A new episode of our podcast, “Show Me the Science,” has been posted. At present, these podcast episodes are highlighting research and patient care on the Washington University Medical Campus as our scientists and clinicians confront the COVID-19 pandemic.
The omicron variant of SARS-CoV-2 arrived in the United States around Thanksgiving. Within a few weeks, it was the dominant variant in the country, and hospitals suddenly were crowded with COVID-19 patients again. More patients were hospitalized in the St. Louis region as the omicron wave hit than at any other time during the pandemic. The good news is that although there have been breakthrough infections in vaccinated people — even in those who received booster shots — omicron doesn’t make most quite as sick as earlier strains of the virus. Virologist and immunologist Michael S. Diamond, MD, PhD, has found in animal studies that omicron does not attack lung tissue in the way prior strains did. Diamond also found that some of the monoclonal antibodies that worked as treatments for other strains of the coronavirus are not effective against omicron. The FDA recently withdrew its emergency use authorization for two of those antibodies, so they no longer can be used to treat COVID-19 patients. Diamond says that although omicron doesn’t make most people as sick as prior strains, it still makes many very sick and is deadly for some. And he says there’s no guarantee that future variants won’t evolve to be as infectious as omicron and as deadly as earlier strains.
The podcast, “Show Me the Science,” is produced by the Office of Medical Public Affairs at Washington University School of Medicine in St. Louis.
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. As we continue to detail Washington University’s response to the COVID-19 pandemic, in this episode we look again at omicron. The extremely infectious variant first arrived in the United States around Thanksgiving, and it has become the driving force behind an unprecedented spike in COVID-19 infections and hospitalizations around the country. Washington University researchers say when it comes to omicron, there’s good news and bad news. Dr. Michael Diamond, who studies viruses and vaccines, says at least in animals, omicron doesn’t damage the lungs as much as prior strains of the virus did. But his laboratory also has found that a couple of monoclonal antibody treatments that had worked well against prior strains don’t work against omicron.
Michael S. Diamond, MD, PhD: So the antibody therapies, all of them don’t work except one. The mutations, they no longer bind the virus, so they don’t work. However, there are other drugs, of course — remdesivir and a few other newer ones as well — which still maintain potency, so they could be used.
Dryden: The U.S. Food and Drug Administration now has withdrawn its emergency use authorization for two of the monoclonal antibodies that are not effective against omicron, meaning they no longer are available to patients. Meanwhile, Diamond says that although the omicron variant does not seem to make most people as sick as prior strains of the virus, it is so infectious and making so many people sick that even a tiny proportion of such a large number of sick people has pushed many hospitals to their limits. Diamond says he remembers being concerned about all of the genetic changes in the omicron variant.
Diamond: When we first heard that omicron existed, we also heard about its changes in its genome, particularly in its spike protein. It has a lot of them, and that was very concerning. We had already been studying many variants which had far smaller numbers of mutations in the spike protein and yet still, to some degree or another, were able to evade not only vaccine-derived antibody responses but also therapeutic antibodies. And now we had a new virus, which was spreading throughout parts of Africa and South Africa in particular, which had more than 30 mutations in the spike protein. And so we thought that this would be potentially a major problem for antibody-based countermeasures, therapies or vaccines.
Dryden: Now, in those first few weeks after, it was identified as a variant of concern. It was hard to know what to do because there was so much we didn’t know, like how transmissible it was, how much protection the vaccines would afford. So how did you figure out where to start with this one?
Diamond: Well, first we had to obtain the virus, and this was no easy trick because the initial viruses were in South Africa, and there was a ban on flights. So that created a problem in getting the virus out of South Africa. So the first priority that we had — which took about one to two weeks even after we knew that the virus existed, knew its sequence, thought it might be a problem — was that none of us could work on it until such time that it actually came to the U.S. It actually arrived earlier, of course. We didn’t know exactly where it was going to be. But then we had the initial cases in several places: Wisconsin, California as well as Maryland. And once those cases in the U.S. arrived, then we were able to isolate — our colleagues were able to isolate — the virus and then distribute it to our network immediately.
Dryden: The risk of breakthroughs seems to be more common with omicron, but it’s also kind of like those other variants of concern so far in that vaccinated people, people who wear masks, people who avoid large crowds, they seem to do OK. I mean, it hasn’t turned out to be quite that bad, but it’s certainly pretty bad.
Diamond: At a population level, the data that has emerged both from animal studies and from human studies now, at least the early human data, suggests that omicron is somewhat less pathogenic than the prior variants. And what I mean by that is it’s not as efficiently able to cause lung infection as some of the other ones. That said, it certainly does cause lung infection in some people. And the real problem is that it is much more transmissible than the early variants. And even though, on average, it might not have the same potency in terms of its ability to cause disease, the fact that many more people are getting infected — there are people who get severe disease, get hospitalized, need to go on ventilators, and die from the virus. Now, that said, people who had prior infection or were vaccinated are getting significant symptomatic infection. And that’s because the antibodies and immune response that you have protect but not that well, and that’s because of these 30 mutations. So now we’re seeing a lot of people who were pre-vaccinated or prior infected, and they’re all getting symptomatic infection, but mostly upper respiratory. Whereas those that might have elderly, immunocompromised or never got vaccinated and never infected, they are the ones that are most vulnerable to the severe forms of disease. Although on a numbers basis, the fraction of people that get that is going to be lower. But because there’s more infection circulating, ultimately the number of people in the hospitals are higher, right?
Dryden: Right. And those folks who do get the infection, the bad infection, might be in a little more trouble because some of your work has shown that the monoclonal antibody treatments don’t seem to be as effective against omicron as against prior variants?
Diamond: Correct. So the antibody therapies, all of them don’t work, except one. The mutations — they no longer bind the virus, so they don’t work. However, there are other drugs, of course — remdesivir and a few other newer ones as well — which still maintain potency. So they could be used. But really, probably the severe cases are people who never were vaccinated, people who have other risk factors or comorbidities, as we say, for having severe disease, other diseases, either immunologic in nature or otherwise, which really would have benefited from being vaccinated or boosted.
Dryden: Is that the same reason why this variant might be milder in some cases? Those mutations are being a two-edged sword? That the drugs we have don’t work as well, but on the other hand, maybe it’s not as big a deal, for most people anyway.
Diamond: We don’t exactly know yet why the virus seems to be less pathogenic. It’s speculated that some of the mutations in the spike gene may alter its ability to get into certain cells versus others. But there’s still a lot more research that needs to be done, and nothing is definitive yet. We don’t have a full composite picture yet exactly why the virus seems to be less pathogenic, but it is. That said, it is not not pathogenic, and it can still cause severe disease, and it still kills people. So it is certainly, for people at risk, still can be a very big problem. And we’re seeing that every day because there’s lots of hospitalizations even here at WashU, but also nationwide. We’re at peak levels. So to say that this is a virus that is so highly attenuated it doesn’t cause disease is clearly not the case.
Dryden: How should physicians who are treating COVID patients think about these kinds of findings? About the monoclonal antibodies being less effective? About whether or not lung tissue is going to be infected, that kind of thing?
Diamond: I think there are several issues. One is that if you’re going to administer antibodies, make sure you’re administering an antibody that has activity against omicron, because now, greater than 95% of the cases here in the U.S. are omicron. Even if you don’t know it for certain, it’s likely omicron. The second thing is to not think that just because the virus is somewhat less pathogenic that it doesn’t cause disease and it can’t cause fatal disease or severe disease. It can. What’s different about this virus is that normally the vaccinated people might not have any symptoms, or they might have such mild symptoms that they would ignore them and it’d go away for a day. But you’ll find here people who’ve been vaccinated twice but have not been boosted, let’s say with the mRNA vaccines, are actually getting pretty substantial upper respiratory infections that last several days, that they don’t feel well, and they have to stay home and they spread rapidly to the rest of their family because it’s highly transmissible, so the whole family gets sick. And even if you get boosted, you shorten the course a bit. And some people don’t get symptoms, but still, a lot of people are getting symptomatic and miss school. So there are lots of consequences of getting infected. And this virus, even though it’s not causing on a percentage basis as much severe disease, it’s certainly having a huge impact.
Dryden: A lot of us had heard, anecdotally, that viruses get milder as they evolve because what they want to do — they don’t want to kill us, they want to infect us so that they can thrive. But here we’ve got, it seems, going the opposite direction or not?
Diamond: They don’t care why they evolve or how they evolve. What happens to a human is collateral damage. And all they need to do is to transmit. That’s what they’re evolving for. Or they potentially evade immune responses in some cases. They’re not going to evolve to become attenuated. That is a complete myth.
Dryden [voiceover]: Attenuated means weakened.
Diamond: They may become attenuated, or they may not, or they may become more pathogenic. Remember, in the beginning of the pandemic, every variant that evolved was actually equivalent or more pathogenic than the original one. It just so happens now we’ve evolved one that has more mutations and is less pathogenic, but that doesn’t mean that’s what’s going to happen in the future. Now, the one shining light that you may have heard Dr. Fauci and others say is that if so many people get infected with omicron, we will develop upper respiratory immunity against omicron, which probably will cross over to future variants as long as those future variants look somewhat like omicron. So that you may have substantial protection in the community at large, and this could actually change the pandemic to some degree and make it more like what we see in seasonal flu, where there’s a sort of known number of people that get infected, there’s known people who are at high risk, and everybody else sort of just suffers it out. It’s possible that may happen. It remains to be seen. The virus also could change substantially, and then we would be in the same boat. How would that happen? It could recombine. It could go into a zoonotic reservoir, into an animal, a mink, a mouse, a deer, and change substantially and then come back from that zoonotic reservoir and have substantial changes in its spike that the pre-existing immunity that we’ve generated with omicron is not that effective anymore. So these are things that we need to watch and see how things transpire over time. But it’s very difficult to predict. And certainly, I wouldn’t predict that the virus is self-extinguishing and becoming more attenuated, generally speaking, because this is not how or why viruses evolve.
Dryden: But with omicron, you did find that in mice and hamsters, it doesn’t affect the lungs as much as previous variants did.
Diamond: Correct. But that’s omicron. Who’s to say that that’s what’s going to happen in the next one?
Dryden: So what do we do?
Diamond: As a collective, we try to get as much immunity as possible. And that can happen two ways. One is that you get infected with omicron at the risk of dying from it. Not a great risk. I don’t know if you like to play Russian roulette. But maybe some young people are very unlikely, but you never know who you are. And you get infected with it, you can get long-haul disease, you can get other consequences of it, and you may have a genetic mutation or acquired mutation and you could die from it. So I’m not a big fan in having a virus — unless it’s a selected, attenuated virus, which we call a vaccine. You know, a live attenuated virus, which we know its properties. This one, we just don’t know yet all of its properties in all the population. So I’m not a big fan of saying, “Well, everybody should get infected so that we create immunity that way.” I think vaccine-induced immunity is good, and we can improve it. We can get boosted. We can think about vaccines that change, the variant vaccines, if you will. There’s work on mucosal vaccines that would provide local immunity down the road. So there are ways that we can improve our collective immunity without forcing everybody to get infected, including those who might be at risk, still, for severe disease. I mean, if you put it in perspective, if you have, as I do, 85-year-old parents, even though they’re vaccinated and boosted, I’m not so sure that I’m willing to just say, “Go ahead and get infected. It’s good for you.” I don’t know what the outcome would be. It might be OK, but it might not be. And so absent that, I think we have other things that we can do to improve our collective immunity in the population.
Dryden: Yeah, but I have many friends now who are almost resigned.
Diamond: Well, if you don’t wear a mask, everybody will get infected. Yes. But if you do wear a mask and you socially distance and you avoid certain situations, then not everybody has to get infected. I mean, I’m not a nihilist about this. I think that even though it is more transmissible, it is not absolute. Now, if you go places and there’s large gatherings and nobody’s wearing masks, that’s the setup for super-spreading events, certainly. But if you wear appropriate masks and stay in small groups and avoid certain situations, I think you can still avoid it.
Dryden: You’ve mentioned mucosal vaccines. Your lab has been working on developing a nasal vaccine, like a nose spray, that would block the virus before it enters the respiratory tract, I guess. Where do things stand with that? And what would the advantage be to that sort of a vaccine rather than getting a shot in the arm?
Diamond: So we developed this vaccine with David Curiel, another investigator here at WashU. And David and I have been working on adenoviral vaccines for quite some time. This vaccine we showed in preclinical animal models to be highly effective at generating mucosal immunity. That’s immunity in the upper respiratory tract at the site of attack, if you will, where a virus enters so that you could prevent it from actually entering and infecting the upper respiratory tract and, of course, then the lower respiratory tract as well. That vaccine was licensed to Bharat Biotech in India. It’s called BBV154, and it is now in phase 3 clinical trials. That’s the last stage of clinical trials for vaccine development. And we, as investigators, don’t have much to do with it. The vaccine was licensed. We provide some information every now and then on how it should be working and what it does, but it’s being run independently of us. We were not involved in the design or the evaluation of the data. It is being evaluated independently. So we’re hopeful that there will be data in the next couple of months, in time, perhaps, to use it as a booster. Because by that time, many people will have already had primary immunizations. And there you would boost with it and hopefully enhance your mucosal immunity so that you would actually have local immunity without having had to be infected in the first place. So that’s the idea. And we’ll wait and see. We’re optimistic. But as I said, we’re not really doing any of the studies. It’s being done by the company. I think the more people we vaccinate worldwide, and the unfortunate fact is, the more people that get infected with omicron, that will create a large amount of immunity. And it might temporarily stop the pandemic. But because this is a zoonotic virus, meaning we’re not vaccinating the animals because we can’t vaccinate the animals. I mean, we can vaccinate them in the zoo, but you can’t vaccinate all of the wild animals that are carrying coronaviruses around and related coronaviruses or even SARS-CoV-2 coronavirus. And we have no idea right now, except in the hamsters and mice, that it’s less pathogenic, but what is it doing in other animals? I have no idea. And it’s starting to be studied in laboratory settings, but the concern is that from these reservoirs, which we’re not able to control, we’re going to get every now and then periodic emergence of new variants, which will overcome the pre-existing immunity. So it may be like flu in that regard. So flu drifts every year, and you have to get a new vaccine. And then every couple of decades you get a shift, if you will, an antigenic shift, where there’s a huge change, and that’s presumably because something shifted from an animal reservoir that we haven’t seen. And then you can get a pandemic, as we did in 1918 and then 2009 and then 1967, as it were. And so my suspicion is that we will see epidemic transmission, but perhaps not pandemic transmission, of SARS-CoV-2-like viruses. And then it’ll be punctuated by periods where we have new viruses coming out that are much better able to evade pre-existing immunity. And we may be back to some level of the same boat, depending on how long the gap is in time and also whether we continue to vaccinate.
Dryden: As you talk about moving forward and some of the problems that unvaccinated people have, there is some early evidence anyway that people who have been vaccinated and boosted have some advantages, right? In terms of even if they get a breakthrough infection, it tends to be milder. There’s some evidence, as I understand it, that maybe long-COVID is less common in those who have been vaccinated and boosted.
Diamond: There’s no doubt that boosting is good and it raises your immunity. What we don’t know is how long that will last. And it depends on the platform. Are we going to need to reboost every six months, or will we get to a point where we just boost and we actually plateau our immune responses? And so this is what needs to be found out. Or are we — in some populations — we go up and come right back down after a few months? There is early data to suggest that if you get infected and then boosted, or vaccinated and then infected, you get what’s called hybrid immunity and you actually broaden the immune response and you’re more likely to tackle variants better than otherwise. But how durable that response is remains to be seen. So there’s still a lot of questions.
Dryden: But right now, the problem, or one of the problems, anyway, is that there’s just so much virus. So even people who are vaccinated and boosted are being exposed to such high levels of virus that they’re likely to get sick. And those whose immunity is going to fall immediately after they’re boosted are more likely to be in trouble because there’s just so much virus around.
Diamond: And not only that, but the virus is highly transmissible and your immunity in your upper airway, for vaccine alone, is not perfect because you generate systemic immunity, but not mucosal immunity. So these people, even if they’re vaccinated, or vaccinated and boosted, may still be transmitting. So they’re not taken out of the transmission equation, they’re just taken out of the severe disease equation.
Dryden: Diamond says new vaccines like the new omicron-specific mRNA vaccines that have begun clinical trials, and the nasal vaccine that his laboratory helped develop, may be part of the answer moving forward. And he says it’s likely SARS-CoV-2 is going to be with us in some form for quite some time.
“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 keep you informed and maybe teach you some things that will give you hope. 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.