MedPage Today Editor-in-Chief Marty Makary, MD, MPH, of Johns Hopkins in Baltimore, discusses the mechanics of immunity against COVID-19 with Vincent Racaniello, PhD, of Columbia University in New York City.
Following is a transcript of their remarks; note that errors are possible.
Makary: Hi, I'm Marty Makary with MedPage Today. I have the privilege of being here today with Dr. Racaniello from Columbia University, a professor of virology. Vincent, great to be with you. Thanks for joining us.
Racaniello: Thank you for having me.
Makary: When you get together with other virologists, people that you respect in your field, what are you talking about? What concerns, what are you thinking about? Are you optimistic?
Racaniello: Well, it depends when in this outbreak ... you know, at the beginning we didn't know if we would have vaccines, so we're trying to understand how the virus spreads and how we could get around it. And now that we do have vaccines, the narrative is completely focused on vaccines. And then of course the variant story emerged in January, essentially. And we've been talking a lot about how the variants are going to behave in the face of vaccination. And most recently, we've brought up the T-cell story that I mentioned earlier and how this was largely ignored. And it turns out that they may end up saving us. So I would say in the last few weeks it's all about vaccination. Now, of course, we see side effects or associated effects with some vaccines, we talk a lot about that.
I must say that early in the outbreak last year, when the vaccine development was just ramping up, we talked a lot about this idea that, should they really only be focusing on spike? Shouldn't they be putting some other viral proteins on, and in retrospect it was a good decision to get vaccines out in less than a year, because otherwise it might've been more complicated. But that's partly why all the variants are arising now, because we have only the spike epitopes in there. And so it's easy for the virus to get around that. So, it's two ways, that story. So those are the things that we've talked about.
And also, I should say, we talked a long time about antivirals and whether they would play a role. And, we looked at remdesivir and how it was given so late in infection. And we said, this is not gonna work, it's too late. That's an inflammatory disease, later in infection. And it turned out remdesivir, yes, it doesn't work if you give it in the inflammatory phase. And now we actually don't have any useful antivirals, and the monoclonals can be effective, but again, you can't give them when someone's in an ICU, you have to hit them before. And we've just learned that. And these are some of the things we've talked about over the months.
Makary: Interesting. You know, I'm really interested in what you said about whether or not the spike protein was the right thing to target in the vaccines -- and it turns out it was very effective. Because I was having this conversation with one of my colleagues who does a lot of immunology research. And I asked the question -- I like to put big questions out there to have a discussion -- and the question was, do you think natural immunity or vaccinated immunity is stronger, and which one's more durable, two different domains. And I'd love your thoughts on that. But one interesting thing he said was he thought that maybe natural immunity, if you really get sick and you've got to mount a big antibody response, may be better because your body is developing antibodies and memory to all of the surface of the virus, not just the spike protein, and that may be better immune protection.
Racaniello: I think it's an interesting question and there's no one answer because every virus is slightly different. For example, the human papillomavirus, the vaccines we have make amazing immunity, better than immunity you get from natural infection, because there's so much protein in those vaccines. And you end up having great mucosal immunity, which is what you need there. On the other hand, other vaccines allow infection without disease. Of course, the polio vaccines were only tested to prevent polio, not to prevent infection. That's all we cared about.
Now for SARS-CoV-2, yes, having other proteins in the mix is a good idea. I think it depends on the severity of the disease. We did a paper 6 months ago which studied people who had died from COVID. So this was a very serious disease. And their lymph nodes had no germinal centers, which means no memory B cells to SARS-CoV-2. Even though they had antibodies, they had very low affinity antibodies.
And so the outcome of that was the idea that if you have a very serious disease, then you're not likely to have a long memory response. Now, those are people who died. So we don't know how it applies to people who have lived because they were able to take out their lymph nodes and study them. And it's not so easy to do in people who have survived. So a natural infection can have consequences. So, on the one hand, yes, you make a lot of viral proteins and those are great epitopes for mainly T cells because I think most of the antibodies that are going to block infection are going to be spike directed. But any other viral protein could in theory be a T-cell target. So you'll get more epitopes.
The counter view is that the virus may encode immune antagonists that could alter the immune response in some way that's not as good as, say, a vaccine. So it really depends. And we don't know enough yet. So I think if people are making a blanket statement that natural infection is always better, that's not always correct. It really depends on the virus.
Makary: Yeah, and it seems like we just don't have the data yet on it. If anything, it seems like the reinfection rate after natural immunity is a little higher than the infection rate after vaccinated immunity, understanding they're really two different time courses because we've had natural immunity for a year. We've had vaccinated immunity for 6 months.
Racaniello: Right.
Makary: What are your thoughts on activated T cells that confer some immunity, albeit maybe partial, even when you don't have antibodies in your circulation? Because a lot of people have gotten antibody tests, and we've sort of estimated net prevalence of natural immunity from seroprevalence studies using circulating antibodies. How much more immunity is out there than is being represented in those with circulating antibodies?
Racaniello: I think the T-cell immunity is substantial and really has been ignored. And the reason is, it's very easy to look for antibodies that block infection. You do a neutralization assay with virus in the lab and it's pretty straightforward. [You do a] T-cell assay if you want to know, do infected or vaccinated people make virus-specific T cells? It's harder. You have to synthesize first short peptides covering all the viral proteins. You have a company do that, they make thousands of peptides. And then you have to get lymphocytes from the patient, put them in culture -- they have to be alive, and then you throw the peptide...
Makary: It's not a commercial test basically, right? It's not a commercial test, it's a laboratory test.
Racaniello: It's not a commercial test, it's a laboratory test. It does vary and it takes time and it's expensive. And so that's why it's so infrequently done, and few labs do it. But the few who have, have found that, first of all, as you would expect, many viral proteins can be T-cell targets.
And as I said earlier, the variants do not have changes in T-cell epitopes because -- and this is very interesting -- when you are infected and you make a variant that evades an antibody, that variant can go to someone else and evade their antibody too. So it spreads through the population. If you happen to make a variant that evades a T cell, it's not going to make a difference in the next person because everybody's T-cell epitopes are different. And so T-cell variants of viruses generally take many, many, many years to emerge. So it's not an issue. And so I think the T-cell immunity -- the last defense against an infection, right? To kill the infected cells. That can protect a lot of people in the face of even low antibody response. There are some agammaglobulinemic people who don't make antibodies who have been infected with a virus, and they don't have an unusually severe course, because I think the T cells are actually detecting them.
Makary: I saw some research from Karolinska Institute that suggested maybe as many people [who] have activated T cells and no antibodies, as people who have antibodies. It's unclear how many of those people with activated T cells and no antibodies actually have immunity. But roughly speaking, how many more people have immunity, do you think, from those activated T cells than have circulating antibodies? Maybe roughly another 10%, 20%, 50%? Understanding it's partial.
Racaniello: I don't know, that's a number I can't come up with, unfortunately. I do think that at some point there is a tipping point, right? So influenza virus T cells are also important, yet when the virus changes into B-cell epitopes, we decided to change the vaccine. And so that suggests to me that antibodies do contribute. As a T-cell biologist told me once, I would not want to have no antibodies. Even though my T cells are great, I still want to have some antibodies. So the two work together. So I don't know the number that you're asking for though, I can't provide that.
Makary: If you don't know, I don't think anybody knows.
Racaniello: [laughter] I don't know about that.
Makary: So I'm satisfied in that I've taken it up as far the ladder as I can. In terms of antivirals, there's a promising drug, I believe it's molnupiravir. And it has been found to clear the virus in 5 days. And that was 24% better than the placebo controls in a phase II trial early readout. I heard there was going to be another readout. I didn't see it, but are you optimistic about that particular agent or its class of antivirals?
Racaniello: So this is what we would call a nucleoside analog. So it's a building block for the RNA of the virus and it inhibits the polymerase basically. And this is a great target because cells don't have such an enzyme. So it should be relatively low toxicity. I think molnupiravir is fabulous. It was shown to work really well at preventing transmission in ferrets last year, and now in the phase II [trial]. And this is exactly the drug we need because it's orally available. You just take a pill, and at your first positive test, you could take this and probably completely alter the course of not just disease, but also shedding.
But you know the crazy thing about molnupiravir? It was around 4 years ago. It was sat on a shelf. Nobody pushed it forward. It was a drug that was developed and it was known to inhibit coronaviruses. And I always say, man, if we had brought that to, say, a phase I [trial], so that in January last year we could have then gone into a phase II and III right away, this outbreak would have been completely different. Assuming we could make enough of the drug to treat everyone.
And, of course, the other hand is we're going to get resistance to that drug immediately. So one drug is not enough. Nevertheless, I am very excited about it and I just hope we have some others, cause what we've learned from HIV antiviral therapy, one drug isn't enough. Two is not enough. Three is the magic number that you need to treat people with.
Makary: Interesting, interesting. And would you say remdesivir is potentially one of those three in the cocktail or something like that?
Racaniello: My understanding is that remdesivir, even if given early, is not terribly effective. You know, it works well in the laboratory in blocking virus, but it's not very good in people, plus it's intravenously administered. So that makes it tough. As you know, we're setting up infusion centers so that people can get remdesivir and monoclonals, more particularly outside of the hospital. I don't think remdesivir is part of that mix. So far we just have molnupiravir.
Now there are a lot of other drugs in the pipeline ... molnupiravir is a drug that existed before. But there are others that are being made that are purposefully selected for SARS-CoV-2. And I think it's important to push those forward in case we need to quell outbreaks and so forth. And we need to have a few of them. If we could make them more broadly acting, [that] would be great. Make an RNA inhibitor like molnupiravir that could inhibit many coronaviruses so that when the next one comes out of bats into people, which is going to happen probably in 10, 20 years, we'll be ready to take care of that.
Makary: Do you know when the next readout of a molnupiravir trial is expected? I think they either just finished phase II or started phase III.
Racaniello: Yeah. They finished the phase II a couple of weeks ago and they said they were immediately enrolling phase III. So I suspect they're still enrolling. And you know, it depends where they're doing it because now some parts of the country have fewer cases than others. And so one hopes they're in areas where they're going to get the numbers more quickly, because if there are a lot of cases, they can get their phase III data very quickly. So I'm not expecting that certainly before the next few months.
Makary: Hopefully in time before the fall, if there's a fall threat. It is amazing, isn't it, how the pandemic is regional in the United States? It's almost as if we're looking at different countries, when we look at Arizona versus Michigan or something like that. Anything else you'd like to add?
Racaniello: I would just like to assure people that vaccination is going to take care of this pandemic. You know, there's a lot of narrative about variants and escaping vaccines. By the way, a paper just came out in Lancet showing that the U.K. variant B.1.1.1.7 is not more virulent, as people have been claiming all along. So that's good. And I think that this is going to be shown for most of the variants. I think the vaccines will handle them for now. I think we can get out of this. So please get vaccinated, continue to be safe. And I'm suspecting that in the fall, we can get back to life as usual.
