What’s next in the pandemic?

How long will we need to keep wearing masks? What will vaccinating kids under 5 mean for everyone? What have we learned from the omicron and delta surges that could help prepare us for the next variant? What does it mean for a disease to move from pandemic to endemic? None of these questions has an easy answer. But we’ll ponder them with three smart people and, hopefully, come out with a better understanding of where we’re all headed.

Our guests are Bill Messer, a physician and scientist specializing in viral, infectious diseases at OHSU; Fikadu Tafesse, assistant professor of molecular microbiology and immunology at the OHSU School of Medicine; and Katherine Wu, a staff writer covering science at The Atlantic.

This transcript was created by a computer and edited by a volunteer.

Dave Miller: How long will we need to keep wearing masks? What will vaccinating kids under five mean for everyone? What have we learned from the Omicron and Delta surges that could help us prepare for the next variant? And what does it mean for a disease to move from pandemic to endemic? There are no easy answers to any of these questions. In fact, a lot of them just seem to bring up ten more. But we’re going to do our best to get some clarity on our COVID futures with three folks who all have PhDs right now. Bill Messer is an associate professor in the departments of medicine and molecular microbiology and immunology at OHSU (Oregon Health Sciences University). Fikadu Tafesse is an assistant professor of molecular microbiology and immunology at OHSU as well. And Katherine Wu covers science as a staff writer for The Atlantic. Welcome to all three of you.

Katherine Wu: Thanks so much for having us.

Miller: So Katherine Wu first. For months now people have been talking about the switch that’s going to happen at some point or perhaps it’s already past when we go from a pandemic situation to living with an endemic virus. But you have a new article that just came out today in The Atlantic, that sort of blows up that binary because you point out there’s no one version of endemic? So, first of all, what are some of the various possibilities here, the different versions of endemic?

Wu: I do want to first point out here that this was co-authored with my colleague Jacob Stern. So I definitely can’t take all the credit here. But yeah, this is an incredibly complicated question. I think endemic is this relatively simple seeming word.  It’s got just seven letters in it. It seems like a logical way to say, oh, an end to a pandemic but it really is actually a coincidence that it has the word end in it. It really just denotes a relationship where we are the hosts and we have a pathogen moving among us and doesn’t really tell us much about the nature of that relationship. This could be a virus or a bacterium or a parasite or whatever it may be, something that is moving among us very, very frequently, very, very infrequently. It can cause devastatingly severe disease or be relatively trifling. The word endemic does not dictate which of those qualitative features we’re actually going to embark on. And I think when we use just that word, it doesn’t really convey how complex that is. And it just makes it sound like, hey, this disease is going to go endemic if we kind of just let it go, it’ll end up there eventually and sort of engenders the sense of phew, this is over where it’s way more complicated than that. There’s not even anything that necessarily says endemicity will represent a massive departure from the crisis. It could be reasonably bad for most of the time.

Miller: You have a metaphor that I found to be striking and helpful. Also complicated: a bathtub. Can you give us different versions of the bathtub metaphor?

Wu: Sure. So one of the strictest versions of a definition for endemicity has this idea that once we develop enough immunity, the virus will circulate among us in a very, very stable fashion. So imagine that a set number of people are infected in a population. Over the course of a year, each infected person will on average infect just one other person sort of replacing themselves in the population. I moved from. I can be infected and I have been infected and one other person sort of replaces me in the lineup. You can picture it as a bathtub that is sort of being filled by a faucet and draining from the other end at about the same rate. So the water stays pretty level even though things are sort of moving through it. That’s one very, very strict and fairly simple version of endemicity.  But I think back to all the possibilities that are contained even within that metaphor, we don’t know where the water level sits. Could it be super low on the tub? Could it be super high in the tub? Could it be kind of slightly overflowing the entire time? Could the water be extremely hot or extremely cold? It basically doesn’t tell you about the experience of submerging yourself in that tub. What is it gonna feel like?  We don’t know. And if we expand the idea of endemicity out to we don’t know if it’s going to be stable all the time. Maybe the water levels are fluctuating. Maybe the water is kind of choppy because someone is splashing it around frequently. I think when we think about how complicated and variable endemicity can get, that captures only just the very tip of it and when we overlay that onto something more high stakes, like people dying of a deadly disease, it gets even wilder.

Miller: How much can our behaviors affect the level of endemicity as opposed to just the dumb, good or bad luck of viral mutations?

Wu:  Right. Absolutely. So I would say enormously so. I’d say that human behavior is one of the largest factors dictating what sort of cast endemicity takes on and I think using that word makes us forget that a little bit because it’s so easy to say a virus can go endemic. Where are we in that equation? Really it’s about what endemic future could we be shaping for this virus? But think about all the ways that we have managed to do this. We’ve even managed to take viruses from endemic to pretty much eliminate it, which is what we have done with polio here in the United States. We have essentially done that with measles, even though it causes some rare, occasional outbreaks here. But we can also go in the other direction. If we neglect a disease, it can become endemic in a country and cause

enormously high death and disease rates that we would consider untenable in other parts of the world. But we can also fluctuate immensely. Things that we take for granted like the flu, which is often used as a comparator for what far off, very post pandemic COVID could look like. We managed to really stamp that out during our first full pandemic winter and that was remarkable. Flu levels plummeted to pretty much zero across the board. It was totally unprecedented. Imagine what we could do if we put in place even a fraction of those same measures going forward.

We could really change the picture of a lot of diseases we assumed to just be a normal part of life, a burden that we have to shoulder for decades on end.

Miller: Bill Messer, is seasonal influenza one of the ways that you’re thinking about a possible future of COVID.

Messer: I think in many respects, seasonal influenza is a good starting point for thinking about what the post pandemic future might look like. And there are a couple of reasons for that. The first is we have in the 1918 influenza pandemic a model of how a pandemic moves through the global population and possible ways to think about the outcome.  And part of this touches on what Katherine has alluded to which is that these diseases do not necessarily go away. I think that would be an unrealistic expectation for COVID-19, but the disease movement through populations will take on certain patterns dictated by the way that we respond to those patterns. So, for example, the establishment of a global sentinel system to identify what influenza viruses appear to be going into circulation every year, formulating a vaccine that’s going to be targeting those circulating viruses each year, and then acknowledging the uncertainty around that process. Everybody knows that some years the influenza vaccine is really good at preventing you from getting sick with influenza and some years it misses the mark. And when you happen to be the person who suffers the breakthrough infection, it’s not so trivial, but the fact is we’ve really built that into our thinking about how we manage influenza on a year in year out basis. And I think a similar approach is going to be called for in incorporating COVID-19 into our long term public health planning. And influenza just serves as a potential model for that because we have historically gone through a similar event with the 1918 pandemic.

Miller: Are the speeds at which this once novel coronavirus mutates and the influenza viruses rate or pace of mutation, are they similar enough to have that work? I’m just thinking about the Omicron spread and the time from when it was identified by South African scientists to maybe two months or so and it was everywhere, when it was almost like a whole new pandemic. And even with new MRNA vaccine technology, it seems impossible to imagine large-scale production of a new booster specifically targeting this new variant that could have happened that quickly. Could we have tailored vaccines every year that are going to really hit the right target? How likely is that?

Messer: That’s a really good question and it’s hard to know the answer to at this point.  The mechanisms of evolution between influenza and coronaviruses are pretty different for a variety of reasons. They are both RNA viruses but their genomes are different sizes and look really different when you examine them and lay out their genetics and they have different strategies for undergoing evolution and mutation. It wouldn’t have been possible probably to practically produce an Omicron vaccine in the short time period that it emerged. I think we need to mark the win for surveillance though in picking up on it as it began to emerge, recognizing its potential and at least being able to put out the cautionary warning: Hey, here’s this very transmissible virus that was first picked up, watch out for it. And all of that happened in the time frame that was both real time and created the potential for responses to happen on a large scale. Whether or not they did happen I think is much more complicated and tied up in economics and politics, but score one for surveillance there. I think the larger question in terms of vaccine formulation revolves around two things. The first is because this virus is really new in humans, it’s still evolving to find its, if you like, sweet spot for transmissibility and survivability and whether or not it is going to continue to evolve at the same rate with the same diversity of mutations in perpetuity. I think that is an open question that may actually settle down. The second is that–-and this has been recognized with the vaccines–the vaccines that have already been deployed or the vaccine formulation which is administered in different ways, but all target the same parent virus, does continue to show efficacy against the variants and we may move out of a period of where that efficacy exists at which point a new formulation will be required, but I’m not sure that every new variant will require a new formulation. I think the question that will be asked as variants emerge will be: Do our previously-deployed vaccines still elicit sufficient immunity to provide the critical feature which is protection from severe disease and death? And if the answer is equivocal then maybe that’s time to design another vaccine with enough diversity in it to give it a lifetime longer than the lifetime of Omicron, but a lifetime into Omicron and its descendants. And that is a viable vaccine strategy, I think.

Miller:  Fikadu Tafesse, I want to turn to you. You’re a part of the team that recently published a study that looks into two paths toward what you call super immunity to COVID-19.  First of all, what do you mean by super immunity?

Fikadu Tafesse: Hi, Dave. So let me just summarize what we did and I will come back to the super immunity connotation because that can be a little bit confusing.  So what we did in this study is that we assembled a cohort of more than 100 individuals that were split into three groups–-one that was previously-infected and then fully-vaccinated with two doses of Pfizer vaccines and the other one that was fully-vaccinated and obviously they got breakthrough infections. And we compared these two with those individuals who were in the only vaccinated group. Then the finding was quite profound.  What we found was we measured the antibody levels of those three groups and as compared to vaccines only. Individuals that received the exposure to the virus before or after the vaccination have a significantly higher level of antibody.  So it’s not only the levels of antibodies higher but the potency, the breadth of those antibodies to neutralize different variants of the virus is remarkable.  So what we, for the most at least, found tenfold increase, sometimes up to 20-fold increase as compared to the vaccines only.  Then that is why we kind of called it a super immunity. The improvement of immunity that we found was significant and this is what we called a super immunity. Maybe that is kind of a little bit weird but that phenomenon is now termed as super immunity.

Miller: How do you explain this? What’s the mechanism in our bodies that you’re proposing or assuming that this combination of natural infection induced-immunity and vaccine-induced immunity that the combination is so powerful?

Tafesse: So I think there are two levels to this. One is that the common foundation for all of this is really vaccination. Vaccination provides you this fundamental immunity, just a background immunity to give you that starting point to get this high level of immunity at the time when you get infected. There are two things, right? When you are fully vaccinated, hopefully the kids are mine. And then because there is so much virus circulating in the community, the chance of you getting exposed to the virus is high.  And I think it is really important for our listeners to appreciate the importance of the vaccination here.  Regarding the mechanism, I think when the vaccines are based on one element of the virus that is the spike protein, but the virus when you expose it to the live virus, the virus you get the body is exposed to not only the spike proteins but other components of the virus which are critical in terms of  adjusting and training your immunity. So I think it is just a collective effect in addition to that spike proteins that the vaccination is providing passed are those proteins or elements of the virus that are not included in the vaccines eventually gives you this really good comprehensive immunity against the virus, not only just the original virus obviously but future emerging variants as well.

Miller: Katie, I want to go back to you because everything that Fikadu Tafesse is talking about here is premised on people being fully-vaccinated and it seems if we’re going to be honest about the trajectory of the the next couple of years, we should be clear about what’s what’s obviously happened the last couple which is that vaccines have been readily available in this country, certainly this is not true globally, but readily available and a significant chunk of people driven by partisan divisions have made the decision not to get vaccinated. And it doesn’t seem like there’s any reason to believe that in the coming months or years that’s going to change. So I’m wondering how that fact affects the way you think about the future?

Wu: Yeah. And I think again I am not going to be in the business of making super concrete predictions about what comes next. But I think it is fair to say that a lot of these inequities and a lot of these, oh I think, bits of inertia in terms of vaccine uptake are going to persist and it’s going to have profound implications on how the rest of the pandemic unfolds and how we sort of move towards this post pandemic phase, whatever it is going to look like. Immunity is not just about protecting people from getting really sick or ending up in the hospital, it’s also about how quickly the virus can move through a population, the extent of the burden it causes and also how many opportunities the virus has to copy itself inside of us, acquire new mutations and sort of upend our immunity again. This is all a very interactive, iterative process. And so vaccine equity, sort of distributing high quality durable immunity equitably, that has, I think, really profound implications. And I think we’ve already seen that really good immunity and that certainly includes getting multiple vaccine doses at the very least, has been concentrated among specific populations. It does seem to matter in this breakdown, education status, even things like race and ethnicity and certainly geography, resources on the global scale. The disparities are enormous. I think this is going to really show itself in the future   where COVID is going to concentrate is where good quality immunity does not.

Miller: Bill Messer, I’m curious from a clinical perspective if you treat patients who are immunocompromised and if so what you’re hearing from them in terms of what they think the future is going to look like.

Messer: It’s a really good question and I think it poses a couple of interesting challenges for us as clinicians but also for the patients. I would lead with the observation that immunocompromised patients, particularly those who have undergone things like bone marrow transplant or organ transplantation, are really immunosuppressed. The farther they are out from their transplant, the longer they have lived with this immunocompromised state and what already is really heightened vigilance for transmissible diseases of all kinds. For example, cold viruses that we often think of as being minor influenza viruses can be threatening and then there is also susceptibility to environmental pathogens that don’t usually make people with intact immune systems sick such as fungal infections in particular.  And so there’s a lifestyle and a perspective in a lot of those immunocompromised patients that’s already built around the notion that they are vulnerable and that they need to take measures to protect themselves and have had to since before COVID-19. And amongst the patients that I’ve interacted with who are in that population, there is an incredible amount of anxiety. Probably for some of them it borders on severe clinical anxiety with the emergence of yet another pathogen that they have to be wary of that is demonstrably dangerous for those people and at the same time acknowledging that they’ve been living with these sorts of risks already and adapting to them. Each patient has their own experience. And so I don’t want to generalize too much. But to categorize or to catalog a few individual responses I have encountered exhaustion, fatalism, a desire for vaccination and other interventions that could protect them from getting getting sick like monoclonal antibody therapy on on top of vaccination, which in many cases, the vaccines don’t work really well in these immunocompromised people because they have to have an immune system to react. So there are a suite of different reactions, but I think they’re all predicated on the fact that a lot of them have already been living with that risk and to a certain degree, I think that’s a perspective that’s useful for all of us as one of sympathy and empathy, perhaps recognizing something that we don’t always or haven’t always appreciated in our own encounters with infectious diseases, but also also the fact that that their longstanding risk and exposure does give them both perhaps optimism for control, but also some some real fatigue at looking at yet another novel pathogen that they are at risk of being exposed to. I think it goes in both directions, but it is a unique experience and a unique perspective.

Miller: Katherine Wu, broadly we could put a lot of the changes in our lives over the last years into two categories: The mandates or closures that came from local or state governments obviously super concentrated more in blue states than in red states; and then on the other hand, the things that people have done on their own for their own moral or ethical reasons or personal medical reasons and everything that gets sort of complicated. But in a lot of the country, the mandates I talked about have not been in effect for a long time, but it doesn’t mean that people’s individual choices and behaviors snapped back to pre-pandemic times. What are your senses for the longer term changes in people’s behavior that you think we might end up seeing?

Wu: This is a really good and interesting question. And I think the only thing that is probably safe to say is that everyone has already been embarking on their own behavioral trajectory for a very long time now. And I expect those fates to sort of continue splintering. I think some people have already accepted that they are probably never going to go Back to the full slate of 2019 behaviors and that’s just kind of going to be it from now on. Maybe the degree to which they follow pandemic behaviors will toggle up and down. Maybe it’s with local case rates or what have you, whatever they’re doing to sort of gauge their level of safety, but yeah, it may just fundamentally affect the way they live their lives for the rest of this.  Others have effectively gone back to 2019 with varying results. This is very complicated and I think for people who are trying to decide which lane they want to be in for the foreseeable future or anything beyond that, it is really difficult. And I think one of the few things that has helped clarify this for me– because I certainly can’t ask people what to do or or predict what they will do on an individual or even communal basis– is that you tapped into something very important. There are individual decisions, but they have massive collective consequences. And I don’t think those things always have to be at odds with each other. People who have made great personal decisions like getting vaccinated when they can to get the people around them vaccinated where possible and depending on who is still eligible at this point. Those are individual decisions with huge collective consequences. But people who have made those decisions can also recognize that safety assesses their own personal risk, recognize that they have done some of the most important things to lower their risk of having a severe outcome from a SARS -CoV-2 infection and use that to guide their behavior. I want those people to be able to see each other and make decisions that will make life livable even during the pandemic and in the months as we transition out of it, that does not have to be completely at odds with protecting vulnerable members of the community. I think it all just has to come together in a really complicated decision matrix. But I don’t want people to feel like they’re being extremely selfish by giving themselves bits of happiness. All of these things can be compatible with each other. I think we just all need to reset our risk thresholds and reset our thresholds for what sorts of behaviors are safe for us and the people around us.

Miller: Bill Messer, how much do we know right now about the potential for Long COVID related to Omicron and the potential for Long COVID based on the people who have relatively mild cases of COVID-19?

Messer: It’s really an evolving picture. It’s a good question, one that I’m really not in a great position to answer at the moment with regard to Omicron. I think we’re simply going to have to watch and wait and see how that plays out. I think that the accumulation of data to this point on the earlier strains in their relationship to Long COVID suggests that mild disease is not protective against developing Long COVID. That if anything, it may represent a risk factor. It may be that the symptoms of Long COVID are the result of an interplay between particular maladaptations in the earlier strains of SARS Coronavirus 2. That may be part of what has changed as the apparent virulence of the virus goes away. But it’s really too early to say whether that is happening or not. That’s simply a speculative thought about the two. I wish I could say more about Long COVID but at the moment I don’t have a whole lot more insight to bring to that particular question around the crime. It will be interesting to see. Time will tell.

Miller: Katherine Wu, just briefly, the news last night and today is that we actually could see Pfizer seeking FDA approval for under five vaccines soon, not as soon as a lot of parents wanted, but sooner than most recently we have been led to believe. in a minute or so. What’s this going to mean?

Wu: Yeah, it is an interesting time. We don’t have a lot of clarity on the situation. There has yet to be data publicized supporting what has been reported but I very much look forward to seeing that. It sounds like one of the fastest possible timelines could maybe get us an authorized vaccine for this age group by the end of February, maybe early March. And that would be a huge win. I think it’s important to remind parents at this point. I’m sorry the weight has been so long but it absolutely is still worth getting kids vaccinated. I’ve heard a lot of fatigue lately like why did this take so long? Did it come too late? I think administering a vaccine to children who would otherwise be suffering from a vaccine-preventable disease is never too late. It is never too late to get your kids protection because    as the others on this call have pointed out, COVID is going to be with us for a very long time. Getting vaccinated now is not just an investment in the Omicron surge but an investment in our future and that will really impact where this pandemic goes. I hope it makes an enormous difference.

Miller: Thanks very much for joining us today. I really appreciate it.

Messer: Oh you’re welcome. Thanks for inviting us.

Wu: Thank you for having us.

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