As the Covid-19 pandemic unfolded, scientists raced to develop vaccines against SARS-CoV-2, the coronavirus killing millions around the world. Large segments of the global population, including many people who had not worried much about infectious diseases for decades, were suddenly hanging on the success of those efforts. Vaccines have been around for so long that it’s easy to take them for granted and to be perplexed about how and why they work. Indeed, what is the real purpose of a vaccine — to prevent illness or to lessen its impact? And what should we know about the novel messenger RNA (mRNA) vaccines that were developed during the pandemic?

Anna Durbin is a professor of international health in the Bloomberg School of Public Health and the School of Medicine at Johns Hopkins, where she studies experimental vaccines used to combat Covid-19, dengue fever, Zika virus, malaria and other illnesses. In this episode, she shares her insights into the science behind vaccines with host Steven Strogatz.

Listen on Apple Podcasts, Spotify, Google Podcasts, Stitcher, TuneIn or your favorite podcasting app, or you can stream it from Quanta.

Transcript

Steven Strogatz (00:00): Hi, I’m Steve Strogatz, and this is The Joy of Why, a podcast from Quanta Magazine that takes you into some of the biggest unanswered questions in math and science today. In this episode, we’re going to talk about the science behind vaccines, specifically those developed to work against COVID-19 and what we can learn from this experience of going through the pandemic.

(00:25) In the face of shutdowns and social isolation, researchers around the globe went into overdrive to make a vaccine to battle SARS-CoV-2, the virus that causes COVID-19. The accelerated efforts involved two new ways to make vaccines, one of them being the mRNA vaccine that you probably heard of. As with flu shots, developing vaccines for the coronavirus is tricky because it’s a moving target. It’s always evolving. We make vaccines based on the versions of viruses that we see now, not on the versions that we think might evolve in the future.

(01:01) My guest today, Dr. Anna Durbin, is a professor of international health in the Bloomberg School of Public Health and the School of Medicine at Johns Hopkins. She also directs their center for immunization research. Dr. Durbin studies experimental vaccines for SARS-CoV-2 but also for dengue, Zika virus, malaria and more. She is also involved with vaccine safety efforts through the CDC. Dr. Durbin joins me now to share her insights into the science behind vaccines, including some areas where we might consider focusing our efforts, both today and for future outbreaks. Welcome, Dr. Anna Durbin.

Anna Durbin (01:42): Thank you so much, it’s my pleasure to be here today.

Strogatz (01:45): Could we begin with kind of looking back first. You know, we’ve been making and testing and approving and distributing vaccines for decades. Tell us a little about that old system of vaccine making. Let’s begin with the strengths. What were the strengths of the older system for dealing with infectious diseases?

Durbin (02:05): Well, I think one of the strengths is that it was tried and true methods. So we use the same sort of methods for many different vaccines. So there was a comfort level, I would say, with that. You know, people were familiar with the types of vaccines. Most of the vaccines, I would say they were made with pretty old school methods. So the different methods that we used is we would either take a virus itself, and through different methods make it weaker and weaker, until it would [become] so weak, it wouldn’t cause disease, but would induce a good immune response. And the other method was taking maybe that same bacteria or virus and then just killing it and administering it that way. So it wasn’t high tech, it was pretty low tech. And so maybe you could make a vaccine a little bit quicker given if you could adopt one of those methods. But there’s a lot of unknowns. You know, it was a very, I would say, less specific methodology, and it was a more hit or miss methodology than we have today, as we better understand how these pathogens work. And we have new tools that can really help us refine those vaccines to really try to find a vaccine that induces the specific immune response with fewer side effects.

Strogatz (03:22): Okay, so you’ve — you’ve touched, then, if I hear you right, on some of the weakness of the older method. You say, it had some hit-and-miss character, sometimes unwanted side effects. Were there any other weaknesses we should be aware of?

Durbin (03:34): The greatest — I would say one of the greatest weaknesses that we had with those is just the lack of really good specific immune responses. So for instance, we can take a virus and we can kill it, and we can give it to people. But in the process of killing that virus or bacteria, we affect how the immune response is going to react to that. So we get, I would say, not as good a vaccine as we could, just based on how we killed the virus.

(03:35) The other method I mentioned was what we call live attenuated vaccines, where we take a virus and we make it weaker and weaker through different methods. The most common method is just growing it in cells or tissue that the virus is unfamiliar with. So it has to adapt in order to grow in that, but in that adaptation, it weakens. Sometimes you make it too weak. Sometimes we don’t make it weak enough. And if it’s not weak enough, then we get more serious side effects.

Strogatz (04:37): Oh, that’s all very interesting, because I, you know, like probably everybody, I’ve heard about this idea of attenuating a virus but didn’t really know what the trick was. So that’s interesting to grow it in this unfamiliar environment, huh. Let us, if we can though, now move on to what we’re dealing with today with SARS-CoV-2, the virus that causes COVID. Let’s pretend we didn’t really know what it was for a minute. Like if you had to describe it to somebody, either who never heard of it or not a scientist at all, what are some of the main features about SARS-CoV-2 that stand out for you? What would you say about it?

Durbin (05:12): Well, the first thing that I would say about it, and I think this was scary to everyone, was that it was a virus we really hadn’t seen before. We may have seen what I call relatives to the virus, but this particular virus we hadn’t seen before. And that makes it dangerous because we don’t have experience with it immunologically. So we don’t have an immune system that would recognize it.

(05:36) How I describe it to people who are interested in viruses and things like that is it’s a respiratory virus. So it’s going to enter your body through your nose, through your mouth, through your respiratory system. And that will be important as we talk about these vaccines, how they work, and when we talk about how durable the immune response is, or how protected the vaccines are. But it really enters the nose or the body using this thing we call a spike protein. So it does look like, you know, when you see pictures of these viruses, it looks like a big ball with spikes coming out of it. And that that spike is the protein that the virus uses to enter cells in your body. And so when we think about the virus, and we think about how to make vaccines, one of the questions we always ask when we’re developing vaccines is ‘what is our target?’ What do we want to target on that pathogen to make the vaccine successful in either protecting against infection or protecting against disease. And we typically target that area of the virus that attaches to human cells and enters the body through human cells. And that’s why you always heard about the spike protein and why vaccines are making the spike protein or inducing immune responses to the spike protein.

Strogatz (06:54): Okay, let’s talk a little bit about some of the other viruses or pathogens that you have worked on in a sort of comparative way. So for instance, dengue, Zika, West Nile virus — what is it about SARS-CoV-2 that made developing a vaccine against it a, well, like a qualitatively different kind of challenge than making vaccines against those other viruses?

Durbin (07:17): Well, I think there’s a couple of things. And one of the things that I always like to stress when we talk about vaccines is, what is our goal? What do we want this vaccine to do? Do we want to prevent infection? Or do we want to prevent disease? And I think, early on in the pandemic, you know, these vaccines were so effective at preventing infection that that sort of became the end game. And that is almost impossible with these respiratory viruses.

(07:44) And the reason for that is, when we give vaccines — typically, and with all of the SARS-CoV-2 vaccines — they’re given in the arm, and they induce antibody that’s circulating in the blood. But to prevent infection, you need those antibodies at the site of entry. And I had mentioned this a little bit earlier, at the beginning. These are respiratory viruses. They enter through the nasal mucosa, through the respiratory tract, so you have to have antibody at that site to prevent infection. And most of the antibody that’s induced by the vaccines is circulating in the blood. So you need higher titers of that antibody, so that you get enough that crosses the nasal mucosa and can attack the virus at the site of entry.

(08:29) So I think what has been lost in the two years or so since we’ve had these vaccines is just how effective they are at the prevention of severe disease and hospitalization. That’s maintained throughout most of the pandemic. Where we see waning immunity is in this prevention of infection.

(08:48) And there’s two reasons for that. And I’m going to come back to your question. The first is, one, that we have antibody titers that naturally go down over time. And when they go down over time, there’s no longer enough antibody to cross into the nose. But the second, biggest reason is — and you mentioned this earlier — is how these viruses change, how they mutate. And I think it’s just really, really fascinating. You know, they are vying for survival. You know, they need to change and evolve, just like we do, in order to survive, in order to out-compete all of the other viruses, SARS-CoV-2 variants that are out there. These are viruses that mutate a lot, and some of those mutations are harmful to the virus, and those variants die out. And some give them a survival advantage. And that can be either they’re able to infect people more readily or they’re able to grow to higher titers, so that there’s more virus. That virus then can be spread to more people. Those are the variants that really survive.

(09:55) And it’s also competing against humans’ immune system. So if we have enough antibody to prevent infection or to prevent or abrogate replication of the virus, then that virus population is going to die down. So it feels — it needs to change to evade that antibody response, so that it can continue to infect people and spread. So because these viruses mutate so much, we’re always sort of in a push and pull — trying to contain and prevent the continued spread of SARS-CoV-2. The difference that we see with some of the other viruses — and a lot of the viruses that I’ve worked with have to adapt to different hosts, so when I talk about dengue virus, West Nile, or Zika virus, those viruses are spread from mosquitoes to humans. So the viruses have to adapt to both mosquitoes and humans, and it doesn’t have what we call the “infectivity force,” or force of infection that these respiratory viruses do, because it has to go through additional steps. So for that reason, they’re a bit easier to control with vaccines, because they have a much more limited amount of mutating they can do to be able to survive both in mosquitoes and in humans.

Strogatz (11:14): Oh, that’s an interesting point. Huh. That because they sort of have to be a genetic jack-of-all-trades, or at least two trades —

Durbin: Yep.

Strogatz (11:22): — it’s just a harder job for them. And it makes them a little more feeble — better, easier targets for you.

Durbin (11:27): Exactly. They can’t mutate to the same extent that these coronaviruses can or they won’t survive.

Strogatz (11:34): In your answer, which was fascinating, you raise so many different points. I think I want to go back over some of the things you said to see if I, if I got them — I hope I can remember them. It was really chock full of, of great stuff.

(11:48) So let’s first underline the key one, which is this question of a vaccine designed to prevent infection or at least reduce the likelihood of infection, versus a vaccine that is primarily aimed at reducing the severity of symptoms or the disease that follows. In the case of the early vaccines that were developed, or are being developed now, I think we know the answer to this question, but I want you to just say it again: What was the goal, preventing infection or preventing death and hospitalization?

Durbin (12:20): And I’m gonna say this for all vaccines, and that it still should be the primary endpoint, should be the prevention of severe disease, because to prevent infection is an incredibly high bar. It’s a high bar, particularly for respiratory viruses, because it means that we have to maintain very high levels of antibody. And that’s not really how our immune system works.

(12:44) So when you’re exposed to a pathogen, or you’ve been vaccinated, and then you’re subsequently exposed to that pathogen, your antibody titers go very high. But antibody titers are designed to go down over time, because otherwise, if we maintained really high antibody titers to every pathogen we saw, we wouldn’t be able to pump our blood because it would be so full of protein. And so this — we couldn’t, we couldn’t pump it. So antibody titers go down over time. And your immune system is incredibly well designed, we have this whole arm of the immune system called the memory response. And the purpose of the memory response is to sort of be lying in wait. And when you see that pathogen again, your immune system says, “Hey, I recognize that, I’ve encountered that before. It’s dangerous. Now I’m going to respond, I’m going to gear up and I’m going to attack and clear that pathogen before my person gets sick or before we get sick.”

(13:45) And that’s why we vaccinate: to give that initial exposure. To introduce the pathogen to the immune system in a safe way, so that when you’re then later on in your life, and you see that pathogen again, your immune system remembers it, reacts, and controls the pathogen.

(14:04) So vaccines in general are designed to limit disease, to protect against severe disease. Even if you’re infected — and I hate to use the word “natural infection,” you know, when we talk about immunity from vaccination versus immunity from infection — but even if you’re infected with SARS-CoV-2, we know that you don’t have durable protection against infection. You can still be reinfected. So to expect a vaccine to actually exceed that threshold, I think, is really — it’s not really an adequate or a reasonable expectation.

Strogatz (14:40): Thank you for all that. Now, there was also — in that earlier answer, you mentioned about antibody sort of ready to go in the nose or the nasal passages or the mucosal membranes, versus antibody circulating around in the blood, looking for any point of entry for any particular… I don’t know, I mean, is it fair to say — I don’t know — how specific these antibodies are? Is there, like, a ready-to-go army or civil defense that’s in all the different tissues looking for any kind of trouble?

Durbin (15:13): What a great question. So we have something called secretory IgA, or mucosal antibody, and that’s the antibody that really is at the mucosa. It’s along the mucosa in, in your nose, your respiratory tract, your GI tract. It’s made especially for pathogens that enter that way. But the vaccines don’t induce secretory IgA because the cells that make secretory IgA are really lining the mucosa. They aren’t in the muscle of your arm, or in your blood system where you get the vaccine. So we make — with the vaccine, typically, we make IgG, basic IgG, which is the immunoglobulin that’s circulating in your blood, most commonly. That IgG can move from the blood across the mucosa. But again, you need very high levels in the blood to sort of have that gradient from blood to nose. Whereas if you’re actually exposed in the nose, or on the mucosa track, you can stimulate both mucosal antibody or secretory IgA as well as IgG. And that’s why people are talking about intranasal vaccines for SARS-CoV-2.

Strogatz (16:24): Early on — I think we all lived through this — you’d hear of cases of people getting infections deep in their lungs, and really getting sick, getting terrible pneumonias and sometimes dying, versus later variants — like the one that I had when that one time I had COVID — was kind of like a runny nose and a really wicked sore throat — actually the worst I ever had. But it was, reminded me more of an upper respiratory infection. And so to your point that, I think, a lot of us don’t appreciate that the virus isn’t just competing against the immune system, it’s actually competing against other variants of the virus. I’m reminded of, like, how much easier it was to cough out and shed the virus I had because it was an upper respiratory thing, versus the ones that are deep in the lungs… It feels like it’s no accident that the virus has mutated to become more of an upper respiratory than a deep, lower respiratory disease.

Durbin (17:19): I’m going to take that a little bit further because it’s more than just the virus. That also are those vaccines that are inducing that memory response. And they induce more than just antibody. I’m not going to give an immunology lecture here, but we have antibody, and then we have something called T cells, which clear cells that are infected. And I think the role of vaccines in inducing that T cell response and inducing an immune response that helps protect against that lower respiratory tract illness — the pneumonia, the serious disease — was really underappreciated. We’re seeing more mild illness today, not just due to virus mutation. But it’s also due to the immunity that people have acquired over the past two years from both vaccination and probably previous infection as well. So that you have a good memory immune response that’s helping take care of that virus before we see severe disease. So yes, we have the virus mutating to become more infectious and try to get into that upper respiratory tract more easily. But we also have a better — an immune system that’s in better shape, that’s been training the past two years too, that can better clear that virus once infection occurs.

Strogatz (18:36): So let me see if I get your point there. Is it that we’ve somehow, through our vaccination programs, managed to make the lower respiratory tract more inhospitable? It’s like the virus is trying to evade our defenses and now go to the upper. Is that the idea?

Durbin (18:51): So yes, sort of. It’s that if it tries to go down there, we have cells that will kill the virus — or kill the cells that the virus has infected — and clear it before you develop pneumonia or other severe disease.

Strogatz (19:02): Okay, fantastic. This is all so, so interesting. Thank you. I’m sure you could hear in my voice. I’m, well, of course, I shouldn’t be gleeful about this. The whole thing is pretty serious and terrible and scary. But it’s also such a treat to have you explaining it all to us.

(19:16) I guess where I would like to go with you next is about the new technologies. Because those — you know, many of us who had to — well, the great benefit of getting vaccinated, we’ve been treated to some really interesting science experiments. Let’s start with the one that everyone has heard of: the mRNA vaccines, like the ones famously made by Pfizer or Moderna. Could you tell us as beginners how they work? Like, what’s the idea of an mRNA vaccine compared to — keeping in mind you told us about dead virus vaccines or attenuated viruses. What what’s different about an mRNA vaccine?

Durbin (19:52): So I would think of it this way. So with our old technology, for instance, we had a pathogen, but it was sort of like an opaque black box. We didn’t know the genetic material. We didn’t know what made it tick, what made it work, how to protect against it. So we just sort of took the whole pathogen, or as much of it as we could, and tinkered with it a bit to either make it weaker or kill it or whatever, and give it as a vaccine. Because we didn’t know which parts of the pathogen were important to protect against. Now, fast forward 60, 70, 80 or 100 years, we have genetic technology now. We know the genetic makeup. We can determine the genetic makeup of every single pathogen. We know how, how we can make proteins using genetic material.

(20:41) So mRNA stands for messenger RNA. And all of our cells — animal cells, human cells — we use mRNA as a messenger. Messenger RNA, it’s a code. Think of it as sort of a Morse code if, for lack of a better term, but think of it as a Morse code. And when your body sees that Morse code, it translates it into protein, and it translates it into the spike protein. And the beauty of mRNA is that all of this machinery — where this happens in your body, for any protein that your body is making, it uses mRNA, and then translates that mRNA into different proteins that your body needs. When that mRNA for the vaccine is given to you, it goes into your cells. Your cellular machinery sees that mRNA code, and it makes the spike protein of SARS-CoV-2. And the way it makes it — and again, this is the beauty of mRNA technology — your body can’t distinguish that protein from any of the other proteins that it’s making. So it’s how we — we say it’s presented. So it’s transported through the cell. It’s shown to your immune system in such a way that it stimulates not only antibody response but also that cellular T cell response.

(22:03) So you can use a very small part of the virus, but get a really big-bang immune response from that. You can get an immune response that looks like you gave a live virus with that spike protein, but you’ve just given the spike protein, and you get an excellent antibody response, and memory response, which is so important moving forward.

Strogatz (22:27): It’s really kind of wild to think about it. I guess maybe all vaccines work this way, but now that — the way you’ve described it, it’s stimulating a thought in my mind, which is how weird it is in a way that it’s your own cells making this alien spike protein. And yet your body knows it’s not “self.” Your body figures out — isn’t that interesting, though?

Durbin (22:47): It’s very, very interesting. And it’s really the same way it does for other viruses. For instance, when you have a live virus, when you’re infected by a virus, or you’re giving a live vaccine, those viruses infect your cell, and then your cell processes them, what we call processes them. And as the virus tries to replicate — any virus that infects you, you know … I want to say “hijacks” your cellular machinery. But certainly uses different nucleotides and things that you have in your cells to help itself reproduce. And part of that then, again, shows your immune system parts of that virus that allow a broad immune response. So both antibody and memory (or T cell) responses.

(23:31) When we give just a protein vaccine — so if we were to take that spike protein, and not give it as part of an mRNA vaccine, but give it as just what we call a subunit protein vaccine, which is old school technology. It’s sort of, you know, you can think of the tetanus vaccine or something like that, which is a toxoid, it’s just a protein. But if we were to make that spike protein outside of the body, and then just inject that, you would make very good antibodies to the spike protein. But the way your cells saw that protein and ingested that protein, it would process it in such a way that you really don’t get a good CD8 T cell response. You’d only get a pretty good antibody response. So that’s the beauty of the mRNA technology.

Strogatz (24:16): Oh, let me just make sure I got that because I had never heard that before. So you could conceivably — like, you mentioned tetanus, so we could try that same strategy. We put the spike protein directly into us. Our bodies would say, “Hey, that’s not right. That shouldn’t be here.” Antibodies would go out there to mop it up. But you say it wouldn’t produce — did I hear you right? C — did you say CD8?

Durbin (24:38): Yes. Like what we call a cellular immune response. And that’s because in order for your body … in order to get a good CD8 response induced, that protein has to be produced within the cell and then we say “presented” on the surface of the cell. So it goes through a pathway within the cell, and then little pieces of it pop up on the surface of the cell and engage with different T cells and it’s then stimulating the CD8 T cells. But it can only stimulate those CD8 T cells if it’s shown on the surface of the cell in a certain way. And it can only get there if that protein is produced within the cell, chopped up within the cell, and then presented on the, on the surface of the cell.

Strogatz (25:21): Neat, neat. I see. So, so much better to do it this new way with the mRNA. Exactly. Interesting. Interesting. So that’s one technology that many of us now have, I guess, in our own bodies working away, especially if you go get a booster.

(25:38) But then there’s this other technology that I have to admit I was not familiar with till I started trying to prepare for our conversation. I’m not even sure how to say it. Is it pronounced “AHH-denoviral” (adenoviral) vector vaccine or “a-DEE-noviral”?

Durbin (25:51): I like “AHH-deno” just because that’s, that’s what I grew up with.

Strogatz (25:54): What, now what is that? So am I right, that this is how Johnson & Johnson was pursuing vaccine development?

Durbin (26:01): And AstraZeneca as well. So adenoviruses are DNA viruses that are in the environment. We’ve actually had an adenovirus vaccine for many, many years. It’s called adenovirus type 5, because it causes illnesses, infections, particularly in people who are in close quarters, like the military or on college campuses. So the military had an adenovirus type 5 vaccine for many years. And that’s really what inspired people to use adenovirus as a vector. In the end, it’s been this technology has been used for experimental vaccines for many, many years. There are some HIV vaccine candidates that were using the adenoviral vector technology. And malaria vaccines.

(26:47) So different vaccines were using this technology, but it really became well known with the SARS-CoV-3. And essentially what you’re doing is, you’re using that adenovirus, I like to say, sort of as a Trojan horse. So remember I said with the mRNA vaccines, the beauty is that you get that spike protein produced in the cell. Well, it’s very, very similar with the adenoviral vector vaccines. Because they — what you do is you introduce the coding, and in this respect, it’s the DNA code for the spike protein as a gene in the adenovirus. And then the adenovirus is able to infect your cells, and it delivers that DNA material to your cell nucleus. It’s then made into messenger RNA, which goes into the cytoplasm of the cell, and then again, you use that cellular machinery to make the spike protein within the cell and then it gets presented both for antibody production as well as for CD8 T cell responses.

(27:51) Now, what’s a little bit different with these adeno— with these newer adenoviral vectors, there’s a couple of points, I think that are important. One is that they’re not using the common adenovirus type 5 that people have already been exposed to. Because if you’ve already been exposed to adenovirus type 5, and you have adenovirus type 5 antibodies, it may block the ability of that vaccine to infect. So J&J uses adenovirus type 26, which is not very common in humans, and then AstraZeneca used a chimpanzee adenovirus, which of course humans haven’t been exposed to.

(28:32) The other very important point with both of those vaccines is that the adenovirus itself that’s being used, is what we call replication defective. It cannot replicate. So you don’t have replicating adenovirus that might make you sick. What happens is, it’s really just — and that’s why I called it sort of a Trojan horse delivery system, because it is there simply to deliver that DNA gene of the spike protein to the nucleus of the cell, so that you can get the spike protein replicated and made within the cell and then presented to cells to make antibody and T cell responses.

Strogatz (29:14): Maybe something we could have mentioned back when we were talking about mRNA — and I don’t want to get us off the track, I want to keep going with the adenoviral vector vaccines — but with mRNA, so what’s the Trojan horse for that delivery system?

Durbin (29:26): So that is those lip— what we call lipid nanoparticles. So RNA itself can degrade very, very easily. We can’t just give what we call “naked RNA” because we have enzymes in the body and we have enzymes in the environment that will destroy that. So it has to be — one, it has to be protected. And two, it has to be given in a way that will allow it to actually get into the cell, not just ingested by the cell but actually get into the cell so it can be put into the cytoplasm and can be translated into protein. So for that, lipid nanoparticles are used. (And the “nanoparticle” refers to the size of the particle. It has to be small enough so that it can get into the cell without being seen sort of as an enemy and destroyed, and also the RNA can be protected.) And that lipid nanoparticle may also be acting as what we call an adjuvant, or sort of an immune stimulator. You know, the soreness in the arm, the fevers people have, the aches — most of us in the vaccine field believed that that’s really due to the lipid nanoparticle more so than the mRNA that’s being delivered.

Strogatz (30:35): Oh, interesting, huh. So you’ve told us about these two fantastic ways of making new ways of making vaccines. Is there a practical advantage of one type over the other?

Durbin (30:47): I think there’s a practical advantage of both types. I do think there’s a slight advantage to the mRNA technology. And I’ll explain what I mean by that.

(30:58) So with both types of these platforms, we can be extremely nimble in terms of making new vaccines because all we need is the genetic code. And I think a great example of that was COVID, right.? SARS-CoV-2, we knew the sequence probably the very end of December, first of January. There was vaccine vialed within three weeks. Of mRNA vaccine, because as soon as you know the genetic code, you can then make your vaccine. With the adeno-vectored viruses, you have to make that DNA code, insert that into the virus and make sure that the virus can tolerate it, that you know that you’ll still be able to get enough adenovirus with that DNA-coded protein in there. And that might take a little bit longer because you have to then grow up that virus or get enough of that virus with the DNA code for the SARS-CoV-2 spike protein in there. But in terms of making changes to the vaccine, all you need is the genetic code. So it can be done quite quickly.

Strogatz (32:03): Okay, we’ve already touched on evolution as part of this whole story. And I want to try out an analogy on you to have you react to it. I was thinking, you know, like when we have a situation where a virus can evolve very quickly. And we can also make our vaccines very quickly, we could change them rapidly in response to new variants, because of what you just explained. It reminded me of something that you sometimes deal with when you’re driving. If you have this technology in your car, where your GPS will tell you how busy the traffic is on one road. You know how congested it is. And so then you think, well — oh, like for instance, Waze. Okay, so everybody who’s using Waze says, “I’m not going to take that road, I’m going on this other road, because it’s less congested.” Except now everybody’s going down that other road.

Durbin: Right.

Strogatz (32:54): In other words, when you have these sorts of coevolving systems — like, I could imagine that we make a vaccine for the virus that we have. And now it’s not good anymore because the virus has adapted out from under us. Is that something we have to worry about? The coronavirus evolving to outrun our vaccines?

Durbin (33:11): Well, again — and I think this comes back to a question I asked very early: What is our end game? Protection against infection or protection against disease? So I think these vaccines have induced very good long-term protection against disease in most people. But we know that the elderly — that protection even against severe disease can wane and people who are immunocompromised. And as these viruses evolve, more and more, you get less and less protection against infection. And that’s when we need to start thinking about okay, do we need to make what I call a second-generation vaccine? Do we need to change the target of the vaccine from the original Wuhan strain to something like omicron?

(34:00) And I think we’re now at a point where the answer — or we were at a point in May, June of 2022, where we said yes, we’re at that point, we should make that change. Because, you know, the Wuhan strain has been gone, it’s been gone for more than a year. It was evolved out very early in the pandemic. But the alpha strain, the delta strain, even to some extent the beta strain, were still related enough that we could keep going on with the original vaccine. Omicron is quite different in sequence from the earlier variants. So we reached a point where we said, you know, it really makes more sense to have a bivalent vaccine that is more effective against the omicron variant. And so that’s what we’re seeing now. That’s what’s being offered now. And it makes sense.

(34:48) Now, will we need to do that every year? We don’t know. We have to watch how this virus continues to evolve and what our population immunity is and what the severity of the disease that we’re seeing is to really know that. You know, I have a feeling that we’re going to be seeing annual boosters for a while. How long that is, I don’t know. It may become like influenza, because we’re always going to have that elderly population that seems to develop more severe disease, get hospitalized. Because as we age, our immune system just doesn’t work as well. It doesn’t stay as robust. We don’t get as durable immunity. So we may need annual boosters to help us protect those most vulnerable, whether it be the very young who aren’t vaccinated or the elderly.

Strogatz (35:37): If we can, I would like to move on now to some of your own work, your lab. What you’ve all been doing in terms of SARS-CoV-2 and, and vaccines. Could you tell us a little bit of that, some inside stories?

Durbin (35:49): Sure. So my center — we have different investigators in my center. Dr. Kawsar Talaat is a very close colleague of mine. And during the pandemic, you know, early on in the pandemic, all non-SARS-CoV-2 research was halted. And we got involved in performing clinical trials for two SARS-CoV-2 vaccines. Dr. Talaat was the site PI for the Pfizer COVID vaccine and I was the PI for the AstraZeneca vaccine.

(36:21) So if you go back in time, two and a half years or, you know, we’re now in say March 2020, and everybody’s on lockdown. Nobody can come in the hospital. Only patients can come in. You can’t have visitors in the hospital. Most of us were doing telemedicine, we weren’t seeing outpatients in our hospital. Well, part of these clinical trials, of course, is looking at protection against COVID infection. So how do we see COVID-infected or people who we suspect have COVID, how do we see them? We weren’t allowed to bring them into our clinic. They had to be tested, and if they were positive, they couldn’t come into the clinic. We had no place around the hospital, around the university to see volunteers in COVID studies. And there were other groups who were doing convalescent plasma studies.

(37:14) And so colleagues in infectious diseases and the university got together and we actually created what we call the “COVID village,” where we took — you might have seen, you know, this, the storage pods, right? That people would, that get… So those were converted to exam rooms, and they were in a parking lot. And we had three or four of those storage pods that had been converted to exam rooms. And we put PPE on before we went into, you know, we went… What we would do is we would have the volunteer come in the parking lot. We would swab them for COVID. We had a rapid PCR test that would come back in 45 minutes. If it was negative, we could see them in in the clinic. If it was positive, then we took them into the pod and we did an illness visit and then we brought them back for illness visits in the pod as well. But it took a lot of organization and cooperation from the administration here to get that done. Because, you know, there’s that tension between prevention of infection and these, you know, we’re in a hospital setting and not exposure.

(38:22) And then how do we do the research. We enrolled more than 300 people in the AstraZeneca trial. We enrolled adults, adolescents, children, young children in the Pfizer study. And it’s kind of fun because we’re seeing now people in in the AstraZeneca study for their final visit. It’s nice to catch up with them and see what they’ve been doing over the past year. And that trial’s winding up. And then Pfizer, we’re gonna continue to see those kids and family members until at least two years after their last vaccination.

Strogatz (38:53): What would be the most valuable thing that we could do globally to improve our surveillance of this virus or other viruses?

Durbin (39:00): We need to ensure that we provide funding to set up surveillance in many different parts of the world. We have some flu surveillance going on, you know, and that determines what our new flu vaccine is going to be like every year. But we need that not just for SARS-CoV-2 but for other emerging pathogens. You know, what’s going to be the next SARS-CoV-2, you know? Surveillance is going to give us a hint to that.

(39:26) You know, I will say we learned a lot of lessons during the pandemic. And I think, you know, one of them was how we can work together to get new vaccines and such developed. But I think we also have failed in moving forward in a lot of different areas, and that, I think, are going to come back and hurt us if we have another pandemic. So what do I mean by that? Well, you know, we had a lot of vaccine nationalism. We need to empower, build up, train other countries to make their own vaccine. We need to have regional vaccine manufacturers, or even at a country level in different countries in different regions of the world, so that we have the capacity to make vaccines for the world, not just for, you know, the United States and Europe, but for the entire world. And I think, I’m not sure that lesson is being heeded, you know? We really need to do a better job at sharing technology when we have a crisis or a pandemic like this to make sure that if somebody has the technology for a vaccine, that technology can be shared and we can make vaccine globally.

(40:36) The other area that I think we can do a much better job at is health disparity and trying to really work to get health equity, not just globally. But you know, in Baltimore, in the United States, and globally, everywhere, make sure everybody has access to vaccines, has access to health care. You know, during the pandemic, we learned here in Baltimore that 30%, about 30% of the people who were admitted to the hospital with COVID had previously undiagnosed diabetes. And that’s a direct result of lack of access to health care. So we learned a lot in the pandemic, and I’m really proud of what we did, but I think there’s still a lot more we can do.

Strogatz (41:16): It’s been a great pleasure talking to you today. Dr. Durbin, thank you so much for spending time with us and explaining really so much about the immune system, about virology, about these vaccines. I really appreciate your time.

Durbin (41:29): Oh, you’re very welcome. I really enjoyed it.

Announcer (41:34): If you like The Joy of Why, check out the Quanta Magazine Science Podcast, hosted by me, Susan Valot, one of the producers of this show. Also tell your friends about this podcast and give us a like or follow where you listen. It helps people find The Joy of Why podcast.

Strogatz (41:59): The Joy of Why is a podcast from Quanta Magazine, an editorially independent publication supported by the Simons Foundation. Funding decisions by the Simons Foundation have no influence on the selection of topics, guests or other editorial decisions in this podcast or in Quanta Magazine. The Joy of Why is produced by Susan Valot and Polly Stryker. Our editors are John Rennie and Thomas Lin, with support by Matt Carlstrom, Annie Melchor and Allison Parshall. Our theme music was composed by Richie Johnson. Special thanks to Bert Odom-Reed at the Cornell Broadcast Studios. Our logo is by Jaki King. I’m your host Steve Strogatz. If you have any questions or comments for us, please email us at [email protected] Thanks for listening.