S1E23: Our Immune System versus the Virus / Stanley Perlman & Jon Yewdell

“Antibodies are the easiest part of the immune system to measure. It’s not the only part that’s required for protection against this virus.” – Stanley Perlman

In today’s episode, co-hosts Dr. Celine Gounder and Ron Klain continue their discussion of the immune system. They speak with Stanley Perlman and Dr. Jon Yewdell about what happens when a virus enters the body and the different types of cells involved in each stage of the immune response against the virus. They talk about what is known so far about how the immune system reacts to a COVID infection and the degree of immunity that results post-infection. They also discuss how understanding the immune response is an important factor in developing an effective vaccine for COVID and putting an end to the current pandemic.

Stanley Perlman is a professor of microbiology, immunology and pediatric infectious diseases at the University of Iowa. Dr. Jon Yewdell is a researcher at the National Institutes of Allergy and Infectious Diseases, where he studies viruses, immunity to viruses, and the cell biology of viral infections.

This podcast was created by Just Human Productions. We’re powered and distributed by Simplecast. We’re supported, in part, by listeners like you.

eline Gounder: I’m Dr. Celine Gounder.

Ron Klain: And I’m Ron Klain.

Celine Gounder: And this is “Epidemic.” Today is Tuesday, May 26th.

Ron Klain: Celine, we saw recently, as states began to reopen, a lot of people cavalier about gathering together in large groups, including a massive pool party at Lake of the Ozarks that was all over social media last weekend. That one, and others, were not small get-togethers.

Celine Gounder: People may believe that even if they get COVID at one of these gatherings, they’ll get sick, get over it, and be immune, but it may not work out that way.

Ron Klain: Here’s Stanley Perlman, a professor of microbiology, immunology and pediatric infectious diseases at the University of Iowa.

Stanley Perlman:If the system is working well, what we know is that people will develop an antibody response, and the antibody response will, we hope, be protective. And most of the time it is, but sometimes it’s not. And that’s what we need to investigate with this infection. If you get an antibody response, is it really protective?

Ron Klain: And even if an antibody response is protective, is that enough?

Celine Gounder: Not necessarily.

Stanley Perlman: Antibodies are the easiest part of the immune system to measure. It’s not the only part that’s required for protection against this virus.

Celine Gounder: So what else is required? That’s what researchers are racing to find out, and today two veteran scientists join us to explain what they’re seeing in their initial investigations of SARS-CoV-2. We’ll explore what happens when a virus enters the body, how the immune system reacts, and how a deeper understanding of this response is the first step towards developing a vaccine, and what everyone’s dreaming about, an end to this pandemic.

Jon Yewdell:So a virus gets into your body. Basically, the first thing that happens is a virus gets inside of a cell, and it starts to replicate.

Celine Gounder: This is Dr. Jon Yewdell. He’s been with the National Institutes of Allergy and Infectious Diseases for more than thirty years, researching viruses, immunity to viruses, and the cell biology of viral infections.

Jon Yewdell: Viruses can replicate in, something like, eight to twelve hours. Each cell can release probably ten thousand to a hundred thousand babies, progeny virions. So these are going to go on to infect other cells, and the cell has many, many different mechanisms of sensing the presence of the virus, and when it does, there are various responses that are kicked off.

And what happens first is something called the innate immune response. Cells make this protein called interferon. Interferon tells the body that a virus is present and that something has to be done about it.

Ron Klain: Think of a fire. At the first sign of smoke, the body sounds an alarm.

Celine Gounder: Now the immune system kicks into another gear. It’s called the cytokine response.

Jon Yewdell: Once the cytokines start to get made, the environment of the infection changes and all sorts of cells are recruited.

Celine Gounder: Now it’s a five-alarm fire, with the cytokines recruiting backup.

Jon Yewdell: One of the early changes is that the normal mechanisms for keeping blood cells inside the blood vessels is relaxed, and blood cells can come out into the organ, and there are very abundant cells in your blood called neutrophils. Once neutrophils come out, other cells called monocytes, which then turn into macrophages, come out.

Ron Klain: These neutrophils and monocytes join the battle.

Jon Yewdell: Neutrophils are very good at making toxic substances that can kill viruses directly. Monocytes are very good at eating viruses when they become macrophages.

Celine Gounder: And in turn, they create even more cytokines, which call for more support. Sometimes, the virus has already advanced. And that’s where another blood cell becomes critical.

Jon Yewdell: Natural killer cells.

Ron Klain: Natural killer cells, or NK cells, are the innate immune system’s specialty force, like the ladder truck.

Jon Yewdell: NK cells have the ability to sense whether a cell is infected with a virus, and then actually killing that cell.

Celine Gounder: It’s a powerful process, sometimes, too powerful. The same way a firefighter’s water hose might destroy some furniture to save a burning house, the cytokines might destroy healthy cells in their effort to save the body.

Jon Yewdell: If you have the wrong amount of cytokines or the wrong cytokines, it can unleash the powers of the immune system to do damage to the tissues that’s well in excess of what is needed. They’ve gone from being useful to being harmful.

Celine Gounder: Macrophages can do damage, too.

Stanley Perlman:So macrophages are these big cells that go around and eat damaged cells and eat up bacteria, and basically clean up after an infection has been there or any other process where you have destruction of tissues in the body. So you want your macrophages to be working well to eliminate viruses and other bits of the infection, but you don’t want them to be working so well that they start going on a rampage and destroying tissue that’s not infected or causing other kinds of damage.

Celine Gounder: This is when the body might accidentally damage itself, and when the fire is often extinguished for good.

Jon Yewdell: So these things are all happening in the first few days of the immune response, in what’s known as this innate immune response, and this is playing a critical, critical role in every viral infection. And there are probably many viral infections where you don’t even know you’re infected because the innate immune system has taken care of it, so the other part of the immune system doesn’t even have to kick it.

Ron Klain: That’s a best-case scenario. But as we’ve seen with coronavirus, and HIV, and hepatitis, and the flu, the innate immune system often needs that “other part” of the immune system.

Jon Yewdell: So that’s the adaptive immune response.

Celine Gounder: And if the body is going to build natural immunity to an infection, this is when it happens.

Jon Yewdell:So that’s the part that I’ve spent most of my life studying as a viral immunologist, and that starts immediately. You have two kinds of cells there. One is called a B-cell, and the other is called a T-cell. And both those cells are moving around the body in such a way that they’re looking, looking, looking for viral infections.

Celine Gounder: The B- and T-cells are the search party, attempting to root out the infection, wherever it’s hiding.

Jon Yewdell: They’re actually traveling between the blood and the lymph nodes.

Celine Gounder: The lymph system moves fluid throughout your body, among other important tasks. We’re going to keep the explanation simple here, and only discuss how it relates to viral infections.

Jon Yewdell: And the lymph nodes are very, very carefully designed organs to optimize the presentation of antigens.

Ron Klain: Antigens are proteins within the virus. They are what the immune system reacts to.

Celine Gounder: The lymph nodes are the battlefield where the immune system and virus duke it out.

Ron Klain: But this isn’t exactly neutral territory.

Jon Yewdell: The immune system and its wisdom has a special cell called a dendritic cell.

Ron Klain: A secret spy.

Jon Yewdell: So the dendritic cell picks up the virus. It does something to the proteins that we call antigen processing, and it can present these, this processed form of the virus to the T-cells and to the B-cells.

Celine Gounder: By the time the B- and T-cells encounter the virus, they know how to beat it, and they’ve developed special forces to do exactly that.

Stanley Perlman: So antibodies are really good at preventing viruses from getting to cells. But once a cell is infected, one really needs a T-cell response to destroy that cell so the virus can’t be released to infect other cells.

Ron Klain: We need millions of antibodies and T-cells to win a battle against a virus, especially one as strong as COVID.

Celine Gounder: And that’s where the body has another trick.

Jon Yewdell: These cells have the remarkable ability, once they have bound antigen, to divide faster than any known cell in your body. A B-cell or T-cell, they can divide every four hours. So you can do the math, you can go through six divisions every 24 hours. Six divisions is going to be something like 60 times more cells, and this is going to take five days.

Ron Klain: And as the B-cells and T-cells multiply, they also get better and better at fighting the enemy.

Jon Yewdell: One of the key elements of the antibody response is an absolute remarkable ability of the antibodies to evolve in real-time. So as the response is going on, the antibodies are actually changing. They’re getting better at seeing the antigens. And that happens because of a collaboration between some of the T-cells and the B-cells.

Celine Gounder: And they work fast.

Jon Yewdell: The T-cells are going to start to work on day five. Sometimes in experimental infections, they’re basically done their job by day eight. That’s how good they are.

Celine Gounder: Done, for now, but their role is far from over.

Jon Yewdell: For most viral infections, the T-cells you’ll be able to detect, three or four weeks. The antibodies will persist for a long time. You’ll be able to detect antibodies for at least a year.

Celine Gounder: And even then, the immune system is still working.

Jon Yewdell: Something else happens. The antibody-forming cells, the B-cells and the T-cells, they make something known as a memory cell. And this will last your whole life. And the memory cells are like the other cells, but they’re ready to go. And if they’re a B-cell, they already have the right kind of antibody ‘cause they’ve gone through this other selection process. And the T-cells can divide more quickly, and there’s also more of them, and they’re also in the right place. And they’re ready to spring into action immediately. This is a critical part of the immune response is this memory function.

Ron Klain: It’s that memory function that often dictates what will happen if a person encounters the same virus again.

Jon Yewdell: What we know is that, in most cases, antibodies play a critical role in, either preventing infection completely or reducing the intensity of infection.  And this memory response is one of the reasons why, the second time you’re infected with a virus, if you’re not completely protected by the antibodies from infection, you will have a much more rapid recovery and a much more mild disease typically.

Ron Klain: But does this happen with COVID?

Celine Gounder: We’re not sure yet. Two studies led by a specialist at Boston’s Beth Israel Deaconess have determined that antibodies to COVID indeed do confer immunity. But that’s based on results in laboratory monkeys. While humans and these rhesus macaque monkeys share 93 percent of the same genetic makeup, monkeys are not humans. Human trials will be the only way to definitely confirm immunity. Even if it is confirmed, it doesn’t give survivors a free pass to return to normal life.

Stanley Perlman:We need to make sure that even if they have a good antibody response, that they can no longer transmit the virus to people who are susceptible. I suspect these people will be much less likely to be contagious, but this is speculation because we have to find this out.

Ron Klain: Okay, but once their body completely sheds the virus, they can go back to normal life, free from fear of passing it on, can’t they?

Celine Gounder: Not necessarily.

Stanley Perlman:The cold coronaviruses, the immunity is waned, so that a year after you’ve been infected with one of them, you can be reinfected again.

Celine Gounder: In most cases, that reinfection isn’t nearly as bad.

Stanley Perlman: From what I know about seasonal coronaviruses, it’s very likely they will not have symptoms or signs of disease. The most they’ll get is a cold, and depending on the level of antibody, you might have a more severe or less severe cold.

Celine Gounder: But it would still be contagious. And that puts other people at risk, especially if these other people never had the virus, or a vaccine, in the first place. And that next person could have a much more severe infection.

Ron Klain: We’ve all been hearing a lot about herd immunity. The idea that once a certain percentage of the population has had an immune response to the virus, either through a natural infection or a vaccine, that the overall population is safe, because most people will be immune, and that immunity will stunt the virus’s ability to spread.

Jon Yewdell: It’s almost never that simple. People want simple answers, but life isn’t like that. You know, science isn’t simple, biology is certainly not simple, and we’re doing a lot of guessing based on our other imperfect knowledge from other respiratory viruses.

Celine Gounder: And here again, we need to consider the degree of immunity.

Jon Yewdell: The kind of normal calculations that are made for herd immunity, they don’t really apply here because what we know from the other coronaviruses is that people are infected an average of once a year or less with coronaviruses, and there’s only four of them. Sometimes only two of them are circulating. Basically, you can be reinfected with the same coronavirus in a very short time period, which means that, in this case, you could be kind of partially immune.

Ron Klain: But not completely immune. Which means…

Jon Yewdell:There may not be any such thing as herd immunity with this virus, in the sense that people won’t eventually get infected.

Ron Klain: So those Memorial Day weekend parties…

Stanley Perlman:If I had a comorbidity, or I had a patient who was older and had a comorbidity, I would be very nervous about doing that. And that’s the group you really care about. Most young people are going to do well with the infection. They’re not going to get that sick. Of course, there’s exceptions. That’s why it’s so important that young people not be cavalier about this disease.

Celine Gounder: So what will it take to end the pandemic?

Jon Yewdell:The bottom line is, how immune are you? We don’t need perfect immunity to win the battle against SARS-CoV-2. What we need to do is make a good enough immune response so that, instead of getting a life-threatening pulmonary infection condition, everybody gets a common cold, which is what the circulating coronaviruses do. There are four coronaviruses that are very common in human populations and with rare, rare exceptions, it’s a very mild illness that’s basically a cold.

Well, that’s the goal, I think here, of the vaccination as well. It’s not necessarily to prevent infection, it’s turning coronavirus into a common cold, SARS-CoV-2. And then also having people that can no longer transmit the virus. That’s going to be a crucial part of immunity.

Ron Klain: The only way to build a better understanding is, of course, to study the virus.

Jon Yewdell: It’s not like the world isn’t paying attention to this. I think there’s already been, I don’t know, seven or eight thousand papers that have been submitted on this virus in this very short period of time. And, uh, many, many labs around the world are working on this full time.  And so it may seem slow to the listener about the progress we’re making, but actually, no one’s ever seen anything like this, in terms of how quickly we’re getting information and how quickly we’re responding to this.

Ron Klain: And as reliable results come in, the focus is turning to vaccines.

Celine Gounder: As we start to think about vaccines, how do you decide what part of the immune system is really important here?

Jon Yewdell:Yeah, excellent question. So some of it’s pragmatic. What can you measure? It’s much, much easier to measure antibodies. So that’s the first thing you measure, in terms of immunity. And, but the thing is that the various elements of the immune system, they’re not completely independent. So if you make a good antibody response, you’ve made a reasonably good helper T-cell response.

Ron Klain: And here, it gets challenging.

Jon Yewdell: T-cell responses are much harder to measure because of the nature of the T-cell themselves. Each individual basically makes a different response to a different part of the virus based on what they’ve inherited from their parents. So they’re harder to measure.

Celine Gounder: We’ve been hearing about antibodies and antibody tests for weeks. We don’t hear nearly as much, if anything, about the T-cell response and what the presence of T-cells might tell us about immunity. This is in part because of that challenge of measuring them.

Stanley Perlman:Well, the good news is you can still do it from the blood, but the bad news is you have to have much more sophisticated testing and much more careful preparation of the cells. With antibody testing, it’s really a protein, so it’s much easier to get from the blood. With T-cell testing, you need to be able to isolate a cell that’s still alive. So that requires careful painting the cells, careful processing of it. And then you have to have a laboratory that can deal with handling very low levels of T-cell responses, especially after a few weeks, the T-cell response is very low in the blood, effective but low.

Celine Gounder: Ideally, a lab will determine the role and value of T-cells, and develop a vaccine that stimulates the right T-cells and right antibody response.

Stanley Perlman: We think that the T-cell response is very important for coronavirus infections. And we know from other coronavirus infections that sometimes the T-cell response is more long lasting than the antibody response.

Celine Gounder: As Stanley’s team works to design an effective vaccine, this is an important detail.

Stanley Perlman:Having a good T-cell response may give more protection than just an antibody response, so you have to have the kind of vaccine be something that’ll stimulate T-cells at a high enough level to help protection, both in developing new antibodies and in killing infected cells.

Ron Klain: We’re going to be discussing vaccines next week, taking a look at what vaccines are under development, how researchers are approaching this work, and what the path ahead looks like for getting a vaccine widely available.

Celine Gounder: “Epidemic” is brought to you by Just Human Productions. We’re funded in part by listeners like you. We’re powered and distributed by Simplecast.

Today’s episode was produced by Zach Dyer, Danielle Elliot and me. Our music is by the Blue Dot Sessions. Our interns are Sonya Bharadwa, Annabel Chen, Isabel Ricke, Claire Halverson, and Julie Levey.

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And check out our sister podcast “American Diagnosis.” You can find it wherever you listen to podcasts or at americandiagnosis.fm. On “American Diagnosis,” we cover some of the biggest public health challenges affecting the nation today. In Season 1, we covered youth and mental health; in season 2, the opioid overdose crisis; and in season 3, gun violence in America.

Celine Gounder: I’m Dr. Celine Gounder.

Ron Klain: And I’m Ron Klain.

Celine Gounder: Thanks for listening to “Epidemic.”