The Golden Age of Virology? An Expert's Take on Polio, Monkeypox, and COVID-19

; Abraham Verghese, MD; Jeremy P. Kamil, PhD


September 21, 2022

This transcript has been edited for clarity.

Eric J. Topol, MD: Hello. This is Eric Topol for Medscape, with my co-host, Abraham Verghese, and we're delighted today to have a chance to have a conversation with Jeremy Kamil, who is an associate professor at Louisiana State University in immunology and virology. His expertise is in virology, which we need right now. We're going to be talking to him about that extensively, not just about the COVID-19 pandemic but the other viruses we're confronting right now. Jeremy, it's great to have you on board.

Jeremy P. Kamil, PhD: It's an honor to be here, truly. Thank you, Eric and Abraham, for having me on.

Topol: I thought we'd start, not in sequence. We're going to get into sequence, too, because that's a big part of your interest. Right now, polio is a big worry. The concern out there is the language of vaccine-derived polio.

Could you put in context where we are with polio that arrived in New York, where it's been declared a public health emergency, and this connection with the vaccine?

Kamil: I'm not a medical doctor, but my impression is that we had a sense that we had defeated it. It was a scourge in its last throes of being extinguished in rural parts of India and Africa.

Although in this country, we use inactivated polio vaccine, in other countries, there's live polio vaccine. It was Sabin vs Salk, right? You guys are in La Jolla, San Diego, so you have the Salk Institute. Those two were archnemeses. In certain countries, the Sabin vaccine is still used, and it's more efficacious than the killed vaccine.

The problem is that when children are given the live polio vaccine, the virus can actually evolve stepwise, little by little, to become closer to wild-type or dangerous polio. What looks to have happened here is that, in countries that use live polio vaccine, the virus has become a lot more like wild-type polio. It's vaccine-derived, but it's not the vaccine that's causing the disease. People aren't coming down with poliomyelitis after getting the polio vaccine.

In certain countries that use live vaccine, the virus has been able to reacquire some of its natural poliovirus-like qualities and is spreading as polio naturally did, by the fecal-oral route. It's a rugged virus. It's hard to get rid of, and in countries like the US, we got rid of it with very high vaccination rates.

Unfortunately, we now live in an era with untold levels of skepticism about public health and many doubts about whether the Centers for Disease Control and Prevention (CDC) can be trusted, which is really sad. Before the COVID-19 pandemic, we already had vaccine-hesitant parents and even activists who were against all vaccines. You now have people talking about whether germs really cause disease.

It reminds me of Carl Sagan and the demon-haunted world. You end up with a self-fulfilling prophecy, with these people coming out with half-truths or very sad distortions of what's real and valid. Now there are all these Americans who don't have poliovirus immunity because they chose not to have the vaccine or chose to not have their children get it.

They're sitting ducks to have these low-probability outcomes on an individual level, but when you get enough people with poliovirus exposure, some of them are going to get poliomyelitis, which is an irreversible paralytic disease. Now we know that this virus has made it: Vaccine-derived polio has shown up in England. Now we're seeing it in New York City in large numbers and in other parts of the US. It's a grave concern.

Abraham Verghese, MD: Just to follow up on that, may I ask, do you think this virus has the capacity to further evolve and to actually produce paralytic polio as it evolves?

Kamil: I'll preface by saying, I'm not an expert in vaccine-derived polio or poliomyelitis. I study cytomegalovirus (CMV) professionally. From what I've read, it sounds like there's definitely a concern that this could happen and that this will happen if we don't get immunization rates back up.

Verghese: I grew up in a country where we did use live polio vaccines. There was always a small percentage of people who would, in fact, get a form of polio. The numbers were never very clear. This is really alarming.

Kamil: Yes, definitely.

Topol: Definitely alarming. An interesting thing about polio that isn't generally appreciated is that a vast majority of cases are asymptomatic, something like 70%. Most people have this idea that, oh gosh, if you get the poliovirus, you're paralyzed. That's just not the case. We're not done with this virus now, unfortunately. It's making a comeback, and it's sad.

Before we get to SARS-CoV-2, let's turn to monkeypox. This seems to be on the decline. I wonder what your thoughts are where we stand with the monkeypox pandemic.

Kamil: The first thing we need to do is really be accurate about how it's spreading. There seemed to be some confusion early on about whether this was a new airborne poxvirus. We know that smallpox was much, much more transmissible and could be transmitted efficiently between humans in more modalities.

What appears to be happening with monkeypox is that it has evolved into a largely sexually transmitted infection and that it was predominantly spreading within communities of men who have sex with men, and not just gay men, but men who have many partners.

The gay community deserves a huge amount of respect and applause for getting the correct messages out about how this virus is spreading, and increasing awareness about the importance of getting vaccinated. They were willing to be really honest and forthright, push aside all the stigma and shame, call things by their true names, acknowledge what's happening, and deal with it forthrightly.

It reminds me of ring vaccination. Ring vaccination was so effective in dealing with smallpox because, in Africa, they figured out that if you immunize people near the outbreak, you can stamp it out early, even if you don't have enough doses to immunize everyone on the continent or in the country.

In this case, we have a disease that's spreading within one community. By dealing with the people who are in contact and at high risk first, you can stop the virus from spreading. Indeed, cases are going way down in the US, in Europe, and in all geographies where we have accurate data. That's the situation with monkeypox.

It is really fascinating. I'm not a pox virologist, and I wasn't as familiar with the epidemiology before it hit the news. What I learned from people who do study it is that this virus had been endemic in Africa and had been a problem in various West and Central African countries like Nigeria for decades. The West had not done much to address it or to help out.

The virus kept spilling over from certain types of rodents that harbor it. They're not like squirrels or rats that we see in the US. These are different types of rodents that are endemic to Africa. It was spilling periodically from rodents into humans, and it would cause problems. Some years, there were worse outbreaks than others.

Ironically, the US Food and Drug Administration (FDA) had approved the drug TPOXX (tecovirimat)-- an antiviral drug that's effective against smallpox. It was developed to address the threat that a terrorist organization or rogue nation such as North Korea might synthesize or come up with a way to release smallpox and bring it back, and so we'd have some biodefense capacity to stop that early. We stockpiled this drug, and the FDA approved it for that purpose.

We lost the opportunity to stop monkeypox when it broke out. It's another orthopoxvirus that we expected this drug to work against. Why not offer to help out in Africa and do a clinical trial there? No one bothered to help out in Nigeria when they had an active outbreak.

I learned from an article in Nature Medicine yesterday, a news piece, that in fact, we don't have great evidence in humans that this drug works. We'd like to have better clinical evidence that it's effective. We expect it to, but it's always important to have those data. It seems like a lost opportunity and also a lesson that, if we ignore the health needs of people in poorer countries, in fact, we do that at our own peril.

Verghese: What do you know about the vaccine for monkeypox? Is that sort of like smallpox, a variola type of modified live vaccine?

Kamil: There are two versions: a more classical vaccinia-like vaccine, which is a little bit higher risk for people who have eczema or other skin issues. Then there's the newer one, which is called Jynneos. I think it's manufactured in Europe. That's the one that the CDC is making available for immunization to high-risk people.

It's given subdermally. somewhat like the classical smallpox inoculation, but I don't know if it's a bifurcated needle. There was some controversy when the FDA authorized the use of a dose-sparing regimen. There are only so many doses available, and there is an intradermal type of inoculation that uses one-fifth the amount of vaccine.

They're rolling out that approach so they can give more doses, which sounds reasonable. The advantage of the Jynneos version is that it's less likely to cause problems in people who have skin conditions like eczema. That's my understanding of it, as a nonexpert on that topic.

Topol: Virologists like to pick one virus family, but then you often have to step out of your comfort zone. Even though you were an authority on CMV, you had to become a coronavirus SARS-CoV-2 expert over the past few years, right?

Kamil: Yes. Expertise is always relative. If I'm in the same room with Florian Krammer or Benhur Lee, even though they aren't traditional coronavirus virologists — or Thomas Gallagher, who is — those are people whom I would consider authentic experts on COVID-19. We all gain information from first-hand experiences, and no one starts out on day zero as an expert in anything.

You become an expert, first of all, ironically, by admitting how little you know at the outset and being curious and listening to others. If I've learned anything useful or gained any valid information, it's by starting small and acknowledging what I do and don't know, and of course, applying what I learned about other viruses to this situation.

Topol: We don't have much of that these days. We need more. That brings me to social media for a moment, because you're @macroliter on social media. How did you get to be @macroliter? What is your view of the whole world of Twitter?

Kamil: I came up with "macroliter" because microliter was taken already. It's just a pun. There's no such thing as a macroliter, but it is funny. I didn't put a lot of thought into it.

Twitter is an amazing tool for sharing information and getting information from others. I guess they call it a microblogging service. I don't use Facebook anymore, even though that was really useful to track what my relatives and friends from high school were up to. I found Twitter really useful to follow what's happening in science.

Virology is really an interdisciplinary field, because as a virologist, you need to know cell biology. Then there are all these things that are happening in cryo-EM, bioinformatics, deep sequencing, and next-generation sequencing that are applicable to your work.

As a scientist here, especially in remote northwest Louisiana, it's really important to keep abreast of developments in the field by using tools that could save you time or give you a unique insight to learn and discover things. I found Twitter to be useful for that.

By following people who are productive and/or other curious people in fields related to yours, you can learn quickly and come up with techniques that save your grad students a little bit of time in the lab. Then COVID-19 hit, and that only underscored how powerful Twitter could be.

It was the first days of the pandemic, and I learned quickly that Florian Krammer was sharing plasmids to express the spike receptor binding domain (RBD) and full-length spike, so that you could do enzyme-linked immunosorbent assays (ELISAs) and detect who had seroconverted.

Benhur Lee was a friend of mine from the pre-Twitter era. I met one of his students (who discovered the Nipah and Hendra virus receptor) at an American Society for Virology conference back in 2005. I knew who Benhur Lee was, and I'd gotten plasmids from his lab. I was able to interact on Twitter with him a little bit before the pandemic and invited him to come out and give a seminar, which of course got canceled because of the travel restrictions.

He shared with my lab and with our campus a vesicular stomatitis virus reverse genetic system, or a neutralization assay, basically, that lets you test for neutralization activity in people's blood without having to do a BSL-3 set up or even a BSL-2 enhanced setup. You could just do it at BSL-2. All these amazing people were out there on Twitter sharing knowledge, information, and sometimes reagents.

It was really interesting at the very outset of the pandemic, when you saw selflessness, just people saying, "Hey, this is a public health emergency. My lab developed these standards or controls or tools, and we're happy to share them." It was a great way to connect with other people and bring resources that are unique and powerful to your community, even if you are far away geographically from somewhere else.

That's what Twitter was really useful for, but then of course, it has a dark side as well. Just as useful information can move very quickly on Twitter, deceptive or misleading information seems to move even faster. I'm trying to learn to not react when I see stuff that is way out of line or way out there, but sometimes, yeah, I'm still triggered.

I try to set the record straight on incorrect or alarmist takes on, "Hey, there's this new variant we found. Everyone's going to die in 2 weeks." So far, that hasn't happened, but it's been announced countless times since the beginning of the pandemic.

Topol: We've had many doomsday variants out there for sure.

Verghese: You were sort of a pioneer early on in pushing for sequencing the different viruses that were endemic in different areas, and you encountered some resistance I imagine, initially. But it turned out to be tremendously helpful. Talk a little bit about those early days, and I'd like to get to where you think we are now. I may have read a tweet from you suggesting that maybe severe disease is no longer something that we should worry about, necessarily. It's hard to predict, but I'm hearing the same sentiment from the World Health Organization (WHO), the sense that we may be on top of this. I'd be very curious to get both your thoughts on this.

Kamil: Thank you for that. That's a really insightful comment. I was, again, lucky through Twitter. Early on, I saw folks like Kristian Andersen and those in the GISAID community who are sequencing all around the world, including Emma Hodcroft from Nextstrain and Trevor Bedford on Twitter. They were active early on.

I remember I was visiting friends in San Francisco right around New Year's. Already, there was some chatter from the phylogenetics community putting these viruses on trees. At that point, I wasn't even convinced the virus was going to show up in the United States, but the sequences were out there and people were already gaining insights from them.

When they shut down our campus — I think it was actually Friday the 13th (March 13, 2020) — the chancellor asked the virologists, "Hey, do you know what RT-PCR is, or RT-qPCR, real-time PCR?" For us, it's not an exciting new technique. It's a pretty boilerplate basic thing to set up. It's not just used in virology. It's used to look at gene expression differences. We were like, yeah, of course, it's not hard to set up an RT-PCR assay.

As a state university, we were asked by the governor and one of the senators from our state, Bill Cassidy, to set up a PCR testing center, because there weren't any reliable tests for the coronavirus. This involved buying lots of PCR machines and making the largest orders I've ever done for primers.

Usually, you buy at the smallest synthesis scale possible. IDT is the company I used to buy primers from since grad school at UC Davis in 1998. I was going through the dropdown menu and seeing how big the synthesis scale you could order at. I was like, wow, someone should be buying stock in that company because other people are going to be ordering many primers.

We were frantically ordering primers and machines. One night, I was up a little bit late — I think it was around March 20 or so — I just decided, well, if we're doing all these PCR assays and we're going to find positives, shouldn't we be sequencing? Shouldn't we figure out how to do that? It sounded like a challenge, because of course, there's only minute amounts of nucleic acids in a patient's sample.

I knew from people in my field that folks knew how to do this using panels and enrichment strategies. I just sent an email to my department chair and the vice chancellor for research saying, "Hey, we should really start thinking about sequencing this." The vice chancellor loved the idea and said, "Just get it done. I have your back."

I wrote an IRB proposal and it took a little while, but by early May, we were uploading data to GISAID. We had gotten our first complete genomes, and luckily, I was introduced to Kristian Andersen and Bob Garry by Emma Hodcroft and Nate Grubaugh. We wrote a paper with them describing the outbreak in Louisiana. It was really neat seeing those little dots on the phylogenetic trees pop up.

Of course, they also have technology to look at how the virus is moving through space and time.

You can model transmissions, and it was just fascinating, because immediately, we already saw mutations in the RBD. We were the first to see an F490L mutant in the United States. At the time, no one was worried about that. You're exactly right, Abraham. There was pushback: "Hey, this is a waste of time. This virus doesn't mutate very fast."

That seemed to be true. You'd see these little sparks and changes in the RBD, but nothing was sticking. Then by November, when the Alpha variant B.1.1.7 was first identified, it became clear that variants were going to be an issue. Here we are, so many variants of concern later. We're in sublineages of Omicron now that have each driven their own wave.

That was interesting, and I've had a crash course in the politics of data sharing. I don't think that our country's national health leaders, even Francis Collins–type folks, realistically grasped yet the importance of correct incentives. As scientists, we usually put data out there after we publish a paper, or we put it up in GenBank and ask for it to be embargoed until a paper is accepted. We were not going to do with our data. I knew we had to get it out there immediately.

What I noticed is that, even though LSU Health Shreveport, at that time, wasn't known for viral genomics or anything like that, the edge we had was that we shared rapidly. Other campuses had been generating data and amassing sequences, but they weren't sharing them. People learn lessons by living life. As a scientist, many people learn the lesson to hold on to your data until you can get something for it. Those are the ingrained practices among most scientists.

Eric has been a leader in looking at how technology changes medicine and society, especially when it comes to genome sequencing. That's a very contemporary issue. Like Tesla changing how people drive cars.

Now there are little nanopore devices, and someday — probably in my own lifetime, in the next decade — at least people in wealthier countries will all have an Oxford Nanopore MiniION in their kitchen to find out what kind of cold they have. We're not there yet, but the future is a less patronizing situation, where you don't have to go to the doctor find out what virus you have.

Your doctor is your partner, and you have electronic access to that person who can diagnose and guide you, but the technology to find out what virus is in your nose shouldn't require going to a health center, filling out lots of paperwork, and paying a copay.

There are many barriers to getting data. If we can generate it in real time, we could detect pandemics more quickly. We wouldn't have to wait to find out when someone's in the hospital with pneumonia. Well before that person (maybe an elderly or immunocompromised person) showed up with a pneumonia, some virus was moving like wildfire, causing mild illnesses. And we're not seeing those events happen.

In fact, if you go on to GenBank, there are only 60 human coronavirus 229E (one of the seasonals) complete genomes available in the entire world. That's a virus that causes many colds. Yet, we only have 60 genomes. It's a disgrace.

We've had the technology for a long time to do public health at the genome level with viruses. Indeed, we're already at the stage where we can do single-cell sequencing on zebrafish, mice, and Drosophila to study immune responses. If we're doing entire single-cell transcriptomes for research purposes, why aren't we applying this kind of firepower to public health questions?

It goes back to what Abraham was saying earlier. People look down upon sequencing for the sake of sequencing. What's the point of that? What's your research question? I love hypothesis-driven research. I think it's super important, but when you have a new telescope technology, sometimes you have to point it at the sky and see stuff about moons around Jupiter that you didn't see before. No one's asking NASA to justify why they're pointing a powerful new telescope deep into space, but we're asking biologists to hold off on sequencing technology that now can figure out the entire transcriptome of a cell for pennies because they don't have a hypothesis. Sometimes you just have to look before you can even say that something interesting is going on.

It's just like Leeuwenhoek looking at pond water with the first microscope. He saw all these life forms that he didn't realize were there. We're at the same juncture with sequencing, but basic investments aren't being made in terms of the social practices. People are hiring many brilliant phylogeneticists, but no one's talking to sociologists and economists to say, "Hey, how can we put systems in place, so that people will actually generate and share this information in real time?"

The failure early on in the pandemic was detecting that a new virus was out there. It was a huge missed opportunity because the technology was already there. The systems, social systems, and incentives, I'd argue, are still missing.

Topol: No question about that. Just to take the sequencing story further, it's been extraordinary. I think there are — how many — 12 million sequences of the virus or more now?

Kamil: I think it just crossed 13 million in GISAID.

Topol: Yes, 13 million in GISAID. What we've seen now has been extraordinary — that is, being able to track the variants spatiotemporally around the world, and being able to connect the dots about which monoclonal antibody you should get if you have this particular variant. Of course, as you know very well, there are differences in immune response or immune escape with the different variants.

We have these new variants like BA.2.20.2. They have some scary mutations all over the place, the ones we haven't seen. The question is, are all variants innocent until proven otherwise?

That is, just because you detect them, should you keep quiet about them until they actually show signs of spreading? What's your philosophy about what to do about all these very worrisome mutations, these new lineages and sublineages that seem like they could be very troubling, haven't yet really taken hold?

Kamil: That's a brilliant question because there isn't one clear answer. With Omicron, if you looked on a phylogenetic tree, it was like a space alien. Just detecting one of those, you would say, "Oh, is someone's sequencing machine broken? This is too weird."

If you know that the sequence data are reliable and it's got that long of a branch off of anything else that's been detected, then the change in the spike alone is concerning in and of itself, because of the huge number of changes out of the blue.

Otherwise, something like Delta had a decent number of mutations — about eight substitutions on the spike, maybe a little more when it first showed up, but it wasn't a remarkably huge number relative to others that had been found. It was only seeing how it performed in so many different geographies that gave us the signal to say, "Hey, this thing isn't just a fluke of India. It's showing up in many different places, and it's displacing the existing variants."

That's how we knew that it was going to drive a wave early on. I was a skeptic, because I think it is safer to be the skeptic with a new variant, as you said. Most of the time, people are tweeting or are worried about something that turns out to not be as bad as it sounds — even with the Beta variant, which was first detected, like so many of the important ones, by Tulio de Oliveira and his team in South Africa.

For good reason, they didn't like to call it the South African variant. South Africa is just the place that has the brightest lights on. They're doing the best job with surveillance. Indeed, most of those variants are probably coming from other countries in the African continent. Anyway, until Omicron, that Beta variant was the most immune-evasive one. Even though it reached places like California and other countries, it never really drove a global wave.

Even having those laboratory data on immuno-evasiveness isn't enough to tell you that this virus is going to be the next big one. You need multiple criteria. There's a good cause to use multiple independent bases for saying, "Hey, we should be concerned about this."

At the end of the day, the proof is always in the pudding. It's just unfortunate that you have to actually see a wave on the uptick before you can say, "Ah, we're in trouble." That's the last criterion. Seeing that it's competitive in multiple geographies is the ultimate indicator.

Verghese: Just to pin both of you guys down, do you sense that, given the level of natural infection out there, the level of vaccination, and the fact that many of these "scariants" have not taken hold, is it reasonable for the WHO to state that although we aren't disease-free, we are getting to a state of equanimity with this virus?

Kamil: A detente. I agree with you, and it's really controversial on social media because people say, well, what about the immunocompromised people? It's ableist to observe that once someone is vaccinated and has been infected, they are resistant to a bout of severe disease.

They may get infected a second time. Unless they have a health problem, if they are vaccinated and go on to have two infections, it's very hard to have a third episode that's severe. Most people are not walking around with shrunken brains and unable to do their work, although some people are having lingering symptoms.

I'm reading literature about serotonin and other neurotransmitters being on the table. People who had depression before they got infected are showing up with more issues like long COVID-19. I don't want to trivialize the importance of the long syndromes, but absolutely it seems to be the case that once there have been enough waves and enough vaccination, the threat of the virus goes way down.

It's not zero, but it is low enough that the general public is not going to be concerned about it. It doesn't matter, in some ways, how much people are up in arms on Twitter saying that you're an ableist or we need to wear masks forever until the last person will never get sick. You can say that, and it sounds good to other people who have that mindset, but it's not realistic for countries to be in a constant state of emergency.

People need to be able to go about their business. I'm in Louisiana. We're not necessarily a red state. Our governor is a Democrat, but it is more Deep South about its COVID-19 response. They dropped masking in schools in February of this year after the first big BA.1 wave, the first Omicron wave, died down a bit. My kids weren't wearing masks.

My wife and I weren't going to be the two parents who were insisting that our kids be the only ones wearing masks class. My children still haven't had COVID-19, nor has my wife. We're doing fine. If you go on Twitter, people will say that our kids are going to die or have long COVID-19, and that hasn't happened.

Topol: It's been said that everybody's had COVID-19 now. That's not true.

Kamil: Exactly.

Topol: What you're getting at is potentially at odds with the chance of another Omicron-like hit, another new completely out-of-the-blue, major, 30-plus mutations and not just in the spike. What about the chances for that, given we have tens of millions of immunocompromised people, tens of millions around the world? We have animal reservoirs. Recombinants are happening every day. The deck is stacked for potentially another Omicron hit. You don't think so?

Kamil: I don't. Early on, you'd laugh at people who said that your T cells will protect you. I remember it was mid-June 2020, and a couple of papers had pointed out that in certain people, the S2 domain of the spike has some homology to and some shared T-cell epitopes with OC43, which is a seasonal coronavirus.

There are individuals who have very potent T-cell responses. The folks who have looked at the genetic determinants of resistance to severe disease or even to infection, I guess there's an HLA allele that 1 in 10 people have, and so they generate a very rapid T-cell response that often prevents symptomatic infection. Early on, people were like, oh, well, T cells will save us. Of course, it was baloney because most people still got sick, especially if they were ignoring masking and so forth before the vaccine came out. By the same token, once people have hybrid immunity, it's no longer just about the spike.

You end up with a bunch of tissue resident cells — T cells and B cells and probably some innate lymphoid cells and NK cells that play roles as well. Microscopically, in your respiratory tract, you have this family of sentinel cells that are specific to protect you from COVID-19. If you know about the viral life cycle, the very first protein that's made is not spike. It's ORF1a1b, which makes all the nonstructural proteins that copy the genome and play roles in immune evasion. They shut off your ribosomes, so your cell can't make its own proteins anymore, only viral proteins. If your MHC system, your HLA system, is presenting epitopes from ORF1a1b, those are going to be the first opportunities for T cells to mount a response.

People who've been infected are going to have that level of protection. Even if there's a new supervariant that has every mutation possible in the spike, those T-cell responses are never going to become completely irrelevant. Whatever you learn from being infected does have a great chance to protect you. That is not an argument against vaccination; that is an argument for vaccination.

A breakthrough infection in someone who has spike responses is going to be much milder than in someone who doesn't. You're going to acquire those other elements of immunity while experiencing a gentler infection. It doesn't mean that some people who are vaccinated won't have bad infections.

Overall, we're seeing big differences in the outcomes for people who are vaccinated vs not. I'm a little bit skeptical that a new supervariant would cause disease as bad as we saw before the vaccine era. I don't see that happening, and I hope I'm right.

Topol: Well, I hope you're right, too, but that seems to be anchored on the hybrid immunity story. The sad part is there are still plenty of unvaccinated and incompletely vaccinated people who are otherwise naive to infections who could be vulnerable. We'll see.

I hope you're right, and I hope Dr Tedros is right that the end of the pandemic is near. I hope so, but I mean, by this point in time, it's hard to have much confidence.

Before we wrap up, I want to get your input about vaccines. Right now, we've got the bivalent BA.5 or BA.4/5, but it's really same spike, and half and half, a combo with the original Wuhan strain. That went ahead with no specific human data, only mice data. People say that's OK because we do that with the flu virus — OK, but I don't think our flu vaccines are all that potent.

Kamil: No.

Topol: We have the mice data, and we have BA.1 data that are going to be published soon in The New England Journal of Medicine. We have some Beta data, but we have no data for this in humans, right? My question is, back in June, Moderna and Pfizer went to the FDA with the BA-1 data. They look pretty good, but the FDA advised, "No, we don't want that one. We're already long past BA.1. We're in the BA.5 era. Go back and get us some BA.5." The government ordered 171 million doses of the bivalent vaccines between the two companies. They get it ready in 2 months. Two months!

Kamil: Unbelievable. I love it.

Topol: They had enough vaccine to test it in mice. Couldn't they have tested that in a few people, for the optics of a big campaign?

What's your prediction? Is everything going to be cool here? Was this a misstep, or did you go out and have your bivalent vaccine? What do you think?

Kamil: The misstep was when we went from no vaccine to mRNA vaccines in arms under emergency use authorization. It took from January 2020 to December to have the actual rollout of the vaccine. That's about 11 months.

In about that same time period, we made no moves for Omicron, which was showing up in November of last year, and now we're finally rolling out the bivalent. I would argue that we should have been faster updating the vaccine. You're absolutely right that it is important, even just for optics and to comfort people that we've tested this in some human beings.

They could have pre-identified healthcare workers who are willing and educated enough to understand what mRNA vaccines are and how they work, and who say, "Hey, I'm comfortable being a guinea pig for updating the mRNA sequence. It's not that different from the original, and I'm comfortable to be in that clinical trial, to show that it's safe, and that my antibody responses are better."

Why not put in place innovative programs like that to match the technological innovations in vaccinology with the regulatory frameworks for approval? You're absolutely right, but I also would agree with what you hinted at; that a BA.1 bivalent booster probably would have given us 90% of the benefit we're getting with a BA.4/BA.5.

Topol: That's right. That's what the mice show.

Kamil: I believe it. With BA.4/BA.5, we had this F486V change, which is gibberish to most people, but that escape is a really key class of broadly neutralizing antibodies. There is a chance that by having that one in the mix, our B cells will be able to update that class of antibodies. It remains to be seen empirically, which is important.

Having that antigen in there may help a little bit over the BA.1 in terms of durability, but you're absolutely right. It was another lost opportunity to roll out the vaccine sooner. Indeed, people like me ended up catching COVID-19. I made it through BA.1 and most of BA.2, but in July, I finally got my first case of COVID-19. I was lucky that I didn't get very sick from it. Of course, I've had three doses of the original mRNA vaccine.

Topol: Your point is that the Omicron vaccine could have been developed in 2 months, as we learned with the BA.5, but they sat on it and it took 7 months for that end-of-June meeting that should have happened in February.

Before I hit you about nasal vaccines or mucosal immunity, Abraham, any questions?

Verghese: No, I was just going to say that it's a great time to be a virologist. You guys are like the rock stars of the scientific world. There's so much coming at us.

Topol: I'm learning from Jeremy all the time. He's really a phenomenon, and I'm hearing a pretty optimistic perspective today, which I love, of course.

The problem is that BA.5 may do little to reduce transmission. The way the virus has evolved, it seems to have burned through the shots. They looked great for blocking or inhibiting infections and transmission. Once we got to Omicron, that basically fell apart. I don't know whether we can get that back through shots.

I do think that there's a realistic chance we could get that through nasal, oral, or inhaled vaccines. We've got a couple that look quite good, at least from some of the data we've seen. Would you go after that? You've been a big proponent of getting ahead of things.

The US has made no investment. Many academic labs, like Florian Krammer's in Mount Sinai, had gone to Mexico. Washington University went to India. They can't get the United States to invest a dime. Do you think it's worth it? Or do you think it really isn't necessary?

Kamil: It's definitely worth it. As anyone who's read the papers — and you've shared so many excellent ones — knows that hybrid immunity really seems to be the key to a more durable response. It's probably not a permanent response, because we know, from seasonal coronaviruses, people catch them periodically. You probably don't catch them every year if you are immunocompetent, but you probably catch OC43 more than once in your life. Same thing with 229E, and those cause nasty colds.

I don't know whether hybrid immunity is permanent, but it is probably a big advantage over just having an intramuscular injection and generating some IgG and T cells that don't know exactly where to go. When you get infected in the respiratory tract, you recruit cells that defend you, and they stick around for much longer.

I would argue that it's a really good investment. I think the FDA has an appropriate role here to be cautious. The methods to recruit cells to the respiratory tract are going to be different from just sticking a needle in your arm, and as I think anyone who's been to a pediatrician's office knows, most of the vaccines go intramuscular. There are probably good safety reasons for that.

If we want to roll out a nasal vaccine, it's got to be safe, and it's not just got to be safe in 80%, 90%, or 95% of people who receive them. It's got to be safe in almost everyone. The concern is, of course, if you put a virus or a viral vector or a proinflammatory insult in the lungs or the nasal passages, there's a risk that some people's breathing may be affected.

The safety issues are maybe a little bit more formidable, but I'm sure smart people have been thinking about this problem and already have ideas, and indeed, animal data saying that these platforms can be safe. I just haven't heard yet about anything that's actually close to rollout. Until we're ready to get that approved or we hear an actual solution to that issue, we have a bridge right now, which is to update mRNA vaccines and get them into people's arms.

You brought up Florian Krammer's work. There are less expensive solutions, like this Newcastle disease virus vector that they've worked on with Peter Palese and Dr Krammer that can be produced in eggs, like the flu vaccines, and that seems to be pretty efficacious based on their trials in Vietnam (and they may have done some in Mexico as well). It's important that we don't only cover the bases in countries like the US that can afford many -80 °C freezers and the reliable electric grids to keep them running.

We also want technologies that can make it to developing countries and places that need to use other and less expensive, more traditional approaches, like raising a vaccine by growing a vector in embryonated eggs. We need to push all the platforms forward that show us efficacious results, not only the ones that are good for us here in Western Europe or the United States.

Topol: That's great. Well, we could go on for a few more hours. We haven't even gotten into post-viral chronic syndromes.

Kamil: It'd be fun to talk another time. I really enjoyed meeting both of you in person and not just on Twitter. It's really an honor. Thanks for the kind words, by the way, as you guys are both real, authentic heavy hitters who have made enormous impacts. You wouldn't be sitting where you're sitting if you hadn't done some very important work. I'm truly humbled to be here.

Topol: That's really kind of you, Jeremy. Thanks so much for taking the time. We're going to come back to you if we have another really bad family of variants, when the nasal vaccines hit and really contain the pandemic. We will come back once we have some things to follow up on. It's been a great discussion.

Thanks so much for all you're doing. We look forward to continued dialogues with you.

Kamil: Thank you both.

Verghese: Thank you, Jeremy.

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