S1E21 / Are Antibodies the Holy Grail? / Kaitlyn Sadtler & Matt Memoli

I'm Dr. Celine Gounder.

And I'm Ron Klain.

And this is Epidemic. Today is Tuesday, May 19th.

I have to ask on behalf of a, I think, a concerned globe, how are you feeling, Tom Hanks?

We are just fine and dandy.

That's actor Tom Hanks on a recent episode of the NPR podcast Wait, Wait, Don't Tell Me. Hanks and his wife, actress Rita Wilson, contracted COVID in early March.

We had all of the flu-like symptoms. My wife Rita was a little worse off than me. She had a very high temperature, and we were isolated so that we would not give it to anyone else.

Right.

Hanks and Wilson made a full recovery, and ever since, they've asked the same question.

Now that you've had it, aren't you supposedly like immune? You're superheroes. You can walk amongst us and be immune, or is that just nonsense?

Well, a lot of the—

It would be nice, wouldn't it, if battling a COVID infection made you immune to reinfection? Hanks and another 1.4 million fellow Americans would indeed be modern superheroes.

In recent weeks, thousands of people have taken antibody tests. If the tests detect COVID antibodies in their bloodstream, they can accurately say they had COVID and they beat it, even if they never had symptoms. But can they say they're now immune? Not quite.

When it comes to an infection, we don't know exactly what our immunity is from this infection yet because just because you have an antibody doesn't necessarily mean you're immune.

This is Caitlin Sattler. She's an investigator at the National Institutes of Health.

Mainly, we just need to learn a little bit more on the research side before saying that somebody that has tested positive is considered immune. We need to figure out how much antibody you need and how long that immunity might last.

In this episode, we'll look at how our bodies fight off infections. We'll ask, how do we build immunity to future infections, and how are scientists determining how long that immunity lasts? We'll look at how they're studying COVID antibodies and how their work will bring us closer to returning to normal, whatever that normal might look like.

Popular belief holds that once your body has beaten a particular virus, you become immune to it. Well, that's not exactly true, and we'll explain why. But first, I think we need to understand how the immune system responds to an infection, regardless of what that infection is.

So there's a lot of parts to our immune system, and I'll just speak generally on how our immune system responds to viruses themselves. The innate immune system is the early-acting part of our immune system, and those guys start off the response. They're the first responders, and they also help communicate with the adaptive immune system to say, hey, "Hey, this is what's here. Tell us how to respond to this and we'll tell you what's going on." And that adaptive immune system is things that kind of learn and adapt to the type of pathogen that invades.

You've probably heard by now about antibody tests from friends or on the news or on the internet. Well, those antibodies are an important part of our immune response.

And those antibodies that are produced are from the adaptive immune system.

So why are we so focused on antibodies then? You know, how do we know that's actually what protects us against coronavirus infection, or at least against severe disease perhaps? How do we know that that's the key part in this?

Antibodies themselves are very important in controlling viral infection and preventing viral spread. So what the antibodies do is that they tag these kind of foreign invaders for destruction. They can be very specific for the specific type of pathogen, and we know that these antibodies can help prevent the infection from being as severe as it would be without them.

So basically, when the body goes to war with a foreign invader, the immunity generates one type of soldier that figures out how to beat that invader. Those soldiers are called antibodies, and just like soldiers, antibodies are specialized.

So each organism, in this case the SARS-CoV-2 virus, has different antigens, which are proteins or parts of the virus. And then you can have different types of antibodies to each one of those antigens. So in the case of SARS-CoV-2, the primary one that most people think about generally is the spike protein.

This is Matt Mamoli. He's the director of the Lab of Infectious Diseases Clinical Studies Unit at the NIH, where he usually focuses on developing vaccines for influenza influenza. Now, along with the rest of the world, he's shifted his focus to SARS-CoV-2.

But there's also the nucleocapsid protein, which is another antigen. And then you can also look for antibodies specific to the receptor binding domain of the spike protein, so a smaller part of the spike protein, which is also known as the RBD. And so you can look for antibody against that. So in this case, there's 3 different antibodies already that people have developed tests to look for.

So even with the same virus, you have to select appropriate antibodies to study?

Sure, so it's even more complicated than that.

Really?

There's IgM, IgG, and IgA.

These are different antibodies created at each stage of the immune response.

IgM is the antibody that you first see after an infection. So early on, in the case of the SARS-CoV-2, it's looking like maybe around Day 5 to 7, in that ballpark, you're developing this IgM response. And then as time goes on, as you further get into the infection and then the post-infection period, maybe at 2 weeks out to a month, now you're developing IgG. IgG is typically what you would maintain sort of more long-term. IgM is usually more short-term.

Okay, so if we stick with the military metaphor, IgM is the first wave. It's the body's first attack on the virus. After this first wave, the body brings in reinforcements. Charge! Charge! Charge!

Charge!

Charge!

These are the IgG antibodies that Matt was talking about. These guys hunker down for a sustained fight, like troops in a trench.

And then you also have IgA, which is typically associated with what we call a mucosal response, which means In the areas of your body that are exposed to the outside, like your nasal passages, your lungs, stomach, these kinds of areas, you would secrete this IgA. You have your mucosal IgA, you have your systemic IgM and IgG, and they all pop up at different times and in different amounts. Beyond that, it can even vary per person. Some people may have better IgA responses, some people may have better IgG or IgM.

The antibodies keep firing until they defeat the infection. And then they do something even more important, perhaps. They remember how they did it. The antibodies remember what it took to win the fight.

Wait, uh, did you write that down? Because I didn't write that down.

Someone should write that down.

That memory creates immunity, and it's the reason so many have been looking to antibodies as the holy grail for ending the pandemic.

At the beginning of this episode, we promised to explain why that isn't necessarily true, because here's the catch: the length of that memory varies with every new virus, a foreign pathogen. Sometimes that memory lasts for hours, sometimes it lasts forever, sometimes somewhere in between. Until researchers can really study a new virus like the COVID coronavirus, they don't know if the presence of antibodies actually indicates long-term immunity to that virus.

In the case of some diseases, antibodies never give you immunity, even in the short term. Here are some examples. If you have HIV or herpes or hepatitis C, your body produces antibodies, but that doesn't mean you're immune. It just means your body knows you've been infected. And so far, there just hasn't been enough time to study COVID antibodies how long they last, and how effective they are in protecting us.

What we do know is really based on other coronaviruses, the cold-inducing coronaviruses. If you look historically, there were some challenges done with those viruses, meaning they took healthy people and they gave them those cold-inducing viruses, and in some cases they gave it to them and then they waited a period of time and then they infected them again with them, and they found that people did maintain antibodies and that it did help them in reducing disease the second time around. So the first time they had symptoms, the second time they still had an infection, but they had no symptoms. So that's promising because that tells us that with other coronaviruses, people have been protected by having antibody. But ultimately, we still don't know for SARS-CoV-2, you know, what kind of antibody responses would be protective.

And that brings us to Matt and Caitlin's current research.

This research study will let us know the extent of the spread of the coronavirus infection in the United States. This will help us with several things, one of which is understanding or beginning to understand whether or not some of these antibodies are able to confer immunity.

So Caitlin, if you could explain, you know, how do you even go about conducting such a study?

What we want is to be able to recruit 10,000 people that properly, as best we can, represent the population in the United States.

We are looking for individuals, in this case focusing on people who have not been diagnosed with the disease, because we already know those people have had it, and looking for antibodies against the disease that would tell us that, hey, there are people that never had symptoms, they never went to the doctor, and they never were diagnosed, or maybe they did have symptoms but were never diagnosed, so that we can get a better idea of how many people actually have been exposed or infected compared to what we know about.

This part is so important because right now no one knows exactly how many people have been infected with COVID Last week, the CDC posted a data set that supposedly shows how many people have been tested in each state. If the numbers are accurate, Nearly 11 million people have been tested, and 1.4 million tests were positive. But states are reporting different numbers of tests than what the CDC is reporting, so it's tough to really know anything about prevalence.

And those are just the people who've been tested. How many of us have family members or friends who experience the symptoms but didn't get tested because testing was so limited for so long?

Right. These antibody tests will start to offer a more complete picture, but only when they produce accurate results.

You want to have a test that is going to pick up as many people as possible that have antibody against the virus that you're looking for. But then you also don't want to pick up people who have antibodies that do what we call cross-react, which means they cause a positive signal on your test, even though they're not specifically from the organism or the virus in this case that you're looking for. So for example, with this, we've all been infected with coronaviruses before. A lot of people don't realize this, but there are other cold-inducing coronaviruses that give us the common cold that we've all had in our lives. And some of those coronaviruses can give you antibodies that would give a positive test on some SARS-CoV-2 COVID-19 tests. And so you want to test where that's not happening, or at least you're minimizing how much that's happening. So that you're not picking up people that have had a cold. You're picking up people that have actually had the SARS-CoV-2 virus.

Researchers like Matt and Caitlin have to be careful in designing the test, what we in the science community call assays, tests that only pick up COVID, not other coronaviruses.

The most important thing is making sure that your assay is not going to react with other coronaviruses. And as soon as you've got that validated assay and you've got the good statistics, we can start moving forward and analyzing the samples.

To what degree are you characterizing? Because there's different kinds of antibodies, right? You have antibodies to different antigens. You have IgM, IgG, IgA. How are you sort of trying to tease apart a lot of those details?

That's a great question. We're looking at two pieces of the coronavirus, two different antigens, and these are the spike protein and then RBD, which is within the spike protein. We are looking at both IgG and IgM, and we are currently testing and evaluating IgA as well.

We chose to focus on IgG and IgM because they are the primary systemic antibodies that we expect to see and that most people have seen in the blood with this and other respiratory viruses.

Looking at what they've seen in similar viruses can help inform the decisions, but unfortunately, Historical data doesn't offer much else. Understanding a specific virus takes time, as Matt knows all too well from his research on influenza.

For example, in the case of flu, we're tru— still trying to understand all of this, uh, even after studying flu for 100 years. It's a challenging thing to fully understand because you have so many different antibodies that you could be looking for and dealing with and thinking about. Now, for this new virus, this SARS-CoV-2, It's a little trickier because I think that mucosal immunity is very important, but we are seeing, especially with severely ill people, we are seeing viremia with this disease. So this virus does seem to get into the bloodstream, and we're seeing some systemic effects, a lot of which are unclear at this time. We've heard reports about issues with the kidney. We've heard reports about thrombosis. We're hearing reports now about inflammatory responses in children. There's a lot of different things that are being reported that are more systemic in nature than what you would typically see in influenza. We see some systemic things, but not like this. We may be in a situation here where mucosal immunity may be important because you're getting it through the respiratory mucosa, we believe, but then once you do have that initial infection, it may also be important that you have significant systemic immunity to protect you from these systemic effects, the viremia and the other effects on your body. And so it's unclear right now really what is going to be most important with this disease.

As with everything COVID-related, no one really knows. We're learning as we go. When samples test positive for the presence of IgG or IgM antibodies against the spike protein or RBD, they're cross-tested.

Each positive then gets further tested to look for cross-reactivity. So we test it to see if the antibodies bind to other coronaviruses, and then we do a further testing against other antigens for this SARS-CoV-2 to confirm that it truly is an antibody against the SARS-CoV-2. And so by using large numbers of samples, both positive and negative, and running them through these various assays and testing them very carefully, She's developed this algorithm that will give us a high sensitivity and specificity to help us to make sure that what we're getting is correct.

So what we understand is, A, what do we actually know about the extent of the spread of this virus? And then pairing it with other analyses, starting to understand that idea of immunity.

Caitlin and Matt are among dozens of research teams attempting to understand this idea of immunity. Last week, a biopharmaceutical group in California announced that it has identified an antibody that has a 100% success rate when attempting to block COVID's spike protein from binding to other cells in the body. These are what we call neutralizing antibodies.

If their results are accurate, it's a major breakthrough, but until the results can be replicated, no one can say with certainty that this is the key to immunity. In the meantime, people are flocking to doctors' offices and labs to have their blood tested for antibodies. There are now more than 120 antibody tests available, but they're not necessarily trustworthy. The American Medical Association recently warned that most of the tests have not been granted emergency use authorization by the FDA, never mind final permanent FDA approval. So these tests could be returning false positives. And even when they do return accurate test results, they still don't tell us that it's safe for someone to be around others with coronavirus.

These what we call lateral flow cartridges, those rely on the same general principle, which is an antibody binding to what we call an antigen, which is the protein. However, in the lab, what we can do is run a lot more backups and a lot more controls. And we can look at multiple antigens in multiple different ways. And again, with the cross-reactivity as well, we can evaluate whether or not these antibodies are reacting to other coronaviruses. So most tests out there of these lateral flow cartridges don't have all of those capabilities.

I completely understand why everyone wants to use these tests to get us all out of our homes and back to work and get the economy moving and just get everybody's life back on track. I completely understand it. But we certainly do not know enough about what we call the correlates of protection to know for sure that any test, even a perfect antibody test, would tell us that, you know, you're safe.

So is there any value then in getting one of these antibody tests?

At the moment, The best way to assess your risk is still based on who you are, your age, your health, your other risk factors that are really being defined by all the cases that we've seen around the world. That really, to me, is still the best way to assess risk for people. A test really isn't going to help us on the individual level.

But also, let's not count them out entirely because they can tell us something about immunity.

Now, getting aggregate data from the tests, meaning finding out how many people in different parts of the country, in different industries, in different settings, with different risk factors, you know, different races, different age groups, everything you can think of, finding out how many people have antibody gives us a lot of information to work with. It helps us to understand how widespread the disease has been, how far its reach has been, It'll give us an idea of what effect the social distancing has been having in terms of reducing spread of the disease. And it will also help us as we do open things up.

You could look at the rates of infection in different states and the kinds of antibodies that are popping up. If one state has a spike in the number of COVID cases after reopening its economy and another one doesn't, you could look to see which antibodies are present in the state with fewer cases. —that might be a clue for which antibodies are most effective in fighting off the disease and which we should be testing for.

But if we see both states seeing a resurgence in disease that's similar, then that gives us an indication, gee, the antibodies we're testing for may not be a correlate or an indicator of protection, and we need to investigate that further. To me, the biggest use for these antibody test right now is research. It's trying to understand the disease, understand the immunity, learning what the correlates of protection are so that we can inform better vaccine development, design, endpoints, and so forth, so that we can deal not only with this problem, but also deal with any future coronaviruses that we may have to deal with.

Ultimately, from the scientific perspective, we're very interested in learning more about immunity and more about exactly how long the immunity might last, what level of antibodies we might need to be to be immune, and those sorts of things before we'd be necessarily comfortable calling somebody that had tested positive quote unquote immune to the disease.

And so in answer to the question that everyone's been asking Tom Hanks and everyone else who's beaten COVID: Now that you've had it, aren't you supposedly like immune?

You're superheroes? You can walk amongst us and be immune, or is that just nonsense?

Well, we just don't know for now.

That hasn't stopped officials in the U.S., the U.K., Italy, and Germany from floating the idea of special immunity passports for people who've already survived the virus. These passports would grant them permission to travel, dine out, go back to work, basically enjoy a return to normal life.

In the meantime, if you think you've had the virus, the best thing you can do is to join studies, legitimate studies, to help researchers better understand immunity to COVID. And if you do, you will be in good company.

Well, a lot of the question is, is what now? You know, what do we do now? Is there something we can do? And in fact, we just found out that we do carry the antibodies.

Antibodies that might bring us one step closer to understanding immunity and beginning to develop a vaccine to COVID.

We've not only been approached, we have said, uh, do you want our blood? Can we give plasma? And in fact, we will be giving it now to the places that hope to work on what I would like to call the Hank scene.

Yeah, there could be no better ending to this international catastrophe than if the cure turns out to be the blood of Tom Hanks. Would that not be—

We'll discuss other elements of the immune response and other uses for those donated antibody samples and the big one, vaccines, in the coming weeks.

Next Tuesday, you'll hear more about the immune response to COVID. It's about a whole lot more than antibodies. That's next week on Epidemic. 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 Elliott, and me. Our music is by The Blue Dot Sessions. Our interns are Sonia Baradwa, Annabel Chen, Isabel Ricci, Claire Halverson, and Julie Levy. If you enjoy the show, please tell a friend about it today. And if you haven't already done —leave us a review on Apple Podcasts. It helps more people find out about the show. You can learn more about this podcast, how to engage with us on social media, and how to support the podcast at epidemic.fm. That's epidemic.fm. Just Human Productions is a 501(c)(3) nonprofit organization, so your donations to support our podcasts are tax deductible. Go to epidemic.fm. Fm to make a donation. We release Epidemic twice a week on Tuesdays and Fridays, but producing a podcast costs money. We've got to pay our staff, so please make a donation to help us keep this going. 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. I'm Dr. Celine Gounder. And I'm Ron Klain. Thanks for listening to Epidemic.