with the Department of State or U.S. Government are their own and do not necessarily reflect those of the Department of State or the U.S. Government. We will post the transcript of this briefing later today on our website. Dr. Crotty will give opening remarks and then we will open it up for questions. And with that, I will turn it over to Dr. Crotty. Over to you.
MR CROTTY: Thanks, Jen. Yeah, thanks for having me. I think my mandate for today is to try and cover some of the challenges of understanding the immunology of COVID-19 vaccines, COVID immunity. And so I’m going to talk you through some of that understanding, and then get to Delta, and open it up for Q&A. So really trying to understand COVID-19 vaccine immunity and the impact of variants, or really the alternative title would be sort of understanding immunity, what are the pieces of the puzzle there.
A little bit more about my background. My PhD was in virology, and since then I have turned to immunology, and my lab’s generally regarded as a top lab at vaccine immunology. I’m here at the La Jolla Institute for Immunology here in San Diego, and we’re a nonprofit research institute. We’re on the University of California San Diego campus, and we specialize in understanding the immune system. In fact, myself and a fellow professor here, Alessandro Sette, published one of the first major papers on understanding immune responses to COVID-19 last year. Here’s a copy of the front page of that paper. And it got a great deal of attention, and some of that attention included, if you prefer a live action photo of the paper, here is Dr. Fauci actually holding up a copy of our paper in Congress as he endeavored to explain T cells to members of Congress. And I’ve got to tell you, lots of scientists were really excited about that, lots of immunologists were really excited about that. So we had people who had fun with it, and would send us things like a GIF – (laughter) – of the event, and people saying, “Think of all the uses.”
But it got a lot of attention beyond that, and for a variety of reasons. And I do want to talk through it a little bit, because I think it’s pretty central immunological context for understanding how we think about some of the issues of vaccines and variants and immunity.
So one of the questions going way back, right, to this point in time was there was a lot of fear about do people develop immunity to this virus after they get infected. And another way to think about that is: well, how does the immune system defeat COVID-19? And our thought process there, as viral immunologists was, well, this is the virus that causes acute infections that resolve – or curing those people, right. And so in trying to understand what kind of immunity is important against this virus, we could study all of the immune responses, these three categories in average cases of COVID-19, with the concept that average cases of COVID-19 are people who got infected, and then their immune system made a successful response against the virus and cleared the virus. And so then we can ask, okay, in those people who cleared the virus without requiring hospitalization, what kind of immune response did they make? Because that’s probably a (inaudible) immune response, that’s probably what killed off the virus in their body.
And so the immune system really has three components of that. So that’s what we call the adaptive immune system, i.e. the part of your immune system that makes virus-specific responses. And of those three parts, there are antibodies and then two kinds of T cells, actually: helper T cells, or CD4 T cells; and killer T cells, CD8 T cells. And really it’s fair to think about those as similar to the three different branches of the military. These are tools or groups in your immune system that have different weapons that are good at fighting an opponent, a virus in different conditions, in different environments, and they have strengths and weaknesses and they can compensate for each other in different scenarios.
And so in some viral infections, actually, it’s all about antibodies; in other viral infections, it’s all about CD8s; in other ones, it’s all about CD4s. But frequently it’s a mixture of all of them together that can succeed. And so antibodies, we know, are important. They’re important in almost all currently licensed human vaccines, so we certainly want to measure antibodies. CD4 T cells, or also known as helper T cells, they’re actually required for almost all antibody responses. So if you don’t get a T cell response, you really can’t get a neutralizing antibody response in almost all cases. But these cells are complicated. They can do a number of different jobs, which is a pretty common phenomenon in the immune system, that there is complexity. And these cells not only can help make antibody responses, but they can do other antiviral activities. And so, in fact it’s even known in other contexts of coronaviruses that these cells can provide protection independent of antibodies. And then CD8s, they’re important in many viral infections.
Really, the simplest way to think about this is that antibodies are good at stopping viruses outside of cells, and T cells are good at stopping viruses inside of cells. So antibodies are a great defense as a first-line defense at the front door, but once you get infected, now you have cells that are infected and antibodies are less effective in that context, whereas T cells can actually find the infected cells and kill off viruses inside of cells. And so that’s part of the division of labor, right.
So we ask, well, okay, those are three major parts of the immune system – do they all participate in immune responses against this virus or not? And one of the challenges of doing a study like that is that it’s very hard to measure T cell responses compared to antibody responses, and that’s because while antibody responses recognize the surface of the virus – and almost all of those are going to matter against spike – the T cell epitopes can come from anywhere in the virus. So if you imagine the virus is made out of Legos, essentially any given Lego could be a target for T cells, but not all of them are and they differ from person to person. And luckily, here at LJII, Professor Alessandro Sette is one of the top couple of people in the world at predicting T cell epitopes, i.e. which parts of viruses are actually seen by T cells.
And so together, we measured T cell responses, and we found really what was seen as good news throughout the world, was that, yes, almost everybody made an antibody response – that was being seen by other labs also – but we could also show almost everybody who had resolved the COVID-19 infection made a CD4 T cell response, and most of them also made a CD8 T cell response. And at the time, another key factor was which proteins were being recognized by those T cells, because almost all vaccine efforts were against spike. And so if it turned out that spike was a poor target of T cells, that would be a big red flag for vaccine efforts. But actually, we found that spike was a very good target of T cell responses and infection, which suggested that spike could be a fine vaccine target also. All right.
And so we did learn other things from that study that I won’t go into in terms of the qualities of the T cells and things like that, but they did show that T cells were actively participating in the responses as well as antibodies. And so when we talk about what are mechanisms of protective immunity against COVID-19, these are three main bullet points that I go through. And in fact, I got asked to speak at a World Health Organization conference on correlative immunity, and these were the things that I highlighted there.
Really the simplest option for any vaccine development is high-level, long lasting, neutralizing antibodies, because those can stop the virus at the front door. But if you don’t have that for some reason, are there other lines of defense? Okay. And various lines of evidence point to substantial protective contributions of T cells against COVID-19. And here, as a result of that, I think it’s quite reasonable to consider that hospitalization level of COVID-19 is prevented by any decent combination of these three major components of immunity, okay. And I’ll provide a few more comments about each of these in turn.
So for the first of those, why do I make this statement? Most licensed vaccines have antibodies as either the mechanism of – or correlate – of immunity, and really antibodies are the only mechanism that provide truly sterilizing immunity, because they can stop a virus before infection. But also, antibodies are a lot easier to measure than T cells. So even when T cells are important, in control it’s much easier to measure antibodies. And even if they only correlate somewhat, it’s still frequently a lot easier to measure and it still ends up being a correlate. So for example, antibodies are a correlate of CD4 T cell responses, because as I mentioned before, neutralizing antibodies almost always depend on those T cell responses. And that’s actually a specialty of my lab, is that type of response.
So the second point of, well, what’s the evidence that T cells play a role – well, here are several bullet points on that topic. Regarding the first one, actually, some of that data comes from our lab where we looked at people with acute COVID-19 and disease severity – and this was published in Cell last year – that we actually observed that the presence of virus-specific T cells were better correlated with good outcomes than antibodies were. And in fact, poor outcomes were really mostly correlated with an absence of a meaningful T cell or antibody response in those individuals. But there are studies by other labs as well.
And another aspect of this that comes into play has been the anatomy of immune responses to the virus. This is clearly a fast viral infection of the nasal passages and the oral cavity, but importantly, it’s a relatively slow infection of the lungs, and it’s the lungs where you have the pneumonia that can lead to the hospitalization, and ARDS, and death, okay. And so while this is a fast viral infection of these two tissues, it’s a slow infection of these tissues in the lung. And so that actually gives a lot of time for T cell responses as well as later antibody responses to control the virus even if they don’t manage to control the virus initially in the first couple of days. They can still prevent serious disease, is the operating model, okay. And I can go into some of the additional lines of evidence about T cells if you want in the Q&A.
And so as a result of those data, we do think it’s reasonable to consider that all three of these parts of the immune system probably matter. And so as a result, we said, well, protective immunity is really a function from a vaccine or from natural infection after you’ve cleared the infection. Protective immunity is really a product of immunological memory; that is, parts of your immune system that are remembering this virus infection or vaccine. And those consist of the two kinds of T cells and then the antibodies which I mentioned before, but also actually this fourth component, memory B cells. So memory B cells are the part of your immune system that can make antibodies, but they’re not currently making antibodies. So essentially, they are resting cells that are essentially warehouses of antibodies so that if you do get infected, these cells then activate and can make more neutralizing antibodies to try and blunt or stop the infection after it started.
So we measured all four of those potentially important in protective immunity in natural infection. And in addition to that, in thinking about variants, I love this article earlier this year in Scientific American that really had a great summary of your immune system has really evolved to fight coronavirus variants. And part of that is because variants really have trouble escaping T cell recognition. And in fact, Alex Sette’s lab and our lab published that that’s the case in general variants. Even if they’re escaping – partially escaping antibody responses, they are not escaping T cell responses because T cells recognize the virus in a different way. But also memory B cells are a way your immune system fights variants, because memory B cells are essentially a library of immune system guesses about what a variant might look like. So even if a virus gets past your initial antibodies, you actually have backup plans of different types of antibodies that can probably recognize variants better, and there are a number of papers that have now shown that that’s the case.
So we measured all four of those parts of the immune system specifically for SARS-CoV-2, the largest study ever of its kind for any amount of infection, and asked, what did it look like six months after COVID-19 infection? Did people really have immunological memory to this virus? And the answer was yes. Something like 95 percent of people we calculated had a meaningful amount of immunological memory at six months, and actually at eight months. And this was covered in the news widely, and one of the things we concluded was that these types of responses look like immunity against essentially hospitalization-level disease could last for years, and that’s complemented other direct studies of tracking cohorts for protective immunity.
So how does – and here’s what the data looked like, just to give you a sense of the raw data, and that actually immune memory goes in different patterns, which is complicated, and so that’s something that we have to keep in mind as we interpret those outcomes.
So now to switch to vaccines. So we know from the data that I just showed you and other labs publishing similar results that natural immunity can result in substantial immunological memory. That was a good sign and encouraging for the vaccines. What do we know about durability of vaccine immunity, keeping those things in mind? Well, really, the thing I always say about immune memory is that it is complicated and it’s hard to predict, and so normally, you have to wait at least six months after an infection or a vaccination to get a sense of how long immune memory is likely to last.
And so the clearest data we have for the vaccines at this point is antibody persistence through six months after the second dose of the Moderna vaccine, which is very similar to the Pfizer vaccine. And the antibodies were really maintained rather well within the range that I would expect, essentially a six to eightfold decrease from peak. And then our lab recently posted a pre-print – that’s the first data available – on how long T cell memory lasts after the vaccines.
And in addition, this was a study where we had access to the low-dose Moderna vaccine clinical trial, and this is interesting because the low-dose Moderna vaccine is only a quarter of the dose in the regular vaccine, and so we were also asking: Do people actually make a decent immune response to this lower vaccine dose? Because that’s interesting for future reasons. And for the T cell memory question, what we observed – so here’s a month after the second immunization and now here’s six months later, and in fact, 97 percent of people still had T cell memory six months after the second dose, and in fact, it was pretty much flat, very stable T cell memory over half a year. So that’s actually a really good sign for those vaccines that T cell memory is likely to last for quite a long time to those vaccines. And not only did we do that for the one kind of T cells, the CD4s; we also did it for the CD8s, and again, pretty stable for both of those.
So it’ll be valuable to get those data for other vaccines and from other labs, but really, those are several of the pieces of data that people have looked at for trying to project how long vaccines may be effective. And there are different ways for vaccines to be effective, right – to either just prevent infection, to prevent symptomatic cases, or to prevent hospitalizations and deaths. And going back to what I said about the lung infection versus the nose or mouth, that really preventing hospitalizations is significantly easier because there’s more time for those T cells and memory B cells to respond. So even if you don’t have enough antibody to stop the virus from infecting, there’s actually – if you have a vaccine that elicits T cell and memory B cells, that’s a lot of backup options to help still prevent the severe outcomes. And that memory tends to be more durable, and this is what I was just referring to.
So in thinking about variants, when might things other than antibodies be important in protective immunity – number one is in natural immunity, when some people, right, antibody titers are low, but another is in vaccinated – a vaccine-generated immunity when you might have neutralizing antibody partial escape by some variants. And in fact, the clearest evidence of this has been Beta, the South Africa variant, and the J&J vaccine, where neutralizing antibodies were undetectable in Penny Moore’s lab’s data in about 85 percent of these individuals. And yet the J&J vaccine was essentially just as effective against Beta as it was against other variants, indicating that there’s other aspects of vaccine immunity that were providing that protection, and I think that’s probably T cells. But also, this comes up in different time windows or in immunocompromised individuals or with vaccines that just have different mechanisms of action.
So I’ll end on this slide – well, and two little quick follow-ups directly on Delta and then get to the Q&A.
Really, the main challenge with Delta – Delta is a big challenge, and the main challenge with Delta is that it’s much more transmissible than the original strain. It does have a modest degree of antibody escape. It is unlikely that it has any T cell escape. But any variant, Alpha or Delta, that’s much more transmissible than the original strain is going to be somewhat harder for vaccines to stop, simply because the virus is better at infecting or better at transmitting, okay? So it’s likely to require a higher degree of immunity to prevent infections.
I think the good news has been, again, the immunological data that I was just describing, but then the efficacy data that’s come out of the UK, which was just published in the New England Journal of Medicine last week, that the Pfizer vaccine was still 88 percent effective against symptomatic Delta cases in fully vaccinated people to dual immunized, and that vaccine prevention of hospitalizations was essentially fully retained, was equivalent to earlier data, and that was true both for the Pfizer and the AstraZeneca vaccine, and I think that comes down to – again, it’s easier for the immune system to do this because there’s more time.
And just to be a bit local about it, right here in San Diego, 98 percent of the hospitalizations in the past month have been in unvaccinated or partially vaccinated people, which is really clear evidence that the vaccines are still working quite well against Delta. But I’m happy to discuss some of the other data around it, or if you don’t want to just look at San Diego data – right – here’s actually every county in the United States and vaccination rate versus number of cases. And it’s clearly the low-vaccinated counties that are the vast majority of those cases. Again, pretty clear evidence that the vaccines are working.
So I won’t go through the full acknowledgments. Our work is funded by the National Institutes of Health and I said a lot of this is in collaboration with Alex Sette, and I just want to say we have a great team of scientists here at LJI who have done this work, including some fantastic doctors.
And I’ll stop there and we can go to Q&A and expand on either – any of those immunological questions. I’m really happy to answer anything about vaccine immunology and also things related to Delta.
So Jen, I’ll go back to you, and it’s possible that I’ll have a slide that somebody will – it’ll be useful for somebody’s question, so I might show the screen again.
MODERATOR: Thank you, Dr. Crotty. As a reminder, if you have a question, you can raise your hand in the participant field or submit in the chat box. Before we go to live questions, I do want to take one of our advance submitted questions, which was from Maho Kawachi from the Nikkei in Japan.
Her question was: “How long will the current vaccine immune effect last, and do people need a booster to enhance the effect of vaccination?”
MR CROTTY: Yeah, so it’s a critical question and a central one, and really there are two ways to get that answer, okay? And so one is to make measurements of the immune system and look at how they change over time, and essentially that’s what I was showing you, right – that in the context of natural infection or vaccines, how good was the immune response at, say, one month, and then how big is it still at six months, and then estimate, right, how that’s going to change over time. And one of the things that’s challenging about that that sometimes gets lost, again, is that it’s not just about antibodies. It’s about that mix of antibodies and the T cells and the memory B cells. And then in addition, it comes down to: Is your need or desire to have protective immunity against infection or have protection against symptomatic cases or have protection against hospitalization-level disease? And those all do result in different answers.
The second – right, so there are basically two ways to answer the question. One is either by looking at immunological measurements and protections, and the second would be tracking when are people getting reinfected after vaccination and then implement booster shots at that time. And so right now people are tracking both of those and making estimates about when boosters might be needed based on both of those types of criteria. And so, for example, there have been a number of suggestions that booster vaccines maybe should be used immediately in immunocompromised individuals or immunosuppressed individuals – people who have had organ transplants or who are on certain immunosuppressant drugs – because it’s observed that many of those individuals or certain classes of those individuals don’t make a good immune response to two doses of the vaccine, right, so do you really want to go to a booster immunization relatively quickly for those people as sort of high-risk individuals, right, and that’s part of the complexity of it.
I said in December of 2020 as soon as the vaccines were available, as soon as the RNA vaccines were available, that there was a 50-50 chance that we would need booster immunizations a year later, but that after a single booster immunization it might be that memory would be better sustained and then you might not need another booster for five years. And I’m actually pretty much at that same 50-50 guess right now. I certainly expect that boosters – from an immunological perspective, boosters will be authorized for some groups of individuals relatively soon. As I was sort of describing, certain groups of people who might be at highest risk, and i.e. particularly let’s say maybe people over the age of 70, something like that.
And the need to get boosters obviously depends on two things, right? One is the immunological – how long is immune memory. And as I just showed you, basically one concern was that the RNA vaccines wouldn’t generate very good immune memory. But as I just showed you, they’re actually generating very good T cell immune memory and quite reasonable antibody memory, so those are good signs that make it less likely that boosters are needed.
But on the flip side, the variants, the changes in variants between last December and now, have made it more likely that boosters would be needed. Delta is simply a tougher virus to stop, and so boosters may be needed. Boosters will certainly be needed earlier for Delta than they would have been needed for Alpha, right. It was clear that even one dose of vaccine was really quite successful at stopping the surges in the United States, but one dose of vaccine is not enough to stop Delta, as we’ve seen in the UK and elsewhere.
And Jen, I’ll pause there.
MODERATOR: Thank you. We do have a hand raised, and I’ll call on her next. Magda Sakowska, Polsat News in Poland. Magda, if you’d like to unmute yourself and ask your question.
QUESTION: Thank you very much. Can you hear me right now?
MR CROTTY: Yes.
QUESTION: Yes. Thank you very much for doing this. I have a question. Professor, you showed us the data from UK that shows that Pfizer effectiveness against Delta is 88 percent. But at the same time, we have the study from Israel where the effectiveness was lower than 40 percent, so which study should we believe in?
MR CROTTY: Yeah, it’s a fantastic question, and thanks for bringing it up. And I was certainly expecting that we would be discussing it in the Q&A, which is one reason I led with the slide that I did.
So in the end, the question comes down to epidemiology, actually, right, which is not my expertise. But I can tell you the frameworks as I understand it that epidemiologists use to look at those types of data. The concern – so I’ll tell you what I look at, right, and what I’ve been basing my interpretations on. So one has been the actual clinical trial data, because those are very – well, those are critical data sets, right, very well tracked. And so both for the Pfizer and the Moderna clinical trials, they have protection data out to six months, right, and that’s in fact what’s been submitted to the U.S. FDA and elsewhere for full approval, right – both six months of safety data and efficacy data.
And what was really striking was that between one month post-vaccination – or two weeks post-vaccination and six months post-vaccination, the efficacy went from 94-95 percent down to about 91 percent, right. That’s a very small change in efficacy in those clinical trials. That’s really as good as you could possibly help for – hope for, sorry. Now, that wasn’t with Delta, right, but it gives us a reasonable reference point that protective immunity six months out was quite good for those vaccines against the viruses that were circulating.
And then layered on top of that, asking, well, how good are the vaccines against variants, and the data certainly from the UK but also a number of countries has been that the vaccines were incredibly good against Alpha, which was mostly a problem because it was more transmissible, right, not because of immune escape; rather, similar in characteristics to Delta. Whereas in other scenarios – for example, Beta – the RNA vaccine efficacy against cases dropped from about 95 percent to 75 percent but was still a full 95 percent protective against hospitalizations. But Beta has a lot of immune escape, okay, and so those were the frameworks.
And so then to me, the UK data was critical for getting a sense of vaccine efficacy against Delta for a couple of reasons: One, they generated a lot of high-quality data against Alpha, right, and other things that definitely bore out to be true. Two, it was in a large population. And then three, they had enough cases to age-stratify a case control to get a measurement of protective efficacy. And there’s actually a really nice commentary piece written in The New England Journal of Medicine accompanying that English protective efficacy study last week that explained the epidemiological study design that they decided to do for it. Because one of the challenges that they realized, and lots of people have realized, is nobody’s got a crystal ball to see what all the cases are, right? And so some people are much likely to get COVID tested than other people. And so, for example, health care workers, right, are frequently getting tested every single week, and then other people, they’re not going to get a COVID test for any reason basically, right, even if they get COVID. And so how do you control for those differences, because it’s likely that people who got vaccinated are also people who are more likely to be attentive to going and getting themselves tested, right, or being in situations like that.
And so the UK approach was to take a test-negative strategy so that people had to – for every positive case they looked at, they had to match it to somebody who also went and got tested and got a negative case to sort of control for those population differences, as well as controlling for age of people and where in the country they lived, and things like that.
So on the flip side, the Israeli data – first of all, I think it’s really important to have these types of data from multiple different countries and multiple contexts, but it’s also challenging to just take raw data and look at it because it’s easy to be fooled by the raw data. We’ve seen that in a number of contexts with vaccines, and certainly the Israeli data is concerning and worth paying attention to. And the worry is with calculating a vaccine efficacy, who is it being compared to? And in different countries, again, with different groups of people more likely to be vaccinated or not, if you’re comparing efficacy in older people versus younger people, for example, that’s just not the right comparison. And so those are the things that epidemiologists look at.
And I will say that when people were first looking at Israel as real-world, right, efficacy of the vaccines back in March, there was all kinds of noise being generated by different groups about whether the vaccines were working or not, and it was essentially because people weren’t actually calculating the numbers correctly. And in the end, when the Israeli data was looked at as a whole and was stratified properly, because they had really good health care data, the vaccine efficacy in Israel was, like, 95 percent – almost identical. So very clear evidence that real world, there was good efficacy, and that was published in The New England Journal of Medicine also. And there you can see what the epidemiologists did to go through and stratify people to actually match them up properly to compare vaccine efficacy.
And over the past couple of days, multiple epidemiologists and computer scientists have been looking at the Israeli data more and have seen things that don’t make a whole lot of sense. And at least what I saw yesterday was that possibly a significant issue with the signal being seen is that they were comparing cities that had high vaccine coverage with cities that had low vaccine coverage, and actually the changes in cases are predominantly in cities with low vaccine coverage, and they weren’t matching up those cases well enough, resulting in issues with the calculation of vaccine efficacy.
So I think it’s important to pay attention to that Israeli data as epidemiologists really take a look at it and make calculations, and so it’s definitely, like, I follow epidemiologists on Twitter and look for when they show up in the news because that’s how I end up interpreting those types of data. So I am not taking those results at face value because they haven’t been analyzed in the same epidemiological ways that the clinical trials were and the UK data were, and it doesn’t seem to match as well with the immunological readouts from the vaccine trials themselves in us and others.
So those are the different pieces of the puzzle that I have looked at so far there, including essentially our thoughts that, okay, antibodies are good at stopping that initial entry, right, but then there are additional backup defenses, including the memory T cells and the memory B cells, and we think there are just as many memory T cells and memory B cells at six months as at one month, and so we wouldn’t expect the same sort of dramatic change.
So that’s a long answer, but it’s been obviously a complicated topic and a topic of a lot of discussion this week.
QUESTION: Thank you very much. Can I have one more question, very quick?
MODERATOR: Sure.
QUESTION: Okay. Professor, how do you think – how high is the probability today and in the near future we will face a mutation that will escape all the vaccines that are available right now?
MR CROTTY: Yeah, that’s – so obviously, predicting the future is hard. Nobody’s got a crystal ball. I think the probability of a variant that can escape all immunity is essentially zero. It’s just not the way this virus has behaved, and it’s really not the way the immune system is built. The immune system has lots of different recognition strategies and lots of backup plans, and so I don’t see that happening.
In particular, even more specifically with most of the focus on escape, obviously, is about antibody escape, right? And it’s a lot easier to measure antibodies than T cells. So you see antibodies in the news a lot more because there are far more new studies about antibodies than T cells because of the amount of effort involved, but both – also because antibodies are clearly, right, important in the protective immunity.
And going back to, yeah, December and January, these questions about the virus escaping or partially escaping antibodies – would the virus fully escape antibodies? The answer then was it looked highly unlikely. And the answer now still looks like it’s highly unlikely, and that’s because the virus escaping antibodies are all – all those mutations are in its spike, okay? And the virus still has to maintain a functional spike protein to still be a virus, and so a question of how much can it mutate its spike and still be okay has really been answered by variants popping up around the world. And it’s really come down to really only a handful of mutations in its spike give partial antibody escape, and those same mutations keep showing up again and again independently. And what that tells us is the virus doesn’t have many solutions to that problem, right? The virus has made 10,000 different mutations, but it’s only been a handful of those that are actually giving any antibody escape. And so obviously one of those was the 501; a different one was the 484, which is in Beta and Gamma; but then a different one is the 452, which is in Delta, and that’s also what was first seen in the California variant.
And so it looks like there are limited ways for the virus to escape, and even when it does have those partial escapes, there are other antibodies that still recognize the virus. And one of the things that the immune system should do – and many labs have now proven does happen, and I summarized this in a one-page article I wrote for Science last month called “Hybrid immunity” – is that memory B cells that your immune system has, they have all these mutations and they can better recognize the virus and can even recognize variants. And so vaccinated people have memory B cells that can recognize essentially every known variant because they have antibodies that bind really well. And so I really don’t see immune escape as being a bigger problem in the future than it has been to date.
But so the caveat in there, right, is that the bigger problem with Delta is simply that it is so fast, okay, and it being fast and probably replicating more in people makes it intrinsically harder to stop. So it’s not escaping immunity, right, it’s just more virus and so it takes more immunity to stop it. And since the virus has managed to go from the original strain to Alpha to Delta in this period of time and have those significant jumps in transmissibility or speed, depending on how you want to phrase it, means from a virology perspective – which, again, I did get my PhD in (inaudible) virology – it is hard to bet against the virus potentially coming up with another variant in the future that can be even faster an issue.
But today, obviously, the big challenge is Delta and I think the good news has been that the vaccines do work against Delta, but if you’re unvaccinated you’re definitely in real trouble with Delta, and that boosters – I should have said in the conversation about boosters, really the take-home message about boosters is both from the Moderna booster clinical trial and the Pfizer clinical trial, the take-home message is boosters are going to work. Okay, we didn’t know that. We didn’t know that RNA vaccine boosters would actually work, but in both of those studies the boosters worked really well, and in fact boosting with other vaccines is also probably going to work well also based on other data.
So again, a relatively lengthy answer, and I was trying to take it more from a little more of an education perspective to give you some context, right, as you see – you’re certainly going to keep seeing new data on antibodies and new data on variants for the rest of the year, and hopefully the explanation I just gave will help you give some context for how to interpret those things going forward.
QUESTION: Thank you very much, Professor. Thank you.
MODERATOR: Okay, I’ll do one last call for questions, as we are coming to the end of our time. But in the meantime, we had a series of questions submitted in the chat. There are three from Ra Gore from Free Eurasia Media. Some of these may be outside of your area of expertise, Dr. Crotty, but his questions are: “What is the WHO doing to monitor and understand the impact of variants and the efficacy of vaccines?” The second part is: “How can America prevent future new variants of the COVID-19 virus?” And the third is: “Can testing at CVS be effective in detecting the Delta variant?”
MR CROTTY: Yeah.
MODERATOR: So three very different questions there.
MR CROTTY: Very good ones, but all very good questions. So in terms of what are efforts to deal with and understand variants going forward, I’ll say the WHO certainly has multiple initiatives in place, and one of them is a correlative protection initiative and standardizations of assays to work with groups around the world, and I participate in those some about both how to track variants but then also how to assess likely immunity against variants. And in the United States there’s an NIH-funded program called SAVE that’s doing the same thing, and it’s essentially sort of a SWAT team of labs around the country that pay attention to COVID variant sequences and COVID immune assays, and as soon as possible when variants of interest or variants of concern are identified, labs are testing those variants in a range of antibody assays and T cell assays to get a better sense of which variants are most likely to be troublesome.
The second question was – oh, I forgot it.
MODERATOR: How can America prevent future new variants of COVID?
MR CROTTY: Oh, right. So, I mean, it really is – it’s infections cause variants, right? It’s like every single infection is a new opportunity for a variant. So the way to stop variants is to stop infections, and certainly in this country, if people were vaccinated, we would not have the Delta surges we’re having and those surges are certainly potential sources of new variants. And I think scientists and public health officials have said this over and over again: That is the answer.
The COVID test you can get at CVS or other pharmacies will detect Delta. So there are two different categories of those tests. So some are antigen tests, okay, and those are looking for the presence of viral proteins, and those definitely work on Delta. And the other ones are genetic material tests, right, testing for viral RNA, and those ones are designed so that they also can detect Delta. Yes, they’re from more conserved regions, unlike the S-dropout issue that was a factor for Alpha and some other viruses. So yeah, those are three really good questions.
MODERATOR: I don’t see any other questions, so with that, we will conclude today’s briefing. On behalf of the U.S. Department of State and Washington Foreign Press Center, I’d like to thank you, Dr. Crotty, for sharing your expertise today on these really critical questions. Thank you and good afternoon to everyone.
MR CROTTY: Thanks. Thanks for joining.