Watch the replay of this event held November 18, 2020 (transcript below)

The outcome of infection with SARS-CoV-2, the virus that causes Covid-19, is determined by a person’s immune response. That outcome may be good, when the immune system halts the virus with barely an obvious symptom; bad, when the immune response causes symptoms of disease; or ugly, when an over-cooked response triggers severe or life-threatening reaction.

During this event, two leading immunologists described how our immune defenses recognize and respond to viral threats, tease out the roles that the different components of the immune system play in protection and damage, and discuss the characteristics of vaccines that could generate protective immunity to SARS-CoV-2 in a large fraction of the population.


Akiko Iwasaki, Professor of Immunobiology and Molecular, Cellular and Developmental Biology, Yale School of Medicine

Akiko Iwasaki received her Ph.D. from the University of Toronto (Canada) in 1998, and her postdoctoral training from the National Institutes of Health (USA) (1998-2000). She joined Yale University (USA) as a faculty in 2000, and currently is an Investigator of the HHMI and Waldemar Von Zedtwitz Professor of Department of Immunobiology, and of Department of Molecular Cellular and Developmental Biology. Akiko Iwasaki’s research focuses on the mechanisms of immune defense against viruses at the mucosal surfaces. Her laboratory is interested in how innate recognition of viral infections lead to the generation of adaptive immunity, and how adaptive immunity mediates protection against subsequent viral challenge.

E. John Wherry, Director, Institute for Immunology, University of Pennsylvania

Dr. E. John Wherry is the Barbara and Richard Schiffrin President’s Distinguished Professor, Chair of the Department of Systems Pharmacology and Translational Therapeutics in the Perelman School of Medicine and Director of the UPenn Institute for Immunology. Dr. Wherry’s research has pioneered the field of T cell exhaustion – the fundamental mechanisms by which T cell responses are attenuated during chronic infections and cancer. His work has advanced understanding of how gene expression changes affect this exhaustion, which has led to strategies to improve the effectiveness of T cell-targeting immunotherapies. Dr. Wherry’s lab is a pioneer in defining the concept of Immune Health using systems immunology approaches, most recently applying this concept to COVID-19.


Richard Gallagher, Editor-in-Chief, Annual Reviews

Richard Gallagher has a PhD from the Department of Cell Biology at Glasgow University, Scotland, and spent 10 years in research, five as Wellcome Trust Lecturer in Immunology at Trinity College, University of Dublin, Ireland, working on the immunopathology of celiac disease. On moving to publishing, he served as Office Head and Senior Editor for the Europe Office of Science in Cambridge, England before joining Nature in London, England as Chief Biology Editor, where he managed the publication of the papers describing the sequencing of the human genome in 2001. He was later appointed Publisher of Nature before moving to Philadelphia, Pennsylvania, to become Editor & Publisher of The Scientist magazine. He joined Annual Reviews in 2015.


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This event is part of Reset, an ongoing series of live events and science journalism exploring how the world is navigating the coronavirus pandemic, its consequences and the way forward. Reset is supported by a grant from the Alfred P. Sloan Foundation. Knowable Magazine is a product of Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society.


Richard Gallagher: So we’re at two minutes past the hour now. So I’d like to say hello, everyone. You’re very welcome to this event titled “Covid-19 and the Immune System: The Good, the Bad, and the Ugly.” I’m obviously the ugly. I’m Richard Gallagher, the president and editor-in-chief of Annual Reviews, which publishes Knowable Magazine.

We are fast approaching the one-year anniversary of the report of a cluster of pneumonia cases linked to a seafood market in Wuhan, China. The earliest record of the date for the onset of symptoms was I think, December the 1st, 2019. Before the end of that month, the cause was identified and the sequence of a novel coronavirus was determined. It’s the seventh coronavirus known to infect humans.

The disease was later given the name coronavirus disease 2019 or Covid-19. The virus was labeled SARS-CoV-2. If the time between then and now has been a blur for you, imagine what it’s been like for our two guests today who have become deeply involved in efforts to generate a clear understanding of the disease and why infection with this virus has such a wide spectrum of outcomes.

They are Akiko Iwasaki, professor of immunobiology and professor of molecular cellular and developmental biology at Yale University School of Medicine. Akiko’s research has focused on the mechanisms of immune defense against viruses at mucosal surfaces. And John Wherry, professor and the director of the Penn Institute for Immunology at the University of Pennsylvania. John has worked extensively on a phenomenon called T-cell exhaustion, which takes place during chronic infections and in cancer.

Before we begin, I want to remind you that you can add questions to the chat. If the questions are not addressed in the to-and-fro of the discussion, I will ask them towards the end of the event. Also, you can follow along and comment live on Twitter at #ResetImm. That’s R-E-S-E-T-I-M-M. Akiko and John, thank you very much for being with us today. Maybe I can start by asking how, when and why you became involved in research on Covid-19? Akiko, would you like to start?

Akiko Iwasaki: Yes. Well, thank you. … Can you hear me now? I cannot …

Speaker 3: Apologies for that. Akiko, would you have a pair of headphones you can use? Perhaps we can start with John then.

John Wherry: Sure. Hopefully we don’t get feedback here. Yeah, happy to chat about this just for a second. Our lab has been interested for a long time in understanding human immunology. In particular, we started off studying viral infections and the immune response to viral infections. In the past 10 years or so, we have turned a lot of our energy to really deeply profiling the human immune response during cancer and during immune therapy of cancer.

In early March, we saw this pandemic evolving and in about mid-March I arrived back from a trip just to the news that Penn and every other academic institution was shutting down research, that businesses were being shut down. And we looked around the lab and realized we had all the tools available to start asking questions about what a typical immune response might look like in the setting of SARS-CoV-2 and Covid-19 and really turned our entire research program towards profiling what it might look like when a person gets infected with SARS-CoV-2 and asking the question whether this really looked like a typical human immune response to a viral infection and we can maybe come back and talk about what we’ve all learned over the past nine months about whether it’s a typical response to a viral infection or what features are typical and what features are not typical.

So we really wanted to apply some of our basic approaches for profiling the immune system to ask what was happening in the setting of SARS-CoV-2 and see if we could do it quickly to address some of the key questions in the pandemic.

Richard Gallagher: Do you hear us?

John Wherry: Now I can.

Akiko Iwasaki: Now I can.

Richard Gallagher: So, Akiko, how did you come to pick up the challenge of Covid-19 and understanding the pathogenesis?

Akiko Iwasaki: Right. My story’s a little bit parallel to what John was saying. My laboratory prior to Covid was studying immune response to other types of viruses: respiratory viruses, including influenza virus, rhinovirus as well as sexually transmitted virus, herpes virus. And so I’ve been following the outbreak in China early in January and when the virus landed in America and everything was being shut down, prior to that, I was able to meet with a large number of colleagues at the Yale University Hospital as well as School of Public Health where we were able to put together a biorepository where we can collect patient samples and study them in real time.

And so that’s how I got into this, but my entire laboratory had to shift from doing something else to studying Covid.

Richard Gallagher: Great. Well, we’ll come back to those details. But I wonder if we could start by having you each take the part of one of the actors in this game. Akiko, could you paint a picture for us of the dynamics of virus infection? Once it has been inhaled, how does the virus establish itself? How does it replicate and spread? And what sort of numbers of virus particles are being produced here and on what time scale?

Akiko Iwasaki: All right. We can only speculate because we don’t really know what’s going on in the infected person. But what seems to be happening is that virus is inhaled and probably the first set of cells that are infected are the nasal epithelial cells.

So this virus uses ACE2 as a receptor and ACE2 is expressed on the surface of respiratory epithelial cells as well as epithelial cells of other organs. And so the first thing that happens is likely the replication of the virus in the nasal epithelia. And when replication is successful, it can transmit down to the lung, where it will cause problems.

And so the epithelial cells, when they’re replicating the virus, it’s projected to produce 700 particles of infected cells and releasing within 12 to 24 hours of infection. So you can imagine just multiplying that number over and over again, and there’s an exponential increase in virus throughout the respiratory tract if there is no immune defense to prevent that.

Richard Gallagher: Great. That’s very interesting. John, when we talked earlier, you described to me a kind of race between the virus replication that Akiko has mentioned and the immune system with every barrier that the body can erect, however low and temporary it might be, potentially crucially affecting the outcome of infection. Is that the general picture that’s emerging? And what are all these barriers that the body puts up, in brief?

John Wherry: Yeah, Richard. I think that is it. And it is almost always when you have a viral infection a race between the virus and the immune system. And the immune system has a couple of layers of tools that it can use in that race. When the virus first comes in and infects those first epithelial cells that Akiko mentioned, you activate what’s called the innate immune system. Those first infected cells make proteins that can help suppress viral replication and slow down that rate of growth or limit from 700 new viruses per cell to fewer than that. But that’s usually a temporary barrier. And that usually just tries to slow things down a bit.

That innate immune activation also then is a signal to activate the reserves and to bring in what we call the adaptive immune system. While the innate immune system gets turned on in minutes to days after initial infection, the adaptive immune system can often take a half a week, a week, maybe even 10 days to fully come online. And so what we really have are two avenues that the immune system uses in this race. It puts up an initial set of defenses called the innate immune system and those are proteins made by immune cells, those are immune cells that are sort of hardwired for certain types of responses.

Those are the initial troops at the frontlines. They delay things, they try to contain things locally. But then if that is insufficient, the backup plan is the adaptive immune system comes in. In this case, usually T cells coming in that are capable of making lots of antiviral proteins that suppress the virus further, they’re capable of directly killing virally infected cells before the cell can make those 700 new viruses and interrupt that life cycle and then also start making antibodies.

And antibodies can play a role even in these early times of infection — the first week or two — but then of course, what we’re all interested in to protect us long term from reinfection. They’re really these two parts of the immune system that are acting as the countermeasure to the virus trying to race from one cell to the other, from the upper respiratory tract to the lungs and, in the worst case, from the lungs out to the rest of the body. It’s the balance of this race. And so how fast the virus replicates, how easily it moves from one place to another and the initial dose of the virus coming in all play a big role in how effectively that immune response is going to be able to contain things.

Richard Gallagher: That’s very interesting. We’ve seen huge variations in the responses and the impact of viral infection on different segments of the population. One thing I’d like to talk to you about, perhaps Akiko could answer this first, is the relative resistance to Covid amongst children and maybe youths. Do you have insights into what responses young people have that might be protective and why those responses are maybe waning when people get older?

Akiko Iwasaki: Yeah, there’s still much unknown about why children are protected. One theory is that they have cross-reactive immunity from seasonal coronaviruses. Children are constantly getting the common cold and some of them include the seasonal coronaviruses, which have some shared sequences between SARS-CoV-2.

The other is that they mount a robust innate immune defense as described so nicely by John, this frontline innate immune defense; if they are engaging much more robustly in children, that could also explain the resistance. It is also possible that there might be intrinsic difference in the ACE2 receptor. It’s been reported that children may have lower levels of ACE2 expression compared to adults. And so there might be innate defense differences, cross-reactive immunity. There’s also reports from Dana-Farber [Cancer Institute] that was recently published that showed that children make different kinds of antibody responses. That may have something to do with the resistance phenotype. But right now, we don’t know exactly why they’re resistant.

Richard Gallagher: Is this resistance upon right from very, very early neonatal children or does it develop through that period where kids are much more social and spreading these other viruses around and amongst themselves?

Akiko Iwasaki: So it appears that the resistance is up to adolescent age, probably 16 years of age. There’s something that happens after that age group that allows for more infection and potentially more severe disease. But of course, the most severe diseases are seen in the older population.

Richard Gallagher: Is it possible and has interferon been used as a therapy, as a kind of frontline therapy in any groups of patients?

Akiko Iwasaki: So that is being tested right now with clinical trials of giving patients recombinant interferon, because interferons are one of the most potent antiviral cytokines that the host cell secretes. But in the case of SARS-CoV-2, maybe they’re not secreted early enough to make a big difference. And so by providing interferon early, we might be able to control the virus and therefore disease.

Richard Gallagher: Very interesting. John, could I turn to you to describe what you would consider to be the optimal immune response, which I guess you’ll say is a long lasting T-cell immunity. How does that develop? What’s the time scale for a typical strong T-cell response to a virus?

John Wherry: Yeah, I think this is an important question and one of the questions we wanted to ask with the patients that are getting infected early in the pandemic. Typically, for a normal, for your typical kind of viral infection in human respiratory infection, you’ll have a strong innate immune response that activates your T- and B-cell responses, it typically takes about a week to 10 days to get a T-cell response going so that that T-cell response can be effective in the tissue or the site of infection. And then you mature that T-cell response to form what we call T-cell memory, along the same kind of trajectory and roughly the same timescale, you’re also making B-cell responses and making the antibody to the virus.

We typically think about immune memory really forming starting at the sort of four to six weeks after initial infection or initial vaccination. You can get some protection before that. But good long-term robust immunity really for a virus like this is going to require antibody — very likely memory B-cells that are capable if they get activated of making new antibodies, and also T cells that we think about in this case as very likely a backup plan or a partner for when antibodies either don’t do the job 100 percent effectively or when perhaps the virus breaks through that antibody response and the T cells are there as a backup plan.

Richard Gallagher: Of course, there are a couple of ways in which the immune response may not be optimal, that give different pathogenic outcomes. Can you summarize for us what the various pathways are where the immune system is either overreacting or underreacting, and what the consequences of that are?

John Wherry: Yeah, this is a critical question for Covid-19. To be honest, we don’t understand this completely yet. One of the things many of us have seen is that in a set of Covid-19 patients in the hospital, you will have multiple different ways the immune system seems to be failing — and by failing, and what we may be saying, is that the immune system is responding inappropriately. It’s not that it didn’t respond, but is responding inappropriately, perhaps too aggressively, perhaps the wrong combinations of effects or perhaps it isn’t responding at all. Generally speaking, we’re seeing two or three different manifestations of that.

The first is patients that have a very, very strong immune response and the immune response may actually be contributing to some of the illness, some of the tissue damage. Those are the patients that may benefit from being treated with steroids. Although the benefit is marginal, it’s real and clinically quite important.

We have another set of patients that actually seems to be at the other end of the spectrum. And these are the patients where actually steroids may actually be detrimental and those are patients that perhaps Type I interferon might be a useful therapy. What we don’t yet know about these patients is where they are on the trajectory. Have we just caught the first group of patients who are late in the immune response, where the immune response is trying to catch up to the virus? And is the other group of patients just early in the immune response, where it hasn’t really activated the adaptive immune system yet?

But we also see some other what we think about as manifestations or axes in the immune response, where when mounting a response, that response may not be as effective as we’d like it to be against the virus, but yet it continues to go. And that can lead to various manifestations including cardiovascular disease or thrombosis that we’re seeing. We don’t yet understand the cause of that. But it seems to be something that’s arising from sort of misdirected immune responses, at least partially.

Richard Gallagher: So do these different manifestations of incomplete or unsuccessful immune response inform decisions on what type of therapy the patients would be given?

John Wherry: I think they’re starting to and the dexamethasone, the steroid example, is one where we’ve seen that, where there was clear benefit to a subset of patients treated with dexamethasone. Those patients are likely the patients that are either later in disease or have a more aggressive immune response. At the other end of the spectrum, in those same trials, we saw patients that not only did they not benefit, but there were some hints that actually may have been detrimental.

On the interferon front, we’ve seen the same thing. There are examples of interferon treatment being beneficial, and other examples of using drugs that block interferon also being beneficial. Now, not in the same patients. It’s difficult to compare two different studies done in different trial settings. But we’re seeing that there are patients that run the spectrum of different types of immune response, that means we’re going to need different drugs, different therapeutic approaches to benefit those patients whose immune response is behaving differently.

Richard Gallagher: There’s clearly a huge amount going on here. Not surprisingly, it’s taken a long time to tease out. A couple of questions on that. What is the contribution of genetics and genetic susceptibility to this particular virus playing in the outcome? What’s known about that to date?

John Wherry: Yeah. Maybe I’ll comment and I know, Akiko will have comments on this too, but I do want to make a comment, Richard, that it’s been a long time and we don’t understand everything. This is the fastest we’ve ever learned anything about a human infectious disease, probably in the history of man. It’s the fastest we’ve ever had a vaccine get to this point in the history of making vaccines.

So there’s a lot to do. We’re all working 24 hours a day to try to figure this out. But the amount of knowledge gained in the last nine months about this virus is probably comparable to what we did in the first decade of studying HIV. No disrespect to HIV, the progress there was absolutely astronomical and we have better tools now in all of this.

So one of the things... so there clearly are some genetic components here and probably the one to mention that is really relevant — and I think it’s quite exciting — our recent studies showing that there are genetic variants in genes involved in the interferon pathways. And as Akiko pointed out, that seems to play a major, major role early in infections. If you have a delay in activating the Type I interferon pathways, you’re going to do worse. That type of interference pathway is really critical to the initial containment of the virus.

To me, what was most exciting or most striking about some of those studies is not just that there are genetic components, but there may actually be immune imprints that are separate from genetics. A small subset of patients actually makes autoantibodies against interferons or parts of the interferon pathway that may in fact, give the same outcome in a non-genetic way as some of the genetic polymorphisms in the interferon pathway.

So those have been major advances in our understanding and there are probably other genetic determinants also that are playing a role here. But I know Akiko has played a role in a lot of those kind of studies and probably has some comments.

Akiko Iwasaki: Yeah, it’s definitely true that there are certain genetic mutations that are found more enriched in severe infection and life-threatening Covid. And as John mentioned, there are some biological counterpart or parallel to the genetic mutations in the interferon pathway that also contributes in a similar way to severe Covid.

We now have to expand this sort of preexisting so-called mutation beyond the genetics to see if there are autoantibodies that block some of the key pathways for both innate and adaptive immune responses and so, much to be learned.

Richard Gallagher: Are these genetic roadblocks, if I can put it like that, is their contribution really that they’re slowing up the body’s response and so they’re affecting the outcome, the balance between how quickly you can develop protective immunity as against how established the infection can become or is there something more sophisticated going on than that?

Akiko Iwasaki: Well, if you can’t make any interferon or respond to interferon, all of these host mechanisms to block virus replication is going to be nonexistent. Not having that very early frontline defense is going to crumble down all the rest of the defense system. And so having those layers turn on in the right time in the right amount is going to be very important for recovery from this infection.

John Wherry: Yeah. Richard, I think one of the interesting ways to think about this, exactly as Akiko said, when the adaptive immune system comes in, it’s going to cause some damage. Your T cells are going to kill those cells that are infected, they’re going to create a lot of inflammation. If your Type I interferon system is working and you can limit that initial site of infection to — let’s just make up a number — just 10 cells in the upper respiratory tract, when those T cells come in, you may get a little bit of sinusitis and a little bit of inflammation in your nasal passages. But that’s it.

If you delay that response, just by two or three days, now you might have tens of millions of cells infected throughout your lungs. When the T cells come in, and start killing all those cells, all of a sudden you have problems exchanging air, you have pneumonia and you have considerable damage to a tissue that can’t withstand that kind of damage. So just a little delay in that race, even when the other parts of the immune system do what they’re supposed to do, you now have a pathological situation rather than an effectively controlled infection.

Richard Gallagher: Interesting.

Akiko Iwasaki: Richard, if I can add to that.

Richard Gallagher: Sure.

Akiko Iwasaki: In addition to host defense that’s defective in some of the severe cases, there are environmental factors that also control this early-resistance phenotype. For instance, we have been studying the importance of humidity in the air in our ability to get rid of inhaled viral particles. It turns out that the relative humidity that we inhale in the air is very important for the mucociliary clearance of viral particles. And so in addition to interferon, we may have to regulate the environment in order to promote the best kind of resistance against this virus.

Richard Gallagher: Talking about other factors that might influence the course of the infection, we had a couple of questions: one relating to differences in susceptibility with blood group type and another asking about the impact of diet on the outcome of disease. Do you know of any studies that are informative on these? Or do you have any comments on the various other factors that might also play a role in the outcome of infection?

Akiko Iwasaki: John, do you want to go?

John Wherry: I’ll take a first stab at it, Akiko, and then you can chime in. The blood group data is quite interesting. There are a couple of reports early on in the pandemic, that blood groups were associated. I can’t remember if it was severity or just acquisition of infection. We’ve seen the same thing in our own data. Other people have reproduced that. There have not been a lot of studies getting to the mechanism of what’s behind that. I think that’s the sort of $64,000 question.

There may be some association there with coagulation and some of the sort of coagulation cascade leading to thrombosis and clots, although the data are still emerging on all of that. So the question is still open, what exactly the blood group association is doing. It could be other genetics that are linked to but mechanistically different from blood group antigens.

In terms of diet, we don’t know a lot yet specifically here. But I think a general answer would be the answer that I’ve given and I would give. We know that a healthy diet impacts your immune system. We know that a healthy diet feeds your intestinal bacteria and those intestinal bacteria also keep our immune system fit and healthy. And so we know what kinds of diet are associated with a healthy immune system, the sort of lots of fruits and vegetables, more whole foods, that non-Western diet, so to speak, actually do keep a fitter immune system, but exactly how much of an impact that has for an individual versus sort of population-based diet effects remains to be seen here for Covid-19. Akiko?

Akiko Iwasaki: Yeah, I can’t agree with you more. It’s definitely important to have a balanced and healthy diet. And in addition, just in general healthy lifestyle, with some exercise and enough sleep and trying not to get stressed even though it’s very difficult during the pandemic. So all of these things actually impact the immune system and it’s important to keep a healthy lifestyle.

Richard Gallagher: Well, let’s turn the spotlight on the villain for a couple of minutes, the SARS-CoV-2 virus. Akiko, comparing this to other pathogenic viruses, are there any characteristics that make this one especially dangerous, or indeed are there characteristics of it that we should be thankful for that make it less harmful than it otherwise might be?

Akiko Iwasaki: Right. So the one thing that really makes this virus especially dangerous is the long incubation period where people are infected and replicating the virus, but they do not have the symptoms yet. So this lasts between five to 14 days or so. And this is the time period when people are interacting with others and unknowingly transmitting the virus. So this allows for successful transmission of this virus. And the other thing that’s dangerous about this virus appears to be this long-term consequences of infection and so-called the long haulers who suffer from disease for months and these disease symptoms are debilitating in some people.

Those types of things are seen with other viruses. But because of the sheer number of people that are infected with this virus, the long haul phenotype is becoming a very dominant thing in society, so we really need to understand what the mechanism of this long-term disease is so we can provide a better therapy and hopefully promote the recovery of these people who are suffering for a long time.

In terms of what’s good about this virus or what we should be thankful for, is that the virus is not highly lethal in most of us. Of course, there are age-dependent differences in lethality and it’s also slowly mutating, not like the HIV, where we can never catch up with their mutation with respect to immune response. We are still able to make one vaccine that can cover all the viral isolates that are out there. So with respect to vaccine development, we should be thankful that this virus is so slowly mutating.

Richard Gallagher: A specific question from a participant who has just completed a year’s immunotherapy for advanced melanoma and wonders if that makes him or her more or less susceptible to Covid-19?

John Wherry: Yeah. It’s a good question, and with a disclaimer that I’m not a physician and I don’t treat patients and none of this is true advice medically. We’ve learned a good bit over the last few months about which patients are more susceptible to infection and severe consequences. For cancer patients, there’s of course quite a bit of concern and especially because cancer patients are on immunotherapy, so there’s been a lot of focus on tracking what happens.

So far, it looks like most patients, cancer patients who have solid tumors don’t experience either a higher rate of infection or more severe complications than sort of age-matched demographic controls. The exceptions here are lung cancer patients and that may be just sort of anatomical, of course, because the lungs are compromised in lung cancer patients, and then leukemia lymphoma patients seem to do quite a bit worse than their sort of demographically matched counterparts and that may have to do with immune ablative therapies that get rid of your immune system to treat the leukemia lymphoma.

Overall, we’ve not seen a major imprint of cancer-related immunotherapies making patients more susceptible to severe disease or complications. So right now, the data says that cancer patients, even after completing a year of immunotherapy for solid tumors, are not at a greater risk for having severe disease. That said, and I am not sort of guessing the age of our question asker here, but most cancer patients tend to be in the older demographic, who may be at higher risk anyway, so I would look at it from that perspective.

Richard Gallagher: We did have a couple of questions about health, disease in the elderly, which I think you’ve addressed there. We also got a question about potential patients at the other end of the age spectrum: neonates or even prematurely born babies. Is their immune system sufficiently developed or is it underdeveloped and makes them special risk?

Akiko Iwasaki: Neonates in general are more susceptible to infections, because they don’t have a fully developed immune system yet. But if they are getting breastfeeding, the mother can transfer her antibody to the neonates, potentially being able to protect against infectious diseases. So really depends on what the situation is. But in terms of pregnancy, we have seen some rare cases in which there are infection of the placenta, and whether that leads to severe disease or not, is still unclear, even though we have seen a patient where the placental infection resulted in severe outcome in pregnancy.

So this goes to show that the tropism of this virus is quite diverse. It’s not just the respiratory tract but we have seen infection in other organs like the intestine, the brain, the heart and placenta and potentially other places.

Richard Gallagher: To the good news: the patently phenomenal success of the trials for Covid vaccines, more than one Covid vaccine reported to date. Are those results surprising to you given the spectrum of severity and the variation of individual responses? How well do you think these incredible results will translate into vaccination of the population in general?

John Wherry: A lot to unpack there. But let’s pause for a minute and I think just acknowledge how absolutely incredible it is that we have two vaccines moving towards widespread use — we can talk about “widespread” in a minute — within 11 months of having the virus sequenced. It’s absolutely unprecedented. Tremendous achievement for everybody involved. These are great results. These vaccines have looked very promising in early trials. I think many of us were very hopeful, but almost afraid to say so out loud from the early trial data that the results would be quite good.

I’m not sure many of us would have put our $5 bet down on 95 percent effective for these vaccines. But let’s remember, the numbers are still low. These are still clinical trials and when we get into real-world scenarios, I think we’ll see very good numbers with these vaccines, but it will fluctuate a little bit.

So I think these are great data. I think that emerging information — actually some just coming out today and yesterday — really suggests that we may in fact get long-term durability of immunity from these vaccines. But even if we needed boosters every couple of years, this is a major turning point for this pandemic. We should also then look at the practical side of this. As exciting and as fantastic as this news is, we’re unlikely to have more than a few tens of millions of doses of this vaccine available in the US before the end of the year.

We’re going to need hundreds of millions of doses of these vaccines to vaccinate the US, and we’re going to have to confront the challenges of vaccinating a large-enough percentage of the population resistant to vaccines to get ourselves to the point of actually eliminating this pandemic. There are major, major both logistical vaccine production and sort of social policy challenges ahead of us to make sure that we get back to life as normal.

Akiko Iwasaki: Yes, I absolutely agree that these numbers are remarkable and we should be celebrating the early success. Of course, I was originally worried about the vaccine being effective in older people who are the most vulnerable to this infection. But this morning’s news from Pfizer indicated that adults over 65 years of age, there was 94 percent efficacy in that group as well. Which is also really amazing, given the fact that for influenza vaccines, it is very difficult to provide protection in this age group. So all around, this is a really, really great news. Even though it’s early data, I suspect that in the long run, we are going to have a very effective vaccine against this virus.

Richard Gallagher: We’re not usually looking at our watches and measuring how long it takes for a new therapy or a new vaccine to be developed. And as you say, John, it’s unprecedented and quite extraordinary. What explains the speed with which these vaccines — and it’s not just these two, there’s many more to come — what explains the speed at which they’ve been developed?

John Wherry: I think there are a couple key things here and let’s talk about the two that are the front runners. There was significant investment over the past 10 to 15 years in background basic science that allowed this to happen. Basic vaccine research largely at the NIH built a platform for making vaccines to coronaviruses that is essentially plug-and-play. There’s everything you need all existing and all you have to do is swap out the little piece of the new virus and put it in and presto, you have your new vaccine.

And so that investment starting really, more than a decade ago, put us in a position to do this faster than anyone could have imagined and there are many great people at the NIH that actually helped do this and around the country who helped do this. But that led to this, and I said it before, this absolutely remarkable achievement, from the day that the virus sequence was made available, it was three days before the vaccine construct was mailed to Moderna and it was 66 days before the first person was given a test dose of that vaccine. That was built not in 66 days. That was built with about 12 years of background investment and being prepared to be able to do this.

We also have, as you look at the other vaccines that are coming through the pipeline, we have a lot of new platforms that you’re able to switch to a new vaccine construct very, very quickly, whether they’re RNA backbones or DNA backbones or virally vectored backbones, that have allowed us to do this very quickly. So we’ve invested in this for a decade or more. The other thing that happened this year, if we can all remember back to March and April, is everything else stopped.

Almost the entire biomedical research community in the United States turned to a singular focus for three months or six months meaning that people that were working on studying X, Y or Z other phenomena were now turning to Covid. And so the advance that happened because of that, because of our collective effort to address this question, I think was also one of the other forces that was moving this along quickly, helping clinical trials, helping knowledge along the way to know what we needed to look for in these clinical trials.

Akiko Iwasaki: Yeah. Just to add a little personal anecdote to what John so nicely described, I did my PhD thesis on the DNA vaccines over 25 years ago. And this was one of the first examples of nucleic acid vaccines. And at that time, there was a huge enthusiasm for using DNA as a platform for vaccines. But it takes a long time for this kind of idea to make fruition into human vaccines and it’s really decades of research that have built this knowledge and platform that allows this very speedy development of stereoscopy to vaccine. So I think it’s a reminder that we should continue to invest more in basic research and understanding of immune responses in general.

Richard Gallagher: Absolutely. You’ve both talked with pride and pleasure about vaccine development and the research progress that’s been made. I’d like to ask you about the experience of working on a problem that’s so intense and so immediate. What are the mental and the physical tolls, and what are the emotional and intellectual rewards for you? And the team of scientists that you work with, at the scientific frontier, how is it impacting the people that are doing the work essentially?

Akiko Iwasaki: Yeah, so it does take physical toll. My lab members are working 24/7 as John mentioned and it’s really a difficult work because many of our research is done in biosafety level three, which requires a lot of PPE and safety precautions. But we also feel very energized and privileged and honored to be working in this pandemic, to be able to use our current knowledge to contribute something to help understand how this virus infects us and causes disease, so that we can come up with better therapies to treat the patients and potentially prevent infection all together. I think the hard work and long hours and all these tools are countered by this emotional drive to contribute to society.

John Wherry: Yeah. I agree, Akiko. I think that the mission-oriented nature of this is helping to overcome quite a lot. But as this continues on, the emotional toll and the psychological toll for people in the lab is starting to add up. We’ve been going at this literally working seven days a week since March 18th and haven’t stopped. And we look up and kind of see all of these efforts being countered by a lot of activity that’s making it just much harder to solve the problem.

I think people are looking — people at least in my lab and that I see around our campus — are looking around wondering, how can we keep going like this if we’re not getting a little bit of help along the way? And it’s becoming increasingly difficult to maintain that very high level of morale. Partly for those reasons, we’ve all been drained by things this year emotionally. I think also the landscape of career trajectories has now changed completely. We didn’t just simply give up one job and get a new job. We got a new full-time job — in fact, more than full-time job — on top of the things that we still have to do anyway.

That’s adding up for a lot of people. And they’re wondering, how do I balance all of this? How do I continue to contribute to this really important mission that drives all of us, but yet, I also at some point need to make sure I have a career, and is this now in a new career or do I have to go back and revisit those other projects I had as a student or a postdoc or a junior faculty member? And so it’s created a little bit of — not a little bit — it’s created a lot of anxiety for a lot of people in the research community and a lot of soul searching on how our efforts are being received externally.

Richard Gallagher: Yeah, there’s obviously going to be a lot to unpack over the next few years as decisions are made about how science is funded, what’s funded and how the people that have contributed so much are respected and recognized for their contributions. For you personally, has the involvement in these projects — do you think it’s going to have some kind of impact on your future research plans? Has it changed the way you view science or the type of questions that you would like to ask for the next phase of your research programs?

Akiko Iwasaki: Yeah. This has certainly impacted the way I personally view science. Particularly for me, I had never really done a lot of human immune research before. Most of our research focused on animal models of viral infections. But now having done this in human and understanding how to do translational research, has really encouraged me and my laboratory to be able to do this in other viral diseases and potentially cancer. So it really opened up this whole new field within my lab and that’s going to continue.

John Wherry: Yeah, I agree. I think this is, I hope this has changed science in general. It certainly has changed my perspective on a couple of things. And the first, our group has always been a very, very collaborative open group. Just about everything that gets done in my lab is done by group activities. Some of our major projects have three, four, or five, maybe even more people as co-contributors to doing everything. But the extent to which we can do that as a community around the country, because of Covid, has been dramatically increased. It’s broken down barriers. It’s made it easier for us to figure out how to orient around a mission rather than individual success and that, I think, is philosophically changed the way we’ll approach some science going forward.

I think it has also opened the door to recognizing where immunology may fit in our medical practice. In other words, we need to understand what the immune response is doing, not in Covid-19 infections as a blanket statement. We need to understand what the immune response is doing in that patient sitting in that hospital room to make decisions about that patient. And that changes where immunology sits in the overall spectrum of the medical enterprise: from a research activity that supports knowledge that then influences treatments for patients (plural) to an activity that might inform how I treat that patient (singular). That’s a major sea change in how we think about immunology in academic medical center.

Richard Gallagher: I’m certainly all for putting immunology front and center. We’ve had a few questions come in that I haven’t specifically addressed, I think, and I wonder if we could do a quick-fire round here because we only have a few minutes left. Just issues that people are anxious to know about. The first one is what percentage of infected individuals will develop severe Covid? Is it limited to elderly and immunocompromised people only?

Akiko Iwasaki: It’s not true that severe Covid is limited to elderly and immunocompromised individuals. We have seen young and otherwise healthy people die from this infection. There’s a lot of heterogeneity in how a person responds to this virus infection. Of course, if you look on the average, vast majority of severe and deadly infection is occurring in older folks. And also there’s a little bit more prevalence in male with respect to severity and mortality compared to a female.

John Wherry: Yeah, and comorbidities play a major role here. And so preexisting cardiovascular disease, diabetes, obesity, kidney disease, all play a major role. And Akiko’s right. It’s not confined just to the elderly who have severe symptoms and morbidity and mortality. We are seeing young people suffering. And just remember that some of the things that aren’t captured in the statistics are these long-term consequences, where it’s a relatively mild infection — it may still need medical attention, but not ICU. And yet these people are suffering with consequences of this for months afterwards. The burden for the individual is extreme, the burden for the health care system is something we shouldn’t overlook in that too.

Richard Gallagher: Thanks. In many parts of the world, we’re experiencing resurgence of cases as the second wave seems to be higher and more intense than the first wave was. Is there an explanation for that, why there are so many cases now?

John Wherry: We’ve managed to make it 55 minutes before entering into this realm. I think the simple answer is it’s behavioral. This is pandemic fatigue, if you want to say it in an apolitical way. But I think it’s behavioral and it has to do with whether or not communities, local governments, state and even federal governments are actually willing to put the effort in place to limit the activities that are causing spread. I think we could talk about that for an hour, but my opinion is it’s that simple.

Richard Gallagher: Let me move on to a question about the virus then. Akiko, you mentioned that one cell produces up to 700 virus copies. Can you compare that with other viral infections like influenza? Is that typical that that would be the ratio?

Akiko Iwasaki: Yeah, by the way, that 700 number comes from the mouse hepatitis virus in a culture dish. So we don’t know exactly in human respiratory tract how many particles are produced by an infected cell. But yeah, the virus’s production vary between the different types of viruses. I would think it’s in the range of typical viral production. Some viruses are much faster in replicating and others are slow but can release for a long time. So it really depends on the virus type.

Richard Gallagher: Another couple of practical questions for you on the impact of humidity on transmissibility, are there any lessons that we should learn about the environment that we’re in and how to minimize the risk of exposure?

Akiko Iwasaki: Right. So what we might not realize is that most of us spend, like, 90 percent of our lives are spent indoors. When we talk about seasonality of infection, much of that transmission is happening indoors. We really need to pay attention in regulating the indoor environment for a better respiratory resistance. One of the things that I recommend to people is to make sure that you humidify your rooms, particularly your bedroom, because you’re inhaling dry air all night long and that can impair the mucociliary clearance if the air is very dry.

The other thing is obviously to consider our ventilation, making sure that you’re importing fresh air and getting rid of the virus in the room. There are many sort of building-based approaches that we could be taking to minimize the transmission. But of course, the best thing to do is to avoid crowding indoors because that’s where all the major spreading is happening.

Richard Gallagher: Great. Two more quick ones if I can squeeze them in. How common are autoantibodies to interferon?

Akiko Iwasaki: So that study that John was referring to, I think it’s about 10 percent of the very severe patients had those antibodies. And interestingly, they were mostly male patients. There may be some sex difference in the development of these types of autoantibody to interferon. But I think we need to look more globally to see how prevalent these types of antibodies are and what it does to virus replication and disease.

Richard Gallagher: And one last question — maybe for you, John. What role will therapeutics that have been developed for Covid-19 play when these promising vaccines are approved and widely available? Will the therapeutics still have a relevance?

John Wherry: Oh, absolutely. Remember that we’ve only eliminated one virus from the face of the Earth and that’s smallpox; polio, we’re very close. So even with the best vaccine, the best vaccine implementation strategies, Covid-19 is not going away. We’re going to need therapeutics, we’re going to have people who can’t get vaccinated, we’re going to have people who won’t get vaccinated. We’re going to need therapeutics.

Richard Gallagher: Great. Thanks very much. That’s all we have time for. Thank you to everyone for joining this event. I’d like to thank the Alfred P. Sloan Foundation and the Gordon and Betty Moore Foundation for their terrific support of Knowable Magazine. Obviously and of course special thanks to Akiko Iwasaki and John Wherry for this fascinating and I think quite uplifting discussion about the extraordinary race for knowledge about Covid-19.

This conversation will be posted on the Knowable website,, where it will be free to review and share. And there will be additional resources including articles that Akiko and John have written for Annual Reviews' journals will be freely available on the website.

Just to close, I’ll remind you that this is one of a series of conversations. The next one takes place on the 8th of December and will address the science of stress and resilience. And then on December the 16th, we’ll be talking about preventing the next pandemic. And the best way to keep up with everything to do with Knowable is to sign up for the weekly newsletter. That’s all from us. Please stay safe, stay well and enjoy the rest of your day. Thank you.