Podcast: Updated boosters and progress toward a nasal vaccine

Jim Dryden (host): Hello and welcome to “Show Me the Science,” conversations about science and health with the people of Washington University School of Medicine in St. Louis, Missouri … the Show-Me State. During the first two years that we produced this podcast, we focused entirely on how School of Medicine doctors, researchers and trainees responded to the COVID-19 pandemic. Now, as the pandemic, we hope, is receding just a little, we also are reporting on some of the other research, lifesaving and just plain cool work being done at the School of Medicine. But fall has arrived, and so have new COVID vaccines. FDA-approved boosters now are designed to boost the body’s immune response not only against the original strains of SARS-CoV-2 but also against more recent omicron strains. In addition, Washington University researchers have developed a nasal vaccine. It was the first in the world to be approved when it recently was approved for emergency use in India. Now it may be on the path to being available in the U.S., Europe and Japan after Washington University licensed the technology to Ocugen, a U.S.-based biotechnology company focused on developing and commercializing novel gene and cell therapies and vaccines. Dr. David Curiel and Dr. Michael Diamond began work on the nasal vaccine during the early days of the pandemic, when mRNA vaccines also were being developed. But Curiel, who had some experience with the mRNA platform, says the researchers always thought their approach to nasal vaccination was a good idea.

David Curiel, MD, PhD: The most important issue we were trying to address was the transmission problem, so that’s what Mike early on showed we gained with the intranasal route. That was one of the contexts that the current vaccines didn’t address.

Dryden: The idea behind developing a nasal vaccine is to amp up the immune response in the nose and the throat, where the virus first gets into the body, rather than the current vaccines that fight the infection once it’s already in the system. In theory, a nasal vaccine also would make it harder for vaccinated people to infect others, because while shots that deliver the current vaccines put antibodies in the immune system on the lookout for the virus, the virus still does have to get into the body first. So the nose, where the virus enters, might be a more effective place to stop it. And when Curiel and Diamond compared the vaccination approaches in mice, Michael Diamond says the nasal approach worked better.

Michael S. Diamond, MD, PhD: We did a study in the laboratory, where we head-to-head compared intramuscular vaccination and intranasal vaccination with the same vaccine and the same dose. And what we saw was superior results when we gave it by intranasal route. But we felt, once we saw those results, that this kind of a vaccine would have the opportunity to restrict transmission or to cut down transmission substantially, whereas the other ones wouldn’t.

Dryden: Meanwhile, new mRNA boosters are available now in the United States, approved for use in children as young as 5 or 6, depending on whether it’s the Pfizer or the Moderna shot. It’s hoped that the new boosters will be more effective against new variants of the virus that causes COVID-19.

Rachel Presti, MD, PhD: So they are using the sequence for BA.4 and BA.5, which is the same spike sequence. So the viruses are different, but their spike sequences are the same. And what they’ve done, in the vaccines that are available now, is combine them so that they’re giving you half, sort of, a stimulation with the original vaccine and pair that with a new version. Kind of to tell your immune system, “OK, remember this? This is what that looked like. Here’s its cousin, and you want to get just as good of an immune response to that.”

Dryden: That’s Dr. Rachel Presti, an infectious diseases physician and one of Washington University’s principal COVID vaccine researchers. She’s been involved in studies of new vaccines pretty much for as long as there have been COVID vaccines. Although these latest available vaccines still involve a shot, that may change as Diamond, an infectious diseases researcher, and Curiel, from the Department of Radiation Oncology, continue their collaboration. The nasal vaccine deploys a virus that’s a cause of the common cold, called an adenovirus. In this case, the virus itself has been disabled so that it can’t make you sick, but it delivers the SARS-CoV-2 spike protein, causing the body to mount an immune defense. Curiel says the two had continued to work on their adenovirus nasal vaccine while the mRNA vaccines were being distributed because he had learned from previous experience that immunity from mRNA vaccines might begin to wane over time.

Curiel: It induced immunity, but it would wane. So that was a piece of information that just made me think that alternative approaches might well be developed. It was early in the game with the COVID mRNA vaccines. People didn’t have data of waning immunity, but I suspected it might come to play. So there were kind of different reasons we thought about the intranasal adenovirus approach, but they converged on something that addressed some of the shortfalls. The issues that came up with the current programs were, obviously, vaccine hesitancy, longevity of immunity and then the big one: transmission. The most important issue we were trying to address was the transmission problem. So that’s what Mike early on showed we gained with the intranasal route was a sterilizing immunity. And as —

Dryden: ‘Sterilizing immunity’ is an immune response that’s so robust that the person infected with the virus doesn’t get sick or pass along the virus to anyone else.

Curiel: And as things came to pass, that was one of the contexts that the current vaccines didn’t address.

Dryden: It’s also cheaper. Correct?

Diamond: I think that there are two issues here. One, cold chain.

Dryden: ‘Cold chain’ refers to the requirement that vaccines must be kept at very cold temperatures all the way from production through storage and distribution, requiring special freezers to keep vaccine doses very cold.

Diamond: MRNA-based vaccines are lipid-based. And lipids have to be handled at a certain temperature to keep them stable or they’ll break down, and they lose efficiency of the vaccination. Whereas adenoviral vectors are much hardier particles. So that’s one thing. So this allows your distribution chain to be able to go into parts of the world where it may not be so easy to actually administer mRNA-based vaccines. The second is biohazard waste and injectables. And so every time you have an injection, you have a needle, and you’ve got to get rid of that needle. And it’s even though we don’t think about it too much, but when you’re in the remote areas of the world, you’ve got to carry around all that waste. Whereas if you have an intranasal vaccine, it’s much simpler in terms of waste streams. So I think the key points are administration simplicity, administration waste and then really cold chain, which allow greater distributions of adenoviral-vectored vaccines.

Curiel: Mike and I didn’t invent intranasal vaccination. It’s been around. But the COVID pandemic has now highlighted the deficiencies of current vaccines and the benefits that may exist with intranasal. So in the same way, it may be the thing that brings to wider recognition the value of this approach, which has been around a while.

Dryden: And do you envision this nasal vaccine being used mainly as a primary vaccine or as a booster? Which way do you think it’ll be more effective? And do you think it will last longer than the mRNA platforms?

Diamond: It’s hard to know exactly how to answer the question, but what I can say is that likely over time it will be used as a booster. And that’s because over time there are going to be more and more antigen-experienced people. So either they’re boosting because they were infected or they were boosting because they had another vaccine. And so the number of people that are completely immunologically naive — meaning never got vaccinated, never got infected — is dwindling on the planet. While there may be some subsets of individuals who would get two doses of this as a primary vaccination series — for example, young children who didn’t get vaccinated at all or some people who are hesitant to get shots otherwise — I think that over time, boosting is probably going to be the way it’s going to principally be used. When they did a study in their clinical trial, they did two arms to it. One arm was as a primary vaccination series, and the other was as a booster. And my guess is that ultimately they’re going to want to use it both ways.

Dryden: Although you guys developed this technology, with this study in India you were not involved at all. It was licensed to a company that did the research there.

Curiel: Once they licensed from Wash U, we were very involved, and there was lots of crosstalk in terms of helping them upscale and consulting them. But no, they executed the trial.

Diamond: They, I don’t think, had done adenoviral-vectored vaccines before. So they really needed help, mostly from David’s lab, on how do you grow these things? How do you know what you got? And then once they learned, pretty quickly, then they really didn’t need us too much anymore until it was time for variants. And so we’ve been in touch with them about the possibilities of variant vaccines and what that means and what it means for immunity.

Dryden: Variant vaccines now are available in the United States, at least in the old-fashioned shot-in-the-arm variety. But the hope at the moment is that nasal vaccines might show up relatively soon. Curiel says a recent White House summit on COVID-19 reached that conclusion.

Curiel: The leadership of the NIH met and defined the highest priority in the field, and they defined intranasal vaccines. And they said there should be something like a warp speed-type initiative. I think there’s broader recognition that the international approach should be implemented and advanced.

Dryden: Is it as easily adaptable?

Diamond: Basically, all you have to do is just make the mutations in the existing gene or just synthesize the new gene and put it into the adenovirus and then generate the virus. It doesn’t take very long. It’s a little longer than mRNA, I think maybe a week or two, but it’s within that range of time. So if you can go from 0 to 100 in an mRNA vaccine and it’s two to three weeks, probably it’s three to four weeks for the adenovirus, but that’s about it. So it’s very, very easy to manipulate genetically and then to develop it, grow it, produce it. So I think it’s slightly slower than mRNA, but not much.

Dryden: Vaccine researcher Rachel Presti says scientists have known from the start that the mRNA vaccine format could be updated relatively quickly as new variants emerged. And that’s what has happened this fall.

Presti: I think the feeling was it’s clearly just as safe. It looks like it gives you a somewhat broader immune response if you use a variant sequence and that it is definitely likely to be just as good as giving another booster of the original vaccine and most likely to be better. There is animal data. If you give this booster to animals, you protect better against the BA.4, BA.5 variant.

Dryden: I’ve heard some folks say you should go and you should get your COVID booster and you should get a flu shot. Where do you stand on that?

Presti: I’d say you should get both. It’s reasonable to get the flu vaccine now for the anticipated upcoming flu season. Part of the problem with all of these viruses is we never know exactly what kind of season we’re going to have until we’re in the middle of the season. And you’re always better off being prepared. There’s been an ongoing concern as we drop precautions for COVID, which worked really, really well to drop flu numbers as well, that we would start seeing a surge of flu. We didn’t see that last year. We saw sort of a mild flu season, a more normal flu season than the nonseason we had in 2020-21, but still not a really bad flu season. I think we always worry that when we haven’t had a bad flu season, we’re sort of due for one. So I think it’s reasonable to get both vaccines. It is safe to get both vaccines at the same time. That has been allowed for quite some time.

Dryden: With that connection to the flu shot, there’s been conversation lately that maybe COVID will become an annual vaccine, and I wonder about that. Is that because we’re anticipating that the virus will continue to mutate, and there will continue to be new forms? So you’ll need a booster sort of like the one that has become available now? Why the talk about an annual COVID booster at this point?

Presti: I think it’s partly because what we’ve seen is sort of waning immunity that seems like it correlates with increasing numbers, but I think more importantly it’s because we’ve seen the virus manage to escape sort of the efficacy of the shot. I am not 100% certain that we’re going to see the COVID vaccines become just as much annual vaccines as the flu vaccines. Hopefully to some extent, this new technology, a lot more interest in vaccine development will actually eventually lead us to a more long-lasting protective immunity. And the reason the flu immunity doesn’t last is because the flu changes. And I think probably the reason that the COVID immunity doesn’t last is probably more because of changes in the virus and changes in people’s exposure to the virus than it is really a lack of immunity. But we know with other coronaviruses, while they don’t cause severe disease, people get them every couple of years. We’re not yet at a point where we can completely prevent them. Hence, the old saying that there’s no cure for the common cold. This is looking like it could be a common cold. So I think what we’ll see is annual COVID vaccines until we have enough data that says there’s not enough benefit to continue to do that. And we’re not there yet. We’re still seeing enough people die from COVID that we really need to boost people’s immunity so that we protect more people from severe disease and death.

Dryden: One of the other things that has complicated this is that there has been so much virus around. And one of the reasons, I guess, that there’s been so much virus around is because so relatively few people actually went and got boosters. Numbers in the 30% to 40% range that seem kind of low. So even if this new booster is really good, we got to get more people to get it, don’t we?

Presti: We do. We know that you have immunity from natural infection, but we don’t understand that as well. And it doesn’t seem to be as predictable as the immunity you get from the vaccines. And so a lot of people think, “Well, I don’t need a vaccine because I got the infection, and now I have superimmunity because I was infected.” But the data doesn’t really support that.

Dryden: A nasal vaccine that was developed here at Wash U was approved for use in India. From your perspective, might there be advantages to a nose spray rather than getting a shot like the one that we’re currently receiving?

Presti: I think that’s definitely the hope. And the way you get COVID, right, is by inhaling it. And so the first site of exposure where you’re getting infected is in the nose in the upper airway. And your immune response in those mucosal surfaces like your nose and your upper airway is different, somewhat different antibodies and then different sites. So having a lot of antibodies in your blood means that they don’t get activated until the virus actually is seen by your blood. Whereas if you had antibodies in your nose, you could maybe keep everything in your nose and not wind up with a systemic infection and be systemically sick.

Dryden: As Diamond and Curiel work with the adenovirus platform to make nasal vaccines more effective, we are currently getting closer to another winter, a time when hospitalizations and cases have increased dramatically the past couple of years. And while the hope is that someday soon we might use a nose spray to boost immunity, at the moment, more traditional shots in the arm are required. And Diamond, Curiel and Presti all agree that it’s extremely important that as many people as possible get boosted with the updated mRNA vaccines as we head into the winter months.

“Show Me the Science” is a production of the Office of Medical Public Affairs at Washington University School of Medicine in St. Louis. The goal of this project is to introduce you to the groundbreaking research, lifesaving and just plain cool work being done by faculty, staff and students at the School of Medicine. If you’ve enjoyed what you’ve heard, please remember to subscribe and tell your friends. Thanks for tuning in. I’m Jim Dryden. Stay safe.