Harlan Robins on How T-cell Focused COVID Vaccines Can Move Us Toward Endemicity

Why T-Sales are the key to ongoing success against COVID next on Mendelsohn. Welcome to the program I'm Ferrell Timson. The vaccines that we've all received are most of us, or many of us, who are designed to induce antibodies. But new research done in the past few months has shown that T-Sales might have been a better correlate for protection against the coronavirus and its ongoing variants. Joining me today to talk about this latest science is the author of some of these recent papers, and the co-founder and chief scientific officer of Adapted Biotechnologies. He was also former head of computational biology at the Fred Hutchinson Cancer Center, Dr. Harlan Robbins. Today's show is sponsored by CGLife, the leading marketing agency at the intersection of science and healthcare. Get started today at CGLife.com. Welcome to Mendelsohn. Thank you, and thanks for inviting me. Thank you for joining us. I've seen your name popping up quite a bit the past month with this T-Sales story. You have an op-ed in the Wall Street Journal with Andrew Von Eschenbach, the former head of the NCI. Will you tell us about this research? Sure. Probably thinking about the flu and flu vaccines is an easier place to just start, which is that the reason you need a different flu vaccine every year is that the flu mutates and the vaccine induced against last-year flu no longer applies because the antibodies are off-target. It's the same thing with surprisingly, we didn't think so at first, but SARS-CoV-2, the virus is mutating even faster than flu. We thought it would be much more stable and wouldn't mutate as fast, but it turns out it's mutating super fast. So the antibodies induced by the vaccines, the original vaccines, which were designed against the original strain of SARS-CoV-2 that came into the population, are now considerably off-target for their antibodies. What that means is that they don't -- how much detail should I go into on the technical side, do you think? Oh, sorry. Our audience is researchers, so you're talking to your peers, so feel free to do all the technical stuff. If we stay too long, I mean, I like to get an overarching story, so if we -- what I tell people is if we stay too long down in the weeds, I'll probably come down there and pull out. Okay. Yeah, for sure. Okay, so the part of the virus of SARS-CoV-2 that binds to and allows entry into lung cells is the spike protein, and it's just the tip of the spike protein that binds to the ACE-2 receptor to allow entry into lung cells. And as you can imagine, if you want to neutralize this virus, prevent that from happening, you want antibodies to specifically bind to the neutralizing antibodies, specifically bind to that tip of the spike protein. So it's a very small region where the neutralizing antibodies can actually neutralize. And so it doesn't take much mutation to completely make that binding irrelevant, right? So those small mutations that we got even in Delta and the beta variant -- some of the earlier strains, they almost completely knocked out the antibody binding to that particular region. But then Omicron came around and it completely blew that off. So the positions that neutralizing antibodies that are induced by the vaccine bind basically don't exist on Omicron. So Omicron was quite different? Yeah, it had so compared to just in the spike protein alone, the normal -- so the other strains, Delta, et cetera, all of these strains had arranged up to about 12 mutations across the entire spike protein relative to the original strain. And Omicron had had 32, so it had three times as many -- at least three times as many mutations just in spike as that. So you can imagine if you got most of the antibodies knocked out from Delta, it's completely annihilated. Omicron. Wow. Okay. So why did it make a difference if we had a booster then? I mean, I knew the numbers of our resistance was going way down by the time Omicron hit. But why did the booster help? Yeah. So the booster -- okay, so in a couple of ways, if you -- you have a bit of residual antibodies that still can sort of neutralize, and if you -- for some very short period of time, if you massively jack up that specific immune response, you'll get some -- some neutralization, but it's pretty minimal. Plus, antibodies can neutralize -- it can be a bit more technical, but there's a little -- there's some other ways you can have antibodies have some neutralization effects that are much, much weaker, but you can sort of go around this specific spot that they need for the neutralization binding. But basically, you get a very temporary, very weak ability to prevent -- for neutralization to work with a booster. So as you know, I'm sure you know tons of people that got boosted and still got infected myself because of their breakthrough. Yeah. So, okay. So you've showed us why we're screwed with antibodies. So take us over to the T-cell story. Yeah. So T-cells aren't restricted to one small -- you know, sort of -- we'll call it geographical location, they -- the T-cells bind to parts of the virus that are -- so just how T-cells work, we need to take a little step back is that almost every protein in your body, in a cell, a little -- some small fraction get chopped up and then presented on the surface of the cell so that your T-cells can see inside of cells and then get rid of cells that are either infected or somehow apparent, cancerous, something wrong with them. It's sort of the window into the cells from an external perspective. Antibodies can't do that. They can only see stuff externally. They can't -- they don't have the specific window to see inside. And the way -- so T-cells -- the antigens that T-cells will see are from chopped up pieces of protein so they can come from anywhere on the entire SARS-CoV-2 genome, not just the little tip of the spike protein, which is a small, small fraction. And they're -- there are many more of them, they're much more diverse. So there's a huge number of antigens and they're all spread out. And so -- so far, even with the Omacron 32 mutations in the spike protein, there's only a handful outside of spike. So the vast majority of positions that we're generating at T-cell response aren't affected by these mutations. Okay. So T-cells more like having a wildcard. It works with more options. It does, absolutely -- the caveat is that it's not going to -- they don't bind to the viral particles. So they're not thought of to generally prevent you from getting infected in the first place. But if you think of cells as sort of the factory that makes more virus -- so basically how viruses work -- viruses can't replicate themselves. They need the machinery of cells to do it. So they infect a cell, then they use the cells of factory to then make more viral particles which then go out and infect more cells. So T-cells aren't going to prevent the initial viral particles from getting in and infecting cells. So you're going to -- you still could get an infection. You're likely to get an infection if you don't have a neutralizing antibody response. However, T-cells come blow up these factories. They kill the cells that are making more viral particles. So they clear the infection. Whereas antibodies don't do that. So the reason that no one ever -- I mean, people who are vaccinated and boosted the rate of going to the hospital, it's certainly the rate of getting severely ill is vastly reduced. Because your T-cells are standing, ready to go, and on target. And as soon as these lung cells get infected, they're sort of jumping into action and killing the lung cells that are infected. So effectively keeping that infection from becoming detrimental, seriously detrimental. So what does your research mean for all of us then? Are you advocating for a combination then of using antibody and T-cells in some kind of vaccine or treatment? I think ideally, you know, the immune system is a system. We have all the parts for reasons. So if you could ideally engage all of it, that would be fantastic. I think your T-cells are your safety net that prevent you from getting more -- really getting severely ill. So if we're at the point where we have a T-cell memory at high levels against SARS-CoV-2, that should flip this to an endemic state where the harm should be, except for perhaps some people who are immunosuppressed, we should have the harms at the level more of what we're seeing with Omicron going forward in the vaccinated and already infected, which is that you'll get sick for a day or two, but -- or maybe a few days, but it's not. This is something that we live with all the time. There's many other viruses and pathogens that cause the same thing at the same rate. And every time you get infected going forward and get sick for a couple days, you'll now create antibodies against that strain, which hopefully, as this thing evolves, your antibodies will always be behind, but they'll catch up to some extent over time. The fact that we have vaccines against the strain from two years ago, if we make a vaccine against the Omicron strain, then whatever comes next will have some on-target neutralizing antibodies, but the virus is going to escape them quite quickly, and they won't maintain on-target. Well, we're always going to lose the -- it's going to evolve faster than we -- we're going to be able to generate and disseminate vaccines. So we're going to -- this is going to be a losing battle, but we'll get some protection both from previous strains of the virus that you get infected with, plus hopefully updated vaccines and designed to induce an antibody response. That's why you brought up the flu vaccine scenario in the beginning, because if we just keep chasing each variant, it's kind of a losing battle, that's how you'd like to see us focus on T-sales, because this moves toward a kind of endemic situation. That's exactly right. A situation where, you know, I don't think if the harms of SARS-CoV-2, even if it spread like it did, but it was the equivalent of endemic cold, you know, this wouldn't have -- I mean, it's a totally different ballgame, right? I mean, we don't -- we have endemic colds, everybody, which, by the way, are also, you know, a third of them are caused by coronavirus, and we live at them. And so I don't -- I think if we can get a baseline T-cell immune response, we should be able to control this virus pretty readily. What's the best way to get to a baseline T-cell response? There's two ways to get there. One is to -- I mean, I'll say three ways to get there. The one is to -- once you've gotten infected with the virus, you generate a baseline T-cell response that fades over time, but definitely is stay strong for quite a while. This is how your immune system evolved. This is why it's there, right? There was no such thing as vaccines. You would get infected, and then that you have this system of immunological memory to keep you from getting severe harms when you get re-infected with -- so it doesn't -- didn't just go around the village and around the village, it would -- actually, you know, you'd have some time without it, you know, be protected, and when it came back, you wouldn't be harmed in the same way. That's one way. The other way is vaccination, which sort of splits into two spots. One is the completely -- you know, the vaccines that were designed to go after antibody response. But luckily, a lot of them did generate a really nice T-cell response, the mRNA vaccines. I don't think anybody even, you know, gave much thought to whether or not they would generate a whopping T-cell response, but they happen to have done pretty well. They're focused only on the spike, because they only have one gene in them, because that's where the antibodies were neutralizing antibodies are all, and only the spike protein. So you're really limiting what you're looking at by only looking at one gene out of the, you know, 11, and that you could be looking at in the entire genome. So you're really, you know, at a tenth of what you could possibly have. So the best way to do this is to design a vaccine that just looks at what the broad T-cell response could be, and picking the best antigens across the genome, and putting that into the vaccine and inducing a response against that. So it's sort of -- But designing it specifically to generate T-cell response. Yes. Uh-huh. Yeah. And, you know, certainly there's some smaller players we've been working with with one called NICode. There's another one called Grid Stone that are involved in this. And I think the bigger players, the J&J Moderna and Pfizer's in the world are going to -- I hope start incorporating this as well, and start going after inducing a bigger T-cell response intentionally. Okay. I heard it. Yeah. So there were three ways to get to this base level. Yeah. T-cell. I just split the -- sorry, I just split the vaccine into the unintentional and intentional one. Oh, okay. The unintentional and the intentional. Now, adaptive, your company is working on a vaccine, right? We're working with NICode on a vaccine, and we're not doing it as a separate -- we've been -- we have a T-cell-based diagnostic, so we can assess the -- by looking at T-cells, we can look at the response someone had or didn't have to -- to SARS-CoV-2. So it's the only FDA-approved T-cell-based diagnostic market. A T-cell diagnostic test. Because you guys have been looking at T-cells for a long time in your work on cancer. Yeah. Okay. So you've had this diagnostic test. So you've had quite a bit of data there. And so then how's your trial then going on the vaccine with NICode? Yeah. It's good. It's fairly recently started, but we've dozed a whole set of people already, and it's progressing in -- it's in Europe. This is a Norwegian company, and yeah, it's moving, I think, you know. As you can imagine, we started ramping this up the trial right as Omicron hit, so there was a lot of uptake and I think -- and a renewed need where it wasn't -- I think before Omicron, it wasn't clear that how the virus would evolve and then came storming back, and pretty much when ripped across the entire world. And so, you know, we don't know what the virus is going to do next. Hopefully, it's not going to evolve to something more virulent, but we certainly know it's going to evolve to escape our immune response, and we will -- even the immune response induced by people who got Omicron, though it'll evolve again, so that the Omicron induced antibodies aren't going to protect you long-term either. So we'll see what the next stage of this virus is, but I'd love -- if by that point we're really prepared with a really strong baseline T-cell response and just keep people from going to the hospital, keep people from dying and seeing if we can continually reduce harms over time. Right. Okay. So you're at the beginning stage, but it could be critical. These new vaccines, which you say are in the intentional camp, the intentionally designed to generate T-cell response. These could become a new generation, and it looks like the pandemic is going to be around for a while, and so they could be a critical category of vaccines. For sure. And, you know, one of the other things, I mean, I think we -- you know, what do they say? Necessities, the mother of all invention, you know, know what -- people have systematically ignored T-cells, which are half -- it's half the immune response in sort of vaccine development over the last 50 years, and part of it's that we didn't have the technology to really assess it properly, and part of it's just that we have a dogman in the field, and hopefully this also changes that dogma so that for not just -- for -- not just for SARS-CoV-2, but for other pathogens where we've struggled to develop vaccines that we can start truly incorporating the T-cell responses, part of the vaccine development paradigm, and maybe start having more success against a whole variety of pathogens that we have to date been relatively unsuccessful against. The next time there's a virus out there, I mean, this happens every so often -- SARS, I didn't even mean that, I mean -- Ebola -- that are already out there, like, like, RSV, you know, there's flu viruses -- flu, RSV -- I mean, there's a lot of viruses out there, but also preparedness for the next pandemic, but also I would just meant for the circulating pathogens that we haven't been able to vaccinate against, which is, you know, most of them, the number of the pathogens that, in fact, humans, the number that we're able to vaccinate against is relatively small, small fraction. So this party has paradigm, paradigmatic shift for vaccine development? Absolutely. And we've been, you know, we've been talking to even some of the major farmers are -- and there's some viruses that replicate in sort of different ways that where the antibody response is probably playing a much more minimal role. And so the -- we've had very little success against some of those viruses, like RSV, where I think, you know, the next generation, we could have some pretty whopping successes. What about HIV? HIV is an interesting one, where that one -- the evolution, it evolves very, very fast across the entire board. It's been interesting because there was a whole kind of revolution for a while where people did try to go after the T cell response for vaccines and had sort of great success in monkey models, but then they didn't do very well in humans. So, you know, hopefully we're at a stage now where we can do vastly better. We just didn't -- it wasn't right, the technology wasn't right to go after, but, you know, there's other massive advantages now, too, like for the mRNA vaccines. Those didn't really exist at the time, right? There was no Moderna and BioNTech and all that. So now there's these great new technologies and delivery systems that hopefully can -- that really do induce a really nice T cell response. I mean, even unintentionally, imagine what it could do if it was targeted. So I think there's lots of potential with some of the great new technologies out there to really go revisit some of the places where we've really failed on vaccine development. I'm curious. Do you think the FDA -- do you think our regulatory bodies should have a new attitude and require some of this attention to T cell when they're looking at vaccine? Yeah. You know, submissions. 100% they should. And I think, you know, there -- you know, we talk to them regularly and we're going to have more and more conversations coming up. And I know some of the players in the, like, grit stone in the U.S. is really thinking this way as well for their intentional vaccine. And I think it's not that the -- you know, there's some great immunologists and virologists at the FDA and they're aware that the T cells play just as an important role as B cells. The issue has really been one case of, you know, I would say dogbaw and sort of slow moving, but also they didn't really have the tools prior to assess T cell response at scale because it required live -- measurements of T cells and traditional methods require live cells. And you can imagine if you're doing a worldwide study, live cells are just finicky. You can't do a standardized measurement across -- across, you know, a 30,000 person vaccine study where you have to measure something from live cells, it's not possible. But that's where our diagnostic came in, where we changed that so that we can do a standard molecular measurement, which is meaning we just have to sequence a bit of the DNA of these T cells to get the information about what the immune -- the T cell response looks like. So now they're -- that excuse sort of disappeared. We can do this at scale across large groups and -- and so it is possible now to add these in -- on the practical side to -- the FDA can act for them. And so we're working hard to make sure that they start asking for it because it's important. I mean, I don't know, I got really unhappy. I mean, I have a four-year-old and -- and, you know, when the vaccine -- they -- the Pfizer had a -- Pfizer BioNTech went through a trial where they gave a really small dose to children. And all they -- they didn't measure efficacy. They didn't measure T cell response at all. They just measured the antibody response and said, "Oh, it doesn't induce a big enough antibody response to -- so we're -- we're -- we're going to -- we failed the trial. But the antibody response is irrelevant as we talked about in the beginning, right? It was an antibody response to the original strain that came out of -- out of -- out of -- of Wuhan, right? That -- what does that have to do with -- it's like totally irrelevant. >> It's recent. >> Yeah, it's -- it wasn't -- yeah, those antibodies weren't going to do anything against Omicron anyways, and working -- and then, of course, you know, month later, my four-year-old got -- got -- got -- got -- got infected, and -- and that's why I got it as well. You know, fortunately, you know, his -- his fever did spike, but, you know, he's fine. You know, they recover quick, and it's not -- no, the harms are pretty small with kids at this point, but it was just -- it wasn't very inspiring that -- that -- how that -- that went down, right? There was no reason -- we -- and not to say, I mean, maybe it didn't induce a T cell response at all, and that shouldn't have been, you know, past their trial, but they didn't even ask the question, right? And they weren't required to ask the question. So -- so we really need the -- the -- the FDA to say, okay, we -- we agree that T cells play a vital role, and we now are convinced that this can be measured in a practical way. We can actually ask the question, let's move, so we've been -- we've been having that discussion. Let's put it this way. We're definitely making more traction than we did before. When we first started this in, you know, March, 2020, no one even wanted to talk to us, but now -- now, you know, T cells is -- look, we're on this -- I'm on this podcast. I mean, I think there's been -- as you said, there was a -- the Wall Street Journal published an op-ed. We've had -- not just us, but many other groups have had some movement in some -- many of the big journals, as well as popular media outlets. So I think we're making headways just slower than I would like, given that we're in a pandemic, you know? Right. Yeah. Slow in a normal world. But this isn't a normal world. So I'd like to go fast. I saw your research, you know, coming through on the nature newsletter, you know, front and center, and then they had it on their podcast, as well. So I've seen the story getting out there. And what you were saying just a minute ago was part of the reason could be that you feel like T cells have been hard to measure, this -- you're giving -- that could be part of the excuse and part of the inertia, and that may be why it's just being developed now is a technology thing. I'm alright. Absolutely. Okay. A hundred percent. It's just that, you know, we got FDA approved for a molecular diagnostic version, you know, a year ago now, it's not -- you know what I mean? So it's -- Yeah. It's pretty new. It's new, but not that new in a pandemic world, you know, where you could imagine things have been moving fast enough now that we could get real -- policy could be changing faster as all I'm saying. Even though they didn't have the tools to ask the question, even when the pandemic first started, in March 2020, when the vaccine makers started working on this, there was no measurement they could have done on the T cell side, but certainly anything that's happened since, you know, since 2021, they did have the tools, so the FDA could start in good faith asking for them, asking for the T cell measurements. Well, thank you for coming on and sharing this with us. I'm super interested in adaptive, and I hope you'll come back and talk to us about your work in cancer. You know we're a genetics podcast, so I'm, you know, I'm very interested in your background. You've studied mathematics, behind genetics, you're originally a physicist, and then I mentioned you were head of computation and biology at the Fred Hutchinson Cancer Center. So will you come back and talk to us about what you guys were usually doing? I love to, and it's a good time for it too, we're a program, we work in partnership with Genentech and on sort of a cellular therapy where we're literally creating, it's personalized cellular therapy where we're creating different therapy for each patient, and it's really moving in a good direction, it's probably a good time, so I'd love to. Cool. Thank you. Yeah, well, before I let you go, I have to ask since you have this background. So because, you know, I'm the podcast host, so I like to troll people like you on philosophy of biology questions, so I have to ask, so are you a hardcore reductionist when it comes to biology, then do you think biology can be reduced to physics? I do not, certainly not in our lifetime, so I do think that we can do a much better job of putting a mathematical framework around how biology works, which is really the key to describing physics and the way that we do, but I think the, it's too complicated for any mathematics that we have right now to do more than just sort of get loose approximations. I think we're going to be a long way from having predictive mathematical models at anything like what we have in physics. Harlan Robbins, everyone, has become the voice for the importance of T-cells in our approach to COVID. He's the co-founder and chief scientific officer of adapted biotechnologies. Thanks, Harlan. All right, thank you very much, appreciate it. Today's show is sponsored by CG Life, the leading marketing agency at the intersection of science and health care, get started today at CGLife.com.