Reducing Risk Now, While Preparing for the Next Pandemic

; Abraham Verghese, MD; Angela L. Rasmussen, MA, MPhil, PhD

Disclosures

December 30, 2020

This transcript has been edited for clarity.

Eric J. Topol, MD: Hello, I'm Eric Topol for Medscape, and this is Medicine and the Machine. I'm so glad to have my colleague and partner in this podcast, Abraham Verghese, with me from Stanford. Today, we have the rarefied privilege to discuss the whole pandemic story, the virus and vaccines, with one of the country's leading virologists, Dr Angela Rasmussen. Welcome, Angie.

Angela L. Rasmussen, MA, MPhil, PhD: Thank you so much for having me, Eric. It's wonderful to be here.

Topol: As a bit of background, Angie started out at Smith College before she earned multiple advanced degrees, primarily at the University of Washington in Seattle and Columbia University in New York. In the new year, she'll be taking on a new role. Maybe you can start with that, Angie?

Rasmussen: Yes. I will be moving to Canada, where I will be starting a lab at VIDO-InterVac, a vaccine research institute on the University of Saskatchewan campus. I'll be an associate professor at the university and the research equivalent at VIDO-InterVac, studying emerging viruses and host response, which is what I've been researching for the past 10 years or so. I'm really excited about that.

Topol: Congratulations. In some ways, you have been warming up for this pandemic unknowingly through all of your career.

Rasmussen: I have. There have been a couple of false starts with emerging viruses coming out that we thought had pandemic potential: MERS (Middle East respiratory syndrome–related) coronavirus, H7N1 influenza, and Ebola, of course — although personally, I don't believe Ebola had pandemic potential, but there were obviously some significant outbreaks. I wouldn't say I've been waiting for this moment, but I've been prepared. I would have been much happier if this had never occurred. But at least I'm used to seeing a new virus emerge and rapidly switching my priorities around to start working on it.

Topol: This is moving now with unprecedented dynamics. On the worst side, we have the public health response, particularly in the United States, and on the bright side, we have the vaccine trials and vaccines that are finally getting out. Where would you put us right now? What's your overview?

Rasmussen: I think we're still in a bad place in terms of vaccine availability. I'm concerned not only about the supply of vaccines, but the willingness of the American people to take them. People have wanted to spend more time with their families and loved ones during the holidays, and we are at a place right now during the pandemic where we have more transmission than we've had before on a national scale. We're essentially experiencing the equivalent of a 9/11 every day in terms of number of deaths; our hospital systems are becoming overburdened. I think we're going to be dealing with this for some time to come, even after people get the vaccine, because certainly long COVID is real, and that's a protean set of conditions. You would know better about the cardiac consequences than I would. There are also consequences that are similar to chronic fatigue syndrome. Those are debilitating conditions that can last for years, even decades. We may be looking at an epidemic of long-term disability and loss of functional ability in many of the people who have had COVID.

So we're in a really bad place, and as much as I'm delighted and overjoyed that we can see a glimmer of light at the end of the tunnel, thanks to these vaccines, I'm concerned about how things are going to be as we get to that point.

Abraham Verghese, MD: I have come to admire your tweets. One of the challenges of science has been the communication gap between what scientists like you know and the degree of misinformation out there. You've been quite brave and clear not just about how the virus works, but also how it doesn't work. And you've been calling out the bad actors who seem to want to capitalize on this pandemic. Are you surprised that you should wind up playing that role just as much as you're playing the hardcore scientist role?

Rasmussen: A little bit. At the beginning of this pandemic, I was feeling pretty frustrated. For the past four and a half years, I'd been commuting between New York and Seattle, where my family lives. I was in Seattle in early March when we realized that I probably shouldn't get on a plane to go back to New York and that I was going to be staying home for some period of time. I wasn't sure how long it would be, but I thought I'd rather be with my family in Seattle than by myself in my Manhattan apartment. And I felt helpless and to a certain degree, because my lab was 3000 miles away, I wasn't able to do anything immediately to contribute to the response efforts. But I realized that one thing I could do was to try to break down some of these preprints and some of the news coverage that was coming out.

Putting the misinformation aside, early on there were some really bad preprints that were getting a lot of press coverage. It wasn't necessarily because people were intentionally spreading misinformation, but perhaps more because the media didn't know how to cover some of these topics. There was the whole HIV-SARS coronavirus 2 hybrid paper that came out as a bioRxiv preprint. That fed these smoldering conspiracy theories about COVID being a biological weapon, et cetera. So I started explaining to the public what those preprints actually say. As time has gone by, I've become more and more frustrated, which is why my tweets have become more and more frank and sometimes outright angry. But I believe it's helpful and the feedback I've gotten has been overwhelmingly positive. People like to know what's going on.

My philosophy about public health is that you can't have it without the engagement of the public. And my philosophy about communication is that information empowers people to decide for themselves. I thought that was one way I could contribute until I got data and samples from my collaborators and was able to start doing some work.

I'm a little surprised that I've gotten such a large following, but I'm grateful for the privilege to be able to help by communicating what people should and should not take from all the emerging research. I didn't expect the US president to contribute to the misinformation in the way that he has. I didn't expect things to be this political with regard to the emerging science. But I feel that it is a huge privilege to be able to try to dispel some of that confusion and misinformation and put the power in the public's hands to do their part in ending the pandemic for good.

Topol: That's how I got to know you so well, through Twitter and telling it like it is. And that's why it's no surprise to me that you've become a go-to for media and for the people who want to know what's really going on. One of the first things I learned from you was about reinfection. And this is still an unresolved topic — that is, how many people will develop an immune response and then months later develop reinfection? Can you explain why that is a difficult diagnosis to make and what you think is going on with reintroductions of virus after natural infection?

Rasmussen: I've thought about this a lot because it gets back to one of the biggest problems of the pandemic, and that is logistics; sample availability; and, to a degree, research funding. One of the reasons reinfections have been so difficult to study is that most of them don't seem to cause severe disease the second time around. Some of the reinfection cases that have been reported have resulted in hospitalization, but if this were happening on a large scale, we wouldn't need to go back to archival samples to see whether people were coming to the hospital repeatedly with COVID. I think the prevalence is unknown largely because to prove reinfection, you have to get samples from the first time a person was infected and sequence them and then get samples from the second time they were infected and sequence those and compare the viral sequences to see whether they're actually the same virus.

To a certain degree, maybe it doesn't matter if someone is persistently infected, meaning they get sick and they still have the virus but they don't know it, and then they get sick again, or if they actually are reinfected. It doesn't look like that's happening very often — either that someone has a recrudescence of symptoms with persistent infection or that someone is getting infected again. The problem is that oftentimes, especially from early in the pandemic, samples that are collected during an emergency are not necessarily going to be put in the freezer and banked so that you can go back and access them right away. So you might suspect that someone has been reinfected, but you won't actually be able to confirm that with a sample from their first infection. That is what we have seen with some of the earliest bona fide reinfection cases: They had samples to sequence from both times, but they won't necessarily have a serum sample from the first infection to see whether the patient seroconverted, whether they developed antibodies after the first infection. It really is a practical problem.

How should we be saving samples? Should we be getting consent from patients to use their samples for research? It's also an ethical issue because you can't keep someone's samples around if they haven't given you permission to use them for scientific research. It's also a problem of freezer space and having the foresight to collect some of these samples for potential downstream work. That's difficult to do during a pandemic. Biorepositories are set up at most major research hospitals, but it's difficult to get samples from them because everyone started working on COVID and everyone wants some of those samples. To a certain degree, a lot of these unanswered questions could potentially be answered, but we aren't collecting the right samples. We don't have funding. We aren't preparing to do the right experiments. So we have to make do with whatever we have on hand, and that's not always adequate to answer some of these most pressing questions, including reinfection.

Topol: There are two other key questions related to reinfection. One is that the virus from the first infection could evolve. Is it hard to distinguish the evolution of the virus over time with actual second infections, or even know the sequences are different? Could it actually be just evolution?

Rasmussen: That would be the situation in which you have a persistent infection and essentially, symptoms are coming back. That's not difficult to determine at all if you're able to sequence viruses from early on and also during the second emergence of symptoms. If you have the same virus, you may have additional new mutations, but it's unlikely that you would have completely different sets of mutations within that viral genome. People can also calculate this because we know the mutation rate of the virus; thanks to such initiatives as Nextstrain, we now have a fair amount of sequence information. We know where variants have emerged in different populations as well. You can go back and deduce that there's no way this virus could have evolved from the original virus in the first infection. Or you could say, this virus is consistent with the virus they had before; there are new mutations, but that's to be expected. So we can confirm intrapatient evolution vs infection with two distinct viruses.

Topol: That's important. Related to that is the infamous biosafety level 3 (BSL-3) lab that you know so well, but that the medical community has little experience with. What is the work environment for introducing viruses and proving things about them? What is it like to work in these labs?

Rasmussen: Most of the pathogens, the viruses I work with are either BSL-3 or BSL-4, although if possible, we like to work at BSL-2 because it's just much easier. There are four levels of containment. BSL-1 is effectively working with pathogens that aren't infectious at all. BSL-2 involves the most common pathogens. I did my PhD, for example, on rhinovirus, which causes most common colds. That's an example of a BSL-2 pathogen. It's something that can infect people, but it doesn't cause severe disease. It's not a huge threat if it gets out, because rhinoviruses circulate in the human population during every cold season. When you work in BSL-2 you wear a lab coat, you have eye protection, and you work on viruses and cells in a biosafety cabinet, which is basically a hood that has airflow inside that keeps the virus from coming out. This is typically what you see when you see pictures of people working in a lab.

BSL-3 is where you would work on SARS coronavirus 2 (the severe acute respiratory syndrome coronavirus that causes COVID) and other pathogens that may or may not be select agents. The classic SARS coronavirus is a BSL-3 select agent, which means that the US government regulates it more tightly because of its potential to be used as a biological weapon or its potential to be a threat to national security. In BSL-3, the types of protective equipment you wear depend on the pathogen you're working with. In general, you'll either wear a powered air-purifying respirator (PAPR) or an N95 respirator, and eye protection. You'll also usually wear a Tyvek suit or some kind of protection for your body. There's usually also controlled entry and engineering controls; for example, there will be an autoclave for disinfecting used disposables before they ever come out of the lab. Sometimes there is a dunk tank where you dunk instruments, for example, in disinfectant according to a validated protocol before going out. Those labs are more tightly regulated, obviously, because those pathogens have the potential to cause epidemic disease and often have a higher mortality rate or cause more severe disease, and there may not be a vaccine or treatment available.

The highest level of containment is BSL-4. This is where you work on Ebola and other select agents That's where you see people wearing the positive-pressure spacesuit, which hooks up to an air supply that inflates the suit. That way, even if you get a tear in the suit, air will be blowing out of it so pathogens can't go in. Once something goes into a BSL-4 lab, other than the people working there, it doesn't come back out. If you take an animal in, you euthanize the animal inside the BSL-4 facility so they can't carry out any pathogens you're working on in there. If you're taking samples out, you have to be very, very rigorous about your disinfection protocols. You can dunk things, such as tubes, in a dunk tank that contains disinfectant. Then you have to shower in a chemical disinfectant shower as you're leaving the lab. Then, after a certain amount of time, you can come outside the BSL-4 and remove those tubes. They've been disinfected, so you're not taking anything out that's infectious.

Inventory is extremely strict in BSL-4, again because most BSL-4 pathogens are considered select agents. You have to be inspected by the US government every year. Any kind of violation in how you maintain that inventory is a violation of federal law. You have to account for every last thing you bring in there, especially your virus stocks.

Most of the pathogens I work with are BSL-3 or -4. There are not a lot of these labs because of the huge burden of maintaining them to make sure you're working within them safely, in a way that doesn't endanger the public and also is not a threat to national security or defense.

Characterizing and Predicting Long COVID

Verghese: I was fascinated that you've done work on chronic fatigue syndrome, which we can all agree is a difficult disease to agree on. We have clinical criteria but the immunologic profile is so varied. COVID-19 may be the first time we have a pathogen that truly seems to lead to a state that resembles chronic fatigue. Is it the same syndrome that is being triggered? And what is it about this virus? What does a virus have to do to become a putative cause for myalgic encephalitis/chronic fatigue syndrome (ME/CFS)?

Rasmussen: That's a great question, Abraham. To be honest, I don't know the answer. Going back to the 1918 influenza pandemic, there was a consequence of that infection that they called encephalitis, which sounds an awful lot like ME/CFS. The term "ME/CFS" refers to a collection of different syndromes. Some people have gastrointestinal involvement; some people can trace it to a time when they had some type of unidentified pathogen; other people have no idea where it came from. It probably is more than a single diagnosis, even before this pandemic.

People with so-called long COVID may or may not have ME/CFS, but it sure sounds like some of them do. I would defer to clinicians who are actually diagnosing ME/CFS to say whether or not they meet those diagnostic criteria, but they may be. Because this is the first time we've had a pandemic with such broad effects on different organ systems, including these neurologic effects, we should take this opportunity to try to understand how an acute viral infection can cause these complex, syndromic, long-term diseases like ME/CFS.

The bottom line is, I don't know if this is the same as ME/CFS from other causes. I haven't worked on ME/CFS extensively. I sat on a panel at the National Institutes of Health (NIH) that I was invited to be on it because I don't work on ME/CFS. Because I wasn't a stakeholder, I could make objective recommendations to NIH on how they should direct their funding. But knowing what little I do know, it seems that the etiology of ME/CFS has been a constant question. This may be an opportunity for us to get on top of that and start addressing some of those questions in real time. I'm pleased to see — and not only because long COVID seems to be debilitating and difficult for patients — all these long COVID research centers popping up. I hope some of that research can address some of the questions you just asked about the relationship between viral infection and ME/CFS.

Verghese: Eric is on top of this more than most infectious disease people I know, so I want to ask both of you: Is there a correlation between long COVID and the nature of the severity of the illness or the particular immunologic profile of that person's illness? Have there been any factors could help us predict who's going to get long COVID?

Rasmussen: I have not seen any studies that characterize immunologic markers of long COVID. There haven't been a lot of studies about it, period. Much of what I've heard about it has been reported in the mainstream press or from patients directly. People have started to report case studies of what I think is now recognized as long COVID. But I don't believe we can say with certainty who will or will not develop it.

One thing I have seen is that it doesn't appear to be correlated with disease severity. There are reports of people with severe COVID who develop long COVID symptoms, as well as people who said they had mild disease and never completely recovered from it. That makes it even harder to predict, because if you have mild disease and it's just like a cold and you're recovering from home, you're unlikely to have your blood drawn for a serum cytokine profile, for example. You may be less likely during your acute illness to contribute samples to a biorepository where they could then be studied. It's a tremendous problem, trying to get to the bottom of it and what the risk factors actually are.

Topol: You see people who are younger and have mild infections with long COVID, and also women tend to be affected. Before all this started, you would have thought that it might have tracked with severity, but it is just the opposite.

Can You Get COVID From Surfaces?

Topol: I want to talk about surfaces. We've seen all the mask and aerosol transmission controversies, but there still is a looming controversy about fomites and surfaces that also brings in this BSL-3 and culturing the virus. Give us the scoop on surfaces. Can you get COVID from surfaces?

Rasmussen: I think you probably can. One of the problems here, and this is something that has been quite difficult to communicate to the public in general, is that a lot of what you would think are basic questions about this virus are not so easy. What's the primary route of transmission? How long does the virus remain infectious? How many infectious viruses do you have to be exposed to in order to become infected? What are the variables determining that? Why can't we just look at all these super-spreading events and these epidemiologic reports and just figure it out? The reality is that in the real world, it's rare to get well-designed natural experiments or to have all the pieces fall into place.

What we do know is that the virus can certainly remain infectious on surfaces for periods of time that can last hours to sometimes days and even weeks, depending on the temperature and laboratory environmental conditions. But is that the case in the real world? Usually when people do environmental sampling, they're using polymerase chain reaction (PCR) to detect the virus, which doesn't look for infectious virus but only looks for RNA. Further complicating things — and people who are not virologists don't always appreciate this — viruses themselves, and especially RNA viruses, such as coronaviruses, make all kinds of mistakes. So any infected cell will produce a bunch of different virus particles called virions. But not all of those are actually infectious. They may have a defective genome packaged inside them. They may or may not even have a genome inside them at all. They may be what's called a virus-like particle. We measure that by something called the particle-to-PFU (plaque-forming unit) ratio. Some people now are using the RNA-to-PFU ratio to determine whether a virus is infectious.

This is how we do that: In a BSL-3 lab, you take your sample, put it onto a layer of cultured cells in the bottom of a plate, and then apply a semi-solid overlay — agar or gelatin — on top of that. Then you culture it for a few days. After a while, any place an infectious virus landed, the virus will start to kill the cells; this is called a cytopathic effect (CPE). When enough cells in that one spot have died, you can take off the overlay and use a dye to color the cells that remain. Wherever cells have died, there will be an empty spot, and we call that a plaque. You can count the plaques, and if you serially dilute this using a 10-fold dilution series, you can calculate back and figure out the number of infectious units per milliliter or whatever unit of volume you're using. That's how we determine whether something's infectious.

Usually there's a large particle-to-PFU ratio, meaning that there are a lot more particles than there are PFUs or infectious units. That makes it challenging when you're trying to find how much infectious virus is on a surface in the real world using PCR.

The other issue is that unlike in laboratory conditions, if you're trying to culture viruses off of an elevator button, for example, or a doorknob, people are touching them and they're getting all kinds of other stuff on there, too. And remember, I said the plaque assay has to be done on cultured cells. If you get bacteria or yeast in there from the doorknob or elevator button, they are going to overgrow the culture medium and you're not going to be able to calculate how many PFUs you have. It makes testing for infectious virus in real-world conditions very difficult.

That said, the evidence is pretty clear that the majority of transmission is probably by aerosols or droplets through close contact.

It's also very difficult, and has been somewhat controversial for reasons I don't completely understand, to separate how much is aerosol transmission and how much is droplet transmission. How much are you breathing in, and how much is related to close contact with someone who may be exhaling and coughing droplets on your hand and then you touch your nose and become infected? How do you distinguish those two things? The aerosol transmission that's occurring is also short-range aerosol transmission that is from being close to someone. So it's hard to separate that in the real world.

That being said, just because those are probably the primary modes of transmission doesn't mean that fomite transmission doesn't occur. There is at least one case report of probable fomite transmission occurring in China in which a man was blowing his nose into his hands and touched an elevator button. Then someone who got into the same elevator and touched the button became infected. The authors speculated that this was likely fomite transmission. But again, it is hard to say in the real world, without a way to confirm this by culturing the virus in the moment. You would have to do all of this in a BSL-3 lab, and thus, it makes it difficult to get to the bottom of this question.

I usually tell people that my suspicion and what the data support is that most transmission occurs via aerosols or close contact via droplets, and some unknown, smaller proportion of transmission probably occurs by fomites but it has to be in the right situation.

I completely agree that we've gone overboard with surface disinfection, as you said on Twitter, Eric, and in that article by Charles Haas, Lindsay Marr, and Joseph Allen showed. We needn't be bleaching everything in sight and disinfecting our produce, our groceries, and our mail and so forth. But we should still do good hand hygiene; we should still emphasize that we should disinfect common high-touch surfaces, such as doorknobs in an office building. But we shouldn't be recommending disinfection at the expense of taking other measures to reduce virus in the air.

Topol: There are a few of these cases, for example, in New Zealand with an elevator button and another from a trash bin, and the one you mentioned in China. But overall, it's so hard to confirm; there may be other many other instances but we just don't have proof.

No PAPR Required; Masks Are Another Thing

Topol: I have another question for you, given your unique perspective. You work in these BSL-3 and -4 labs, you're wearing all this protective gear, and then you leave the lab and you walk or drive around and see people who are naked as far as protection goes. What are your thoughts about the virus and what it takes to protect against it?

Rasmussen: In the real world, it's certainly not necessary for everybody to be running around in a PAPR — this is the device you see when staff are shown in the hospital or the lab that kind of looks like a big, clear hood with a tube going down the back with a motor attached to a belt. I don't think that's necessary. I honestly don't even know how valuable it is for everyone to wear an N95 mask, because N95 respirators have to be fitted to your face. And every year you have to take a fit test, which involves throwing a sheet of plastic over your head while you're wearing an N95 mask and spraying a chemical that tastes bitter or sweet. If you're inhaling that through the mask and you can taste it, then your mask does not fit correctly. Trying to fit-test people nationally is kind of ridiculous because the other thing is, in the BSL-3 lab, you're growing virus in culture and you're probably dealing with much higher infectious titers than people will be exposed to in the real world.

That said, it's frustrating to go out in public and see people not wearing masks, intentionally wearing masks incorrectly, intentionally refusing to wear masks, or giving a lot of attitude if they're asked to put their mask over their nose, when they're just wearing it over their mouth or chin. It's very frustrating because I know a lot of that attitude is not based on science or concern for others. It's been frustrating to try to convince people that they should wear masks for the good of the community and not necessarily themselves. It's been really frustrating to try to communicate that masks are not perfect, they don't provide complete protection, but that doesn't mean that they're useless either. In the real world, there are all sorts of variables that are impossible to model or test in the lab. My feeling is that if risk reduction is additive, if all of these measures — masks, social distancing, and ventilation — add up and create the most exposure reduction possible, you should try to implement as many of those as possible. But because it's been so politicized, it's been very, very frustrating to try to convince people that this is something they should do.

Testing Matters

Verghese: I want to ask about testing. Should we be reporting our PCR testing differently than just positive or negative? Should there be an attempt to get into the degree of positivity, if you will? And what do you think about the saliva-based test that's making its way through for home testing?

Rasmussen: One of the most common questions I've had throughout this pandemic is about the role of testing and how tests are being reported. I was shocked this summer when Apoorva Mandavilli from the New York Times, told me that they actually don't report cycle threshold (Ct) values, which is the numeric value that the PCR test produces and correlates with how much virus you have. I understand why they don't, because these tests have all been given emergency use authorizations, and my understanding is that you can't include the Ct value in the patient's electronic medical record. The doctors do get the Ct values in some cases, and they will make clinical decisions based on that, but it can't go into the patient's medical records. At least that was the case at Columbia. And that's what the head of our clinical pathology lab explained to me. I think that is missing information. It would be helpful to have more information, but even that discussion has gotten confusing in the public eye. So now we've heard that any PCR test with a Ct value above 35 (some people say 30) should be considered a negative test or a false-positive, but that's not really true.

There are different PCR tests and depending on whether you're running that on a Roche instrument or one from some other manufacturer, you might have a different number of overall cycles in the PCR test. That's the PCR or cycle at which the fluorescence that's detected by the test exceeds a certain threshold. The earlier the cycle, the more starting material you had to reach that threshold. If you're running a 40-cycle PCR test and you have a Ct value of 35, that's not very much virus. If you have a 35-cycle PCR test, that's even less virus if you're at a Ct of 35. But it's not as little virus as if you were running a 40- or 45-cycle test. So there are some discrepancies between the different tests that are being used that make that information complicated, at least when it comes to looking at results in a standardized way across all these different tests.

The other issue with calling these false-positives is that if you're testing people who have already recovered from COVID and they're getting these consistently high Ct values, that's probably not infectious virus. But if you're testing someone and it's unknown whether they've had COVID or not, you could be detecting very low levels of viral RNA early on in infection, and those levels are going to go up and that person will suddenly become a transmission risk. If we're not able to test people longitudinally, repeatedly, it's hard to make decisions about which Ct value counts and which does not.

With regard to the saliva test or any type of at home testing, I think that definitely has a place, because we need to increase our testing capacity. We've needed this since the beginning of the pandemic. Anything that can help people make decisions about how they should behave, whether they should go to work, whether they should meet with someone who may be high risk, I think that is generally a good thing.

What's going to be key is presenting it to people in the right context so they know what to do. For example, if they get a positive test at home, it should be similar to taking a home pregnancy test. When women take a pregnancy test and test positive, they don't say, OK, back to my normal life. They probably call their doctor and get that test confirmed and see what they need to do in terms of prenatal care and planning for the new arrival. People now may not know what to do if they get a positive COVID test. Most people are not as well versed as I or any of us who are working within a scientific or medical space are about the dangers of presymptomatic transmission. We've all become acutely aware of the likelihood of presymptomatic transmission.

A lot of people may say, you know, I tested positive, but I feel OK. If I start to feel sick, then I'll go home or then I'll isolate. Without that kind of guidance and a consistent message about what people should be doing if they test positive at home, it could potentially be dangerous to put tests in the hands of everybody. But that should be an easy barrier to overcome, because if we put out rapid at-home tests, made a robust reporting structure and gave, easy to understand, actionable steps that people should take if they do test positive, that could be quite powerful in terms of people being able to involve themselves in the efforts to reduce community transmission.

Topol: What about the saliva test? Is that as good as an anterior nares COVID test?

Rasmussen: I think this has to be decided for every test in general. I'm not sure which saliva test you're referring to. Saliva tests for PCR, such as the SalivaDirect test that was developed at Yale, are actually more sensitive than anterior nares or nasopharyngeal swabs. Antigen tests, though — and I'm not sure whether that's the saliva test we're talking about — are generally less sensitive than PCR tests, period.

Michael Mina, who is at Harvard and is the most vocal advocate for rapid, at-home antigen testing, has made the argument, which I agree with, that home testing could be helpful for determining who is positive when they take that test. Such tests might not pick up those people who are very early on in infection or people who are late and are probably not shedding infectious virus any longer, but if they do test and are shedding enough virus to transmit it to others, they would test positive with those tests. In that context, the home tests could be tremendously useful. The real challenge is communicating that to people and what a positive test means — that you're contagious now, whether you feel sick or not, and that you should immediately isolate.

Vaccine Platforms and Preparing for the Next Pandemic

Topol: We've been fortunate with these very powerful mRNA vaccines — and perhaps others that will come along — being spike protein–directed and so potent. Do you think, with all your experience with pathogens, that we might not be so fortunate in the next pandemic? This virus was potentially an easy target, even though it's been a wreck around the world. What is your sense going forward? We're going to have more pandemics, more viral pathogens. Are we just lucky this time around in terms of the vaccines? Or do you think we'll always be able to come up with a way to quash a pathogen?

Rasmussen: I agree with you that we were lucky, not because this pandemic occurred, but because it occurred with a beta coronavirus that we've already seen a relative of before. There were mRNA vaccines already in development for MERS coronavirus, so we understood the basis for which neutralizing antibodies work to stop beta coronavirus infection, for example. It was just a matter of swapping in the spike protein of SARS-CoV-2 for the spike protein of MERS coronavirus, which was already in development at Moderna.

There will be a next pandemic, and I hope it is with a virus for which we have already developed some vaccines. But it could be something completely new. At least 25 different virus families are capable of becoming human pathogens. It is possible that we may see a pandemic emerge with a virus that we really don't know much about at all. But we now have a wonderful test for vaccine platforms, such as the mRNA vaccine platforms, as well as the viral vector platforms. You know, there was a viral vector vaccine made with the vesicular stomatitis virus that was stuck in preclinical development for 10 years before the West African Ebola outbreak. And that vaccine is incredibly effective. It produces sterilizing immunity to the point where I've been involved in host response studies in nonhuman primates that were challenged with it after vaccination, and you can't detect any sort of host response after challenge. This suggests that the immunity is so robust that the animals don't get infected at all, even an abortive infection. We have these vaccine platforms now that can be rapidly changed out for other viruses.

What we need to do is to begin to understand all these different virus families. Assuming that we won't know the individual virus that emerges, we should put some effort into trying to predict which ones might emerge. But we also need to put some effort into looking at prototypic viruses from these families, using animal models and experimental model systems, so we understand the basis for protective immunity for these other viruses and these other families. The movie Contagion was based on Nipah virus, which fortunately has not become a human pathogen. Nipah is a paramyxovirus. We know a lot about paramyxovirus, but it's a pretty diverse virus family. We should be spending more time working on other viruses within families such as that in case one day a Nipah variant emerges, or a virus comes out that we haven't seen before that's like Nipah, which can be transmitted by the respiratory route and is more transmissible from person to person. We need to be able to rapidly develop vaccines that are likely to be effective so that we don't even have to go through the process that we've gone through with COVID. The process has been amazing and so fast compared with other vaccines, but we really need to have some flexibility in producing these vaccines, making them rapidly, and starting to distribute them so that something like this never happens again.

Topol: And also that we were fortunate that this isn't a rapidly evolving virus, making it even more challenging for vaccines.

You are an amazing resource. I nominate you for the coronavirus and pandemic prefatory task forces of the future. Really, Angie, you're a phenom. I have learned so much today.

Verghese: I want to urge you to keep up your efforts and your voice countering the misinformation. The blurring between fact and opinion is so strong that we need to help people like you underline the facts as opposed to the opinions. Thank you for that.

Rasmussen: Thank you both so much. I do plan to continue my public outreach activities, which at this point have become almost a second job.

In my next position at the vaccine institute, I hope to start addressing questions such as these about the next pandemic. I'm a firm believer in the value of interdisciplinary work. To counter the next pandemic, we will need virologists like me who have subject matter expertise in how viruses and immune responses work. But we will also need people to appreciate this at the policymaking level, to fund this type of interdisciplinary work. We'll need epidemiologists to understand how these viruses are likely to spread, vaccinologists who can get down into the nitty gritty of making an actual vaccine, and anthropologists and sociologists to get people to take those vaccines.

This will be a huge, global effort. Going forward, I hope we appreciate the importance of having people from multiple disciplines all at the table, because that's the only way we're going to succeed at this, especially globally.

Topol: Well, having you at the table, that's key because you're a great educator. Watch out for Dr Rasmussen in the decades ahead. Thank you so much for joining us.

Eric J. Topol, MD, is one of the top 10 most cited researchers in medicine and frequently writes about technology in healthcare, including in his latest book, Deep Medicine: How Artificial Intelligence Can Make Healthcare Human Again.

Abraham Verghese, MD, is a critically acclaimed best-selling author and a physician with an international reputation for his focus on healing in an era when technology often overwhelms the human side of medicine.

Angela L. Rasmussen, MA, MPhil, PhD, has studied a variety of viruses, including Ebola, using systems biology and genomics to examine the virus and host responses. In the current pandemic, she's used Twitter (@angie_rasmussen) to counter misinformation and misinterpretation of data.

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