Why Test to Treat is Imperative Now

; Abraham Verghese, MD; Michael Mina, MD, PhD


March 09, 2022

This transcript has been edited for clarity.

Eric J. Topol, MD: Hello. This is Eric Topol with my co-host, Abraham Verghese, for the Medicine and the Machine podcast. We are delighted to have Dr Michael Mina join us today. He's been training for pandemic-related matters throughout his young life. He was at Dartmouth for his undergrad in engineering and global health, went to Emory for a combined MD and PhD, and worked at the Centers for Disease Control and Prevention (CDC) and the Emory Vaccine Center — one of our nation's leading vaccine centers. He did his post-doc at Princeton and Harvard, and also worked in evolutionary biology. He's an epidemiologist, an immunologist, and a physician. He was on the faculty at the Harvard T.H. Chan School of Public Health and the Brigham and Women's Hospital, and recently he joined eMed. Welcome, Michael. Great to have you.

Michael Mina, MD, PhD: Thanks so much.

Topol: When I think about testing, there's one go-to person in the world and certainly in this country, and it's you. You have a fascinating background. How did you zoom in on the whole PCR and rapid testing front in the pandemic?

Mina: It started back in January of 2020. We were already starting to track the virus and its spread throughout the provinces in China. It became obvious to a lot of people that this was going to become a pandemic. As soon as you see a virus like that spread from Wuhan to every single province in China in no time at all, it's clear that it will spread globally.

At that point in time, I was a medical director at Brigham in charge of molecular virology diagnostics, and I tried to get the hospital leadership to recognize the need for testing. The first time I brought it up, in mid-January 2020, I was more or less laughed out of the room: "Why would we need to do this? We're too busy with everything else we've got going on here. Why would we get COVID testing up and running? COVID is not a problem here." I kept pushing, and ultimately I went to Eric Lander at the Broad Institute and said, "You guys are some of the most efficient biologists in terms of scaling up biology in the world. Can we get COVID testing? Can we start processing COVID tests in the genetics facility you have here?" It's a high-throughput facility. So we started doing that.

I realized early on that I was the only epidemiologist I knew who was talking about testing. Everyone else was asking when the vaccines were going to be here. And it turns out that there was almost no overlap, at least pre-pandemic, between epidemiologists and testing. I think it's because the data are just always there if you're an epidemiologist. You have the case count and you never ask, "How exactly am I getting this data? Where are the instruments? How are they being used?" Obviously, this idea of testing has now become common in the United States, but in 2019, nobody thought about testing. It wasn't common; it was this thing that the doctor does. But I became acutely aware of the need.

As soon as the Biogen superspreader event happened in Boston, it made sense that we had gotten the Broad Institute set up with testing, and that experience got the high-throughput testing program started there. The Broad Institute is one of the world's best, most efficient molecular biology groups, but it became clear that we weren't going to keep up. That's when I started looking at other avenues. I thought, Maybe we're thinking about this all wrong. At the time, the US Food and Drug Administration (FDA) was scrutinizing the sensitivity of every assay. They still are. And I said, "We don't need that kind of sensitivity if people have ready access to rapid tests." On the one hand, I feel like I started certain aspects of the PCR testing program. But it was through that experience that I realized that we needed a different option. That led to a cascade of research around a different type of testing for a pandemic.

Abraham Verghese, MD: You have quite a unique background, in engineering, mathematics, and global health. Do you think that's what brought you a different perspective from that of other epidemiologists?

Mina: Yes, absolutely. Something I've tried hard to do, whether in medicine or public health, is to always incorporate engineering principles. Frankly, the pandemic forced that issue of bringing in these different viewpoints — whether they be evolutionary biology and mathematics, or engineering and medicine — bringing all of that into an orbit together. It certainly gave me a different perspective.

I'm happy to talk about the engineering side of public health, which I believe has been sorely lacking, but I am a clinical pathologist. And wearing my medical hat, I was privileged early in the pandemic to get a peek behind the curtain and to develop what was behind the curtain, if you will, where these lab tests would be processed. What are the challenges we should expect? These are questions from a whole different orbit from where public health people usually live, in infectious diseases. Now epidemiologists are dealing with the laboratories themselves. I think it was that perspective, my medical hat, that gave me this unique understanding of the conversations we were having early in the pandemic about the epidemiology of this virus.

For example, very few people were considering in their math models the growth rate, not of the virus, but of the testing apparatus in a country. Some of the earliest models we built on the growth of the virus across the world, in terms of case counts, weren't measuring the growth of the virus itself. We were measuring the capacity for a nation to process PCR tests. It was seeing these challenges, in terms of getting PCR testing set up, that on the one hand made me recognize that we were probably undercounting much more than most epidemiologists considered. And on the other hand, it made me realize that we needed to rethink testing for a pandemic. If our goal is to stop spread, the kind of testing we were doing was never going to get us there.

Ultimately, where that overlapped with engineering was this question of whether we were optimizing on the right components. In some ways, engineering principles bring some clarity to a pretty messy pandemic and help us begin to reevaluate what we're optimizing — is it individual care or is it stopping the spread? At the population level, those are very different things that in the testing landscape were never well defined before this pandemic. These are still very muddied waters. Is it public health testing or medical testing (for treatment)? In some ways they couldn't be more different from each other.

Topol: We talk a lot about transdisciplinary teams, but you're like the transdisciplinary mind. You have such extraordinarily broad thinking with these different disciplines. But recall that when we started the pandemic in the United States, we had no test and we basically promoted the spread. We couldn't even diagnose people who were coming in with pneumonia but actually had COVID. You were very early to think that not only should we get PCR testing to a massive scale but, as you mentioned, we needed these other tests. Whether you want to call them rapid tests, lateral-flow tests, or antigen tests, we needed them to get to the levels of testing that would be suitable for individual and population management of the pandemic. And as I recall, you were ready to go with rapid tests in late April or May 2020. What happened?

Mina: Just to be clear, I'm not a test manufacturer, but I've been living in the test-technology world for quite a while and talking to a lot of small startups and larger companies about it. There were companies that were able to produce millions of these rapid tests by April or May of 2020. The first time I ever held one of these lateral-flow rapid antigen tests for COVID in my hand was late March of 2020, and I thought it was a slam dunk. There are companies out there making tests that take 15 minutes to run. You could do them on your own. These are transmission-indicating tests and even if they're not as sensitive as a diagnostic, they'll catch everyone who's a superspreader. If that's all they did, that would have been amazing. That would have allowed us to keep society functioning, if everyone was able to perform a rapid test right before going into a location, like a restaurant or a school, on a daily basis.

As much as I hate to say it, the medical establishment put up some of the greatest barriers. It's not a knock on physicians. The real issue is that we keep asking the wrong people the wrong questions. We essentially asked physicians or we asked the ether, if you will, how do we deal with a pandemic through a medical lens? And that was the wrong idea. You can't claw back a pandemic by piling medicine on it. Exactly in the way that we don't think that treating everyone is the right solution to a pandemic, we also can't take medical metrics and apply them to pandemic response. We need to apply pandemic metrics. And if we deal with the pandemic, the medical problems will resolve, but you will never deal with a pandemic by just treating medical problems and hope that the pandemic goes away. That's not how it works.

Unfortunately, I think what happened is that we got very confused as a regulatory body, as a physician body, as a public health body, about what we were doing with testing. Why were we asking people to test? Is it so they can know that they were infected a few weeks ago? And if so, great, that's a physician's job. Why did my stomach hurt? Why was I vomiting last week? Whatever the case may be, do I think it was COVID? Let me use a PCR test to check; let me use an antibody test. But if the question is, am I safe to go out to see my grandmother right now? In that case, a PCR test that you send out and get a result back 7 days later offers no benefit. And we just didn't have a language. We don't have a legal structure, we don't have a regulatory structure — we literally don't have a language.

Kristian Andersen at Scripps and I wrote an article in Science in 2020 that was titled "COVID-19 Testing: One Size Does Not Fit All." We were trying to lay out a framework to do the most simple thing, which is to say that not all tests are for prescribing medicine. There's actually a purpose of testing for public health, and it's remarkable to think that the FDA doesn't formally recognize a test for public health. From the FDA's perspective, there is no such thing as a test that an individual can use for public health purposes, where the purpose of that test is to benefit the people around them and not themselves.

The argument I've made, and I think it is a correct argument, is what if the primary beneficiary of the test is not the test user but the people around the test user? That's a simple definition for a test that's being used for public health. You're using a test on yourself, and the consequences of a positive test not only are not medical but they're antithetical to medicine. I know no physician who has ever prescribed 10 days of isolation to a sick patient for that patient's benefit. It's for the patient's family's benefit that you isolate. So it's not medicine; it's public health. It has been very frustrating to be more than 2 years into this pandemic and still not have a regulatory framework that recognizes that there is a purpose for a test that is more about the public than about the user of that test, and the metrics required for that test are very different from a medical diagnostic test.

Verghese: Do you see the recent adoption of the tests by the Biden administration and sending them out to people as an acceptance of your premise?

Mina: It is certainly a reflection that something I've been arguing for a long time is now becoming accepted as mainstream when we have the President of the United States getting up and talking about the need for these tests to combat the pandemic. What is frustrating is that, despite having the President of the United States on stage saying these are public health tools, nobody is willing to go to the FDA and ask whether we are evaluating these tests in the appropriate way. Are we pushing these tests to be evaluated as public health tools vs medical tools? Or has the regulation continued to lag behind the actual use cases of the tests? Despite having a large number of rapid tests, we could have scaled them much faster during the Omicron surge. When the president first recognized that we were going to need a massive influx of tests, rather than saying, "Our hands are tied, we can't scale up quick enough," we should have said, "Is there a better way to authorize these tests so we could have gotten a portion of the billions of rapid tests that exist across the world into the United States within a timeframe that was actually commensurate with the need?" So, while I believe that the president and arguably the public at large has recognized that this is a smart approach, it did come late. I'm perpetually frustrated that we still don't have a framework or language to talk about this as anything other than medicine.

Topol: When I heard the announcement by President Biden, I thought he should have mentioned you. If it hadn't been for the pioneering and perseverance of Professor Mina, we might not have done this. You should be proud. But the other thing is that you've been kind about the FDA. I think they really messed it up big time because, as you say, they didn't accommodate this idea of infectious vs infected. They never got it. They still don't get it. But there's another part of the story I find especially ironic because that wasn't the only public health agency that was in a state of confusion and couldn't deal with testing. The same day the president announced that we're going to send out free tests, we had the director of the CDC say that you don't need to do testing; isolate for 5 days and then you're good to go if you're not symptomatic or you have mild symptoms. What did you think of that announcement?

Mina: It was a disaster. In my view, it is one of the least scientific announcements the CDC has released. All the data were showing that the relationship between Omicron, symptom onset, and isolation windows were shifting markedly as a result of not having enough tests and having massive pressure from the American public to say, "Why don't we have the tests?" Then the CDC took an approach that said, "You know what? Don't test. Leave isolation early. You don't need the test. We don't have enough tests." That is not the appropriate way to lead in a public health crisis.

Even if we don't have the right resources, we have to make the policy. If the policy can't live up to the science because we don't have the resources, we have to say, "Look, this is the science, this is the biology, this is the reality." And part of that reality is, "I'm sorry, but we don't have enough resources." But we encourage people to focus on the fact that they still might be infectious at 5 days. Do everything you can in your power to get one of those tests and use it before you go back to work after 5 days, because we now know that individuals with Omicron who are at 5 days into their isolation window represent one of the highest-risk groups of people who will transmit virus onward. If we're trying to use our resources wisely, and use our tests in the most effective way, then one of the most effective groups of people to test to stop transmission would be the people who are about to leave isolation at 5 days. Yet we haven't seen a reversal from the CDC on this issue.

There were simple things we could have done. We didn't need to have a test kit in every single person's home for them to exit isolation. Instead, we could have had the administration and the CDC allocate 30 million of their tests to Amazon warehouses around the country and say, "These are tests to exit isolation. If you're positive, you have 5 full days to get overnight delivery of a test from Amazon so that you can exit safely at 5 days or stay in if you're still infectious." We could be using these technological advances and the might of the United States for this kind of effort. But we let the ball drop here.

Verghese: I think we all share your frustration, not just with governmental entities, but also with the failure of the public to have one view about this but in fact, to have a very polarized view. This is not new, by the way. From Camus' The Plague onwards, we've known and should have expected this. How do you write a manual going forward for the next pandemic, that takes into account these things that are certainties — namely, the clumsiness of big institutions, asking the wrong people the wrong questions, and a public that is swayed by politics. How do you factor that in as a public health expert?

Mina: I've thought a lot about this, and I honestly believe that one of the fundamentally core problems of our entire pandemic response has been — okay, social media is part of it — but really it's everyone asking the wrong people the wrong questions. Everyone had to get involved with pandemic response because it's such a big issue, and what that meant is, little by little, facts and understanding that existed before the pandemic get chipped away. A lot of people entered the discussion who didn't know that X, Y, and Z were already known. So they said, we have to reinvent the wheel and we have to go down this rabbit hole over here and believe we're discovering something for the first time. The voice of the expert on that issue was drowned out early. And the effects of people giving the wrong information proliferated. Obviously, our previous president was the greatest contributor to that.

One of the most effective strategies I can think of for future preparedness, without totally changing the world and causing Facebook and Twitter and everything to collapse, something that's actually reasonable and doable, is to create an entity, like a National Guard Reserve of experts who sign up and say, "If something happens in the next 5 years, you can count on me to step in and help." We need a National Guard of experts, and not just in infectious diseases, but people who have expertise that is specific to some sort of disaster response, whatever that might be. We should have a database. I could say, "This is my area of expertise. If you're going to ask me a question, it should be about this issue or this series of issues. Don't ask me about jellyfish; I know nothing about jellyfish. If there's an epidemic of jellyfish in the Great Lakes, I don't want to talk about it because I'm the wrong person to ask." So have people very clearly defined according to their area of expertise.

Then we should have a playbook. Only so many different catastrophes are going to happen. Is it going to be another influenza virus, another coronavirus? Will it be a bioterrorism threat with anthrax? An earthquake? We can have playbooks for each of these. There was no reason that the President of the United States should dictate the way we respond to a biological threat. Biological threats don't respond well to politics. They'll keep doing their thing, no matter who is president. So we need a playbook that keeps the experts in this country, the expertise in this country, catalogued. And people like the three of us can sign up and say, "Over the next 5 years, if you need my expertise, I am at your service, and this is what that service is."

When the next disaster happens, I want the President of the United States to have a button to push that says "respiratory virus pandemic," and it gives him an all-star team of people with defined expertise so that we aren't trying to scramble amid an emergency to ask, "Who knows what they're talking about?" We're so far beyond that; we have enough problems when we're dealing with a virus. The last thing we should be dealing with is misinformation that isn't even intentional.

We don't want to have echo chambers, just a good-enough database. That would at least be a place to start, to have the playbook and know who you're going to call upon in different scenarios. We don't go to war and after we're at war say, "Who's going to be our general for this one?" We don't do that. We know who has expertise in this or that missile defense system and we call upon those people when needed.

Topol: Speaking of expertise, you recently made a career change, to take your extraordinary cumulative experience and background to work in the life sciences industry. Tell us what was going through your mind and what you're doing these days.

Mina: I started to feel increasingly like my hands were tied in academia. I have always liked to build things. Right after college, I did a lot of work in Nicaragua, and when I was in medical school, I started a nonprofit in rural Nicaragua to teach communities how to build generators using solar power and to convert table salt into chlorine for purifying their water. That is an example of me feeling like I needed to build something and put my education into practice. This pandemic has reinforced that desire to build lasting things that can actually help people, but also it has taught me that words in academic papers only go so far.

We all write. We want to publish Nature and Science papers. Then we cross our fingers and hope that some company will pick it up and actually do something good for the world with that research. I found that one of the most impactful ways I could use my expertise is to go out and build something. In academia, it's hard to do that because you always have post-docs coming and going. You can't build good, cohesive teams easily in academia because everyone wants to be a first or a last author. There's no good mechanism for true teamwork, where every person on that team has a pivotal role and is getting the credit they feel they deserve. You might have big teams, but they generally have one leader and a first and last author, and everyone else has their main interest somewhere else. The turnover rate is very high because everyone's going on to their next profession.

As much as I love teaching, I want to create teams that function as a true unified team toward goals that can move the field forward. That's what I'm doing here at eMed. I'm trying to plow a whole new world — a world where we can start to break down the barriers people have in their medical care. If I learned one thing from this pandemic, it's that the system, if you will — I don't like to say those words because they don't really mean much — but the system does not have a good way to enable individuals to know about their own medical condition on their own terms. I want people to have the liberty to say, "I'm curious about if I have COVID today" or "I'm curious if I have flu today, and if so, I want it treated as fast as possible without having to worry about my insurance or going to a physician for these things that aren't complex problems."

I want to create a system here at eMed that enables people to have diagnostics or other devices in their homes or other access that enable them very quickly, on their own terms when they want, to be able to find out information about themselves and act on that information. If I have COVID, I want to be able to test before I go to work in the morning or after I get back from work. If I don't feel well, I don't want to have to take tomorrow off from work to figure out I have adenovirus. I want to use a COVID test at home tonight. If I'm negative, then I go to work tomorrow. If I'm positive, I want to get treatment as soon as possible without having to figure out who's going to pay for it. That's what I'm trying to do at eMed, starting with COVID — to create a test-to-treat model where people on their own terms can have a test available.

I'm not a test manufacturer, but I happen to be holding an Abbott test and you can see the QR code. Scanning the QR code should initiate a whole cascade that allows someone, within an hour, to go from using a test at home to getting a treatment prescribed to them at the local pharmacy without ever leaving their couch. Imagine if parents could do that every time their child gets a sore throat; if they could use a strep test at home and, if positive, be able to get their child treated without having to take half a day to go to the pediatrician. To be able to start their child on treatment earlier. You'd run into many fewer severe cases in the hospital; you'd get people treated earlier and ultimately improve health and the economy.

That's where I'm going right now as I start to take off my academic hat for the time being and try to put these pieces in process. You can see from my varied history and the paths I've taken that I certainly won't write off going back to academia. But for now, I felt a burning need to do something more concrete in this pandemic, and I'm delighted to have made the shift.

Verghese: One of the things we observed with telemedicine is that we were humbled to realize that it was the first time we were actually looking into people's homes. And for all our lip service to social history and family history, it's only when you see people crisscrossing the room, or realize that they're in one room and there is nowhere else to go, or they're parked outside a motel, that you begin to understand how people live. I remember thinking during those interactions that it would be great if we could have more diagnostic equipment situated in the house so these exchanges could be more meaningful. I believe that your kind of testing will pave the way for that sort of thing.

Mina: We see it entering all over, including at Scripps, with digital clinical trials. Scripps is leading the way in that kind of effort to distribute clinical trials and bring them closer to people in their homes, so that the middle of the country, that's not near some academic institution, can participate in any of its cancer treatment trials and things like that. To me, a diagnostic isn't some medical device. To me, a diagnostic is information about ourselves. It's information that helps us with our own health but also with public health in the middle of a pandemic. No one should be deprived of information. We have to make sure we do it appropriately and that people know how to deal with the information. The more access people can have to information, the better. I think that if there's any human right out there, it's knowing what's going on inside your own body.

Topol: I couldn't agree more. Put on your evolutionary biologist hat for a moment: Where are we going? Is there going to be another significant variant in the months ahead? Or is it possible that the pandemic is waning?

Mina: I think we are on the only off ramp of this pandemic. There was no other option. We've built up significant population-level heterologous immunity through a combination of vaccines and infections. I like to think of humans in this pandemic in the way I normally think of babies. A lot of my research before the pandemic was looking at how the immune system of babies develops, and we created a lot of immunologic tools to profile babies' immune systems. Through that process, we were able to see that kids develop their immune systems layer by layer by layer. Every time they get an infection, they throw away 90% of the immunologic education they had and they retain about 10% of it. Then they are re-exposed and they retain a little bit more and a little bit more.

I like to think of our immune systems developing in the same way we use our clothes. When you're little, you go through your clothes real fast, you're always throwing them away and getting new clothes. And as you grow up, everything kind of stabilizes. As adults, we are in this process of growing up our immune systems to this virus. We're aging out of this pandemic. The virus isn't going away but we're building these layers and layers of immunity; we absolutely had to do this and it's been absolutely painful. We'd have to be very naive to think that there's not another variant; history, even the short history we've had with this pandemic, tells us otherwise. But the important thing is the impact of that variant. The importance of it is going to be increasingly reduced as we move forward.

I think we'll definitely have cases spike in the summer, in July and August. We'll definitely have cases surge in the winter. This is a seasonal virus. People question whether it's a seasonal virus, but that's because people keep confusing the course of infection and the fact that the virus can transmit in the summer with the fact that it can transmit a lot more in the winter. We should definitely anticipate that we'll have more cases, but we now have vaccines and we have treatments. Vaccines alone take care of the vast majority — vaccines and previous exposures. We can't discount those previous infections.

We can't undo what happened in the past, but we are in a good position now, relatively speaking, to keep marching forward. We have treatments and if we can tie those treatments to actual access to getting care and to getting those treatments on time, then all of a sudden, the impact this virus has on society starts to erode. It becomes less and less important as we start to see people treated earlier or not getting as sick. That's where we are. And that's why I am glad the CDC is changing some of its thinking from just counting cases to looking at hospitalizations. We do need other metrics. We don't want to be 3 weeks behind the curve all the time, only looking at hospitalizations. As we see cases grow again in the summer and the winter, we will see a very dampened hospitalization curve associated with that, as long as we actually do what we need to do now, which is make sure the processes are in place for people to be treated if they're at risk.

The elderly will continue, probably indefinitely, to have problems because their immune systems will not develop the way that a baby's would or a 25-year-old person's immune system would. The older you get, the more you lose the architecture of that immune memory compartment, and so it's harder to store those memories, just like it's harder to learn a new language when you get older. So we have to be cognizant that in the elderly, no matter how many booster shots, their immunity is still going to wane. So we have to keep making sure treatments are available. Otherwise, we are on the off ramp.

Verghese: That's a wonderful metaphor of adding layers and layers of immunity. I have to ask about your work on measles, because this was such important work before COVID. I'm not sure I fully understood it, but I knew it was seminal work. Could you explain that to us? Measles seems to make you lose your immunity in some paradoxical way.

Mina: What we call that is immunologic amnesia. I was working with Bryan Grenfell, who has developed a lot of the mathematical models to understand and interpret epidemics and outbreaks. He primarily developed those methods using measles as a model infection. Many mathematical modelers love measles because it was so regular in the pre-vaccine era. When we looked at the data appropriately, we saw that there is a long shadow of death that follows measles cases. If you integrate under the curve, if you will, of measles outbreaks and you do some mathematical transformations, you find an extraordinary correlation between the amount of measles cases on the one hand and the amount of death in children that follows over the next 2 to 3 years. This was in 2015. We published a paper in Science that showed that measles seemed to have, at a population level, a very strong impact on mortality. It appeared at a population level to cause children to be at increased risk of death for years following an outbreak.

The next question is, how does that work? The receptor for measles is called CDw150, the signaling lymphocyte activation molecule (SLAM). It's decorating lymphocytes in memory-committed cells, including plasma cells that are in bone marrow, including the cells that make up our germinal centers. SLAM is all over the place as far as memory-committed cells. And that happens to be the measles receptor that was discovered earlier in 2000 and published in Nature. Previous to that, the measles receptor was thought to be an innate receptor called CD46, which turned out to be the vaccine receptor. But in any case, measles works as a Trojan horse. The very cells that are supposed to pick it up, chew it up, and present it, end up getting infected by it. It then gets into the lymph, where it is picked up by dendritic cells, then brought into the lymph, and it just goes to town, chewing up and destroying all of these cells that it turns on and uses for its own replication.

In macaques, you use GFP-expressing measles virus and on necropsy, when you shine a fluorescent lamp on them, you can see with the naked eye all of the germinal centers that comprise the gut-associated-lymphoid tissue, because measles completely obliterates and goes anywhere these lymphocytes are. That led us to say that's a mechanism, that's putatively what we saw in 2015 at the population level. In 2019, we worked with Steve Elledge who was a post-doc in genetics at Harvard, and we staged display systems to present peptides of every virus known to infect humans. That gives us a window into somebody's immunologic memory, through their antibody response against hundreds of thousands of different viral peptides.

We worked with some folks in the Netherlands who had collected blood from kids before and after they got measles to do some cellular work on it. We took some of that blood before and a couple of months after the kids got measles. What we saw was that the antibody repertoire — not just one titer, but the whole repertoire — was diminished anywhere from 20% to 80% after the kids caught measles. To be clear, it is very difficult to screw up somebody's antibody repertoire. Even rituximab and things like that don't screw up your antibody repertoire. It turned out that measles was getting into the plasma cells of the bone marrow and just obliterating a lot of the workhorse cells that produce the long-lived memory antibodies that we have. You can't just recompose those; once they're dead, plasma cells are gone.

One of the most intriguing and sort of satisfying findings was that we actually saw, by the reconstruction of kids' immune responses, that all these kids lost a huge plethora of antibodies. And then we saw that in some kids certain antibodies increased. Some kids' titers went up for a rhinovirus or for adenovirus or for pneumococcus. It turned out, when we actually plotted them out geographically, looking at where their houses were, we saw that the kids who had increases in adenovirus, they all lived right near each other. So we were identifying kids as they reconstructed their immune responses after getting measles. They would see a little adenovirus outbreak happen over here, a rhinovirus outbreak over there. But it wasn't benign. Reconstructing your immune memory is a dangerous feat. It's necessary but dangerous because immune memory is there to keep you safe.

We saw that kids who had lost a lot of their pneumococcal antibodies were actually getting sick with pneumococcal pneumonia or otitis media, for example. So it's not without its risks. I think we got a little window into big population-level effects we had seen 4 or 5 years earlier, from the decades of data we had evaluated across multiple countries, to give us the first inkling that there was this shadow of death that followed measles outbreaks.

Topol: Immune amnesia from measles. But we're not going to be amnestic to this discussion with you. I wish we could go on for a few more hours because I know we'd learn a lot. Thanks so much for this conversation and for all you've done during the pandemic. I know it's been frustrating for you, especially because you knew where we needed to go. We're still not there, but we made some progress, thanks to your Herculean efforts. We wish you well in this new phase, and know you're going to be making lots of great contributions going forward. Thank you.

Verghese: Thanks to both of you. Your Twitter feeds are lynchpins for people getting good information on COVID.

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