• Published on Aug 31, 2020

Video Transcript

[MUSIC PLAYING] JOHN WHYTE: You're watching Coronavirus in Context. I'm Dr. John Whyte, chief medical officer at WebMD. What's the role of antibodies against coronavirus infection? It's one of the biggest questions that we've had over the past six months.

To provide some insight, I've asked Dr. Alexander Greninger, a virologist from the University of Washington, to join me. Dr. Greninger, thanks for taking time to speak today.

ALEXANDER GRENINGER: Thanks for-- thanks for having me. It's great to be here.

JOHN WHYTE: Now there was a very interesting study from a fishing vessel that leads us to believe that perhaps antibodies can provide protection against COVID infection. Can you tell us about this study?

ALEXANDER GRENINGER: Sure. So, uh, we're the Clinical Virology Lab at the University of Washington Medical Center. We've done about 600,000, 620,000 tests so far for PCR tests for COVID as well as about 50,000 serology tests.

JOHN WHYTE: Wow.

ALEXANDER GRENINGER: Serology doesn't have much of a penetration, uh, compared to the PCR tests. People are much more interested in ac-- testing for active infection.

Um, and so we do a lot of testing for different groups, um, and we were doing testing for the fisheries, uh, trying to prevent outbreaks on boats. Uh, and on a couple of the-- the-- the fishery boats, there-- there were outbreaks. In this one in particular, there was, uh, an outbreak that affected 85% of the individuals on board. Then with that high attack rate-- this was in May. And with that higher attack rate, that allows you to get statistical significance with not a lot of people if you're looking at protection.

And since we had blood from individuals before they got on the boat and we had follow up over, you know, 30 days after they got off the boat, we were able to look at correlates of protection before they got on the boat.

And, um, sure enough we saw that the three individuals who had neutralizing antibodies-- now we don't necessarily know they had prior infection, but presumably they had prior infection-- that neutralizing antibody titers that weren't super high, they did not get infected on the boat. And they are the only three people who had those-- uh, those antibodies, based on our algorithm.

JOHN WHYTE: What does this tell us about the presence of antibodies and infection? This has been one of the biggest debates for the past six months.

ALEXANDER GRENINGER: Well, it says that they're a correlative of protection, which means that they are a correlative. So you're not actually proving that the antibodies are-- are-- doing-- are doing the work. But, uh, you know, basically from sort of analogy, we sort of use different, uh, levels of evidence and causality here based um, uh, on [? some ?] analogy as well as our prior experience, we think that antibodies are going to have a role here.

And here we show that they were statistically, uh, significant and associated with protection from the virus. So, yeah, I think that, based on the overall evidence, I'd be pretty comfortable saying the antibodies are definitely associated and probably protective. And then the next questions become, like, how long, right? How long [INAUDIBLE]?

JOHN WHYTE: We don't know that yet, do we?

ALEXANDER GRENINGER: Yeah. That takes time--

JOHN WHYTE: Yeah.

ALEXANDER GRENINGER: --right? So--

JOHN WHYTE: What's your best guess as a virologist?

ALEXANDER GRENINGER: Woo. That's a tough one, I mean, right? So people-- so it's going-- the-- the-- the hedge, right, is it depends. Um, and the reason it depends is because we see, you know, somewhere between a 50- to 100-fold difference in the titers in-- of antibodies that people generate after infection. Uh, so you see that big diversity of response. And so if you're going to see some declining titers over time, you would expect it really depends on how high you started, and so it's going depend on different individuals.

So, you know, we're starting to see-- we've seen some reports out of Europe and Hong Kong and I think we've seen a few cases too, uh, potentially of reinfection. Those are individuals probably infected, you know, at least, uh--

JOHN WHYTE: Well, I want to ask you about that--

ALEXANDER GRENINGER: Yeah.

JOHN WHYTE: --reinfection. Those were people with moderate disease, right? In your study that you looked at, these were people with low to moderate titers, that measurement for-- for--

ALEXANDER GRENINGER: Yeah.

JOHN WHYTE: --people in terms of how many antibodies, yet they still were protected. So what-- what are you thinking about reinfection? Do you think it's-- it's possible? And I'm still going to push back on you in terms of how long you think--

ALEXANDER GRENINGER: Oh, of course.

JOHN WHYTE: --antibodies may provide protection for [? us. ?]

ALEXANDER GRENINGER: So I think, you know, if I had to throw a number on it, I'd say probably about six months you should be able to get, um, out of protection. And then, you know, basically the coronavirus is, especially for significant infections where you drive those titers quite high, uh, you're looking-- you would be looking at year-- a couple years. Um, and so--

JOHN WHYTE: So more antibodies probably means more protection, for those folks that--

ALEXANDER GRENINGER: I-- I think I'm--

JOHN WHYTE: [INAUDIBLE] virology.

ALEXANDER GRENINGER: Yeah, that's what we'd see from other viruses, that titer matters. And so the higher titer you start, then the longer you're going to be protected.

JOHN WHYTE: Do you think reinfection occurs?

ALEXANDER GRENINGER: Uh, yeah. I'm-- I-- I'd bet it does. I mean, it's-- we have individuals who, on mild infections-- we even 10% people sometimes-- this is not our work but other people's work showing that 10% of people don't really show a very strong immune response at all in mild infection. And so those people would be at a much higher risk for, uh, for reinfection. Now, typically those reinfections are milder. They're asymptomatic usually. There's some memory response that gets-- gets-- gets jolted, and there's also some antibody, and there's some T cells. So, you know, it's all-- it's all-- that's all good news.

It's just really going to be how high can we drive the titers in these vaccine studies, and how long lived are they? And so I feel pretty confident and optimistic in the vaccines, especially because we're not having to fight against much genetic diversity, uh, of the virus, really just having to fight against--

JOHN WHYTE: In terms of mutate-- what about-- is the virus mutating? And that's not necessarily a bad thing, correctly?

ALEXANDER GRENINGER: Oh, it's always mutating. I mean, so it throws down-- it throws down two mutations a month, but the big-- the key here is the month, right? So it's-- it's only-- we've only been around for 10 months in people.

You look at the other coronaviruses. You look at, you know, influenza, RSV, other respiratory viruses, and they've been circulating in people for-- for hundreds of years or in different animal hosts that can infect people. So there's incredible amount of diversity. They evolve-- some of them evolve faster. But even just the other coronaviruses have been circulating for tens to hundreds of years in people, and so there's a lot of diversity. You're having to fight against a lot of different strains.

JOHN WHYTE: Now help us break this down because this can be confusing to a lot of people. What if the vaccine is only 50% effective versus, say, 70% effective?

ALEXANDER GRENINGER: The reason people anchor on the 50% number is because that's what the FDA has said that's the sort of minimal threshold, the bar that has to be crossed for them to authorize or approve a vaccine, and I think that's a reasonable floor.

I think with six or seven shots on goal, we'll attain that. And it allows these companies to move forward and invest, and it's also a reasonable-- like, OK, if-- if something's not 50% effective, you know, we probably can find another one that's going to be 50% effective.

Let's be honest. We've never really done this for the coronavirus viruses. You know, we barely made some early candidate vaccine for SARS and MERS. We really haven't done it for the other coronaviruses. They weren't high on the list, and, um, now we're putting all of our attention to it, and we're using a lot of new modalities.

I mean, I think the-- the other silver lining to this cloud is that we're going to be able to test these different platforms, and hopefully one or two of them really, you know, shine through. We're testing some new hypotheses around prefusion, uh, protein, so new ways to make these proteins, new ways to deliver them. New adjuvants are on board. And hopefully one of these will work well and we'll be able to continue the momentum into the rest of the respiratory viruses.

JOHN WHYTE: When do you think we're going to see a vaccine that's approved as safe and effective?

ALEXANDER GRENINGER: Yeah, uh, that's a good question. I think, you know-- I mean, I-- I'm-- the guy who knows the most amount about it is Tony Fauci, and so he says to some [INAUDIBLE]. So why-- why would you-- why would you go against that, I mean, right? You know, he's basically practically designing the trials.

So, you know, it's, uh, I think that's a reasonable answer. I think, you know, I do-- I do want to say that, you know, compared to other viruses such as Ebola or Zika where there have been recent vaccine initiatives for sort of emerging viruses is they sort of tailed away. We don't talk about Zika virus right now, right? There aren't a ton of cases.

Uh, and, you know, that actually complicated the vaccine trials. By the time you rolled out the vaccine trial, the cases were diminishing. Makes it harder to show that you can prevent cases.

If we still have 30,000 to 40,000 cases or 50,000 cases a day in the United States, in Brazil, in South Africa, you know, adjusted for population, that makes-- that means that there's a lot of cases to prevent, um, and that makes the trials a little easier to open, enroll, achieve significance maybe that first time you look at the data. And so it could be-- it could be-- it could be a lot quicker than-- than the average vaccine trial.

JOHN WHYTE: And in the meantime, we'll continue to learn about the role of antibodies, um, and, you know, whether or not that provides protection. One other quick question-- a lot of this-- the current labs that measure antibodies right now, they're not measuring neutralizing antibodies.

ALEXANDER GRENINGER: Nope.

JOHN WHYTE: Is that correct? And that's what you looked at it as-- as the real measure to know, uh, about the effectiveness of-- of, uh, antibodies.

ALEXANDER GRENINGER: Well-- well, so-- I mean, for full disclosure here, I mean, basically we have a clinical lab and also Jesse's-- Jesse's lab at Fred Hutch. And so, you know, clinical labs, um, don't often run neutralizing antibody tests. Most places don't, actually. The--

JOHN WHYTE: Is that what we really need, though?

ALEXANDER GRENINGER: So if you look at all across the whole antibody-clinical-lab spectrum, you have two different antigens. You have the nucleocapsid, which wraps the genome, and you have the spike protein, which is what binds the cells.

Actually, most of the tests that are done the United States are done against the nucleocapsid because it's the most sensitive assay and it's better at telling you were you infected?

JOHN WHYTE: All right.

ALEXANDER GRENINGER: But really what we want are antibody tests that show that [? argon ?] spike, the outside glycoprotein from the virus that's involved in attachment and entry. And if you can get antibodies against that, you can say more about can you prevent infection?

JOHN WHYTE: But that's not what current labs typically are doing, right?

ALEXANDER GRENINGER: Yeah. There's a mix of them. I'd say it's like maybe-- the market is probably, like, 75%, 80% nucleocapsid, 20% spike. And then there's--

JOHN WHYTE: But I really want the spike. Is that what I [INAUDIBLE].

ALEXANDER GRENINGER: Yeah.

JOHN WHYTE: OK.

ALEXANDER GRENINGER: I mean, I think that for the receptor-binding domain, uh, you want to look at the outside of the spike, the part that binds the receptor. That's what you'd like. Um, that I think is a-- is a-- is what's most-- most-- you're most likely going to see in a clinical lab that could be achievable and will be the best, uh, potential correlative protection.

JOHN WHYTE: You've given us a whole virology lesson today. I want to-- I want to thank you, you know, for taking the time today, helping us understand what is the role of antibodies in terms of preventing infection? what's the risk of reinfection? where are we on the vaccines? We've covered a lot, uh, and I appreciate you taking your time.

ALEXANDER GRENINGER: All right, thanks for taking the time to talk to me. Appreciate it. Thanks for doing all this. This is really-- the media is so important when it comes to this-- this pandemic.

JOHN WHYTE: And I want to thank you for watching Coronavirus in Context.

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