Oct 28, 2022

Interviewer: Trying to stay informed about the latest COVID-19 variants can be exhausting. It seems like things change every week, and if you're like me, you're often left wondering, "What do I do with all this information?"

Dr. Stephen Goldstein is an expert in coronavirus. He has a Ph.D. in coronavirus research. And today I'm going to take a step back and try to find out what information is important and what isn't when a new variant is announced, and how you can decide how the new variants might impact your life.

As of right now, Omicron remains the dominant strain of COVID-19. And my first question is do variants of Omicron tend to give people the same symptoms, the same level of sickness, the same chance of developing long COVID, or are they all a little bit different?

Dr. Goldstein: A little different in certain ways and probably about the same in others. So in terms of impacts, like the virulence or the severity, average severity of infection, there's pretty good evidence that, for example, BA.1 was less severe on average than Delta, for example, which was more severe than the original version of the virus.

And there's some evidence from animals that BA.2 was maybe a little bit more severe than BA.1, but all of that is kind of pretty thin and the differences are probably small.

So if I were a person thinking, "Oh, I got a BA.5 infection. This is going to be much worse than a BA.1 infection would've been," the likelihood is that the severity is not going to differ a huge amount between these different versions.

They are different in terms of the way they're recognized by the immune response. And that's where the major differences between different versions of Omicron lie.

Interviewer: And is that in terms of the symptoms how they're recognized, or when you say they're different in terms of the immune system, what does that mean?

Dr. Goldstein: Yeah. So, for example, the original version of the virus, the spike protein had a particular sequence of amino acids, the chain of letters that constitutes the spike protein. And that kind of folds up in a very complicated way into a structure, and our antibodies that are produced as part of the immune response recognize essentially the shape of that structure.

And so Omicron BA.1, the first version, had a pretty different structure or shape on the part of the protein that antibodies are able to access than the original version of the virus. And that meant that if you were infected in, say, 2020 or by Alpha or Delta, then the antibodies you made at that time in reaction to the shape of, say, the Delta spike protein might not be very good at recognizing the shape of the Omicron BA.1 spike protein.

And so you would be at an elevated risk of reinfection. Say your risk of reinfection by the original version was whatever percent chance, then once BA.1 took over, your risk of reinfection went up by some amount.

Interviewer: It's kind of like in the analog world, I recognize a threat by its shape off on the distance, and now if that animal or that critter's shape has changed, I'm like, "Is that . . .? I don't know."

Dr. Goldstein: Yeah, that's a really nice metaphor, I think. And the vaccines until now, until very recently, consisted of only the original version of the spike protein, which has a pretty different shape than the Omicron version. So if you got your vaccines before this fall, your immune system was trained to recognize just the original version, the original structure of that spike protein of the original virus.

This all gets really complicated because there were people who were vaccinated with the original version, but then infected with BA.1, or BA.2, or BA.5. And so all of these different combinations interplay with each other in really complex ways that are difficult even for scientists to really pull apart.

And so individuals should not worry themselves about the details of all of this. They should just know that the vaccines have been updated now to a version of the BA.5 Omicron spike. That is a significant update for your immune system if it was previously trained by the original version of the spike protein or the BA.1 version of the Omicron spike.

Interviewer: And this vaccine that is better at BA.5 is the one that's just recently come out within the past month or two?

Dr. Goldstein: Yeah. Exactly. Just within the past month or two, and I just got mine.

Interviewer: All right. Great. So now you're hearing some subvariants of. . . Are these subvariants of BA.5 or are these variants of their own, this BQ.1 and BQ.1.1?

Dr. Goldstein: So these are sub variants of BA.5.

Interviewer: Okay. So COVID BA.5, and then underneath BA.5 . . .

Dr. Goldstein: And then underneath BA.5 we've got all these diversifying subvariants now. And look, viruses are picking up mutations all the time. So any lineage we have, especially a lineage that's dominant, means there's going to be a lot of those viruses out there in the world. They're picking up additional mutations and splitting off into different sub-lineages all the time, every day. The question is whether any of those sub-lineages are better at replicating and transmitting in people than the lineage they kind of spawned off from.

Most of them are not, so they might occur in a few people and transmit one or two times but not go anywhere. BQ.1 and BQ.1.1 seem like maybe they are better at doing those things than the original BA.5, and that's why they're increasing and why we're talking about them.

Interviewer: And as just a regular person, what should I do with that information? Because part of me is like, "Well, maybe I should pay attention to it," but then the other part of me is, "Although they might just go away."

Dr. Goldstein: You should get the BA.5 booster.

Interviewer: Okay. That's easy, right?

Dr. Goldstein: Yep.

Interviewer: We've taken this very complicated subject and once again it seems to come down to this very easy action that we all take, which is just get the most recent booster.

Dr. Goldstein: Get the most recent booster. There's a really cool immunology that explains why you should get the recent booster even if it's matched to the original BA.5, not to BQ.1 and BQ.1.1.

As your immune system gets exposed to different versions of the spike, it expands what we call its breadth. When you were vaccinated with the original version of the spike, you made antibodies targeting primarily the original version of the spike.

Then if you got infected with BA.1, you made some new antibodies and some new antibody-producing cells that will recognize BA.1. You also boosted your original antibody producing cells to the original version of the spike.

But what you also do is actually make different kinds of antibodies as well that actually end up being able to recognize variants your body hasn't even seen yet that may not exist. And so that's when we talk about kind of expanding the breadth or the scope of the immune response.

So if you've been vaccinated with the original version two times or three times, and maybe you had BA.1, and now you're getting the BA.5 spike, you're actually going to have an antibody response that is able to do all kinds of different things, not just the specific things that it's been trained to do.

And so the BA.5 booster, even if it's not a perfect match for BQ.1, is actually probably going to produce some antibodies that recognize BQ.1 anyway.

Interviewer: Back to the metaphor, you're just gaining experience at recognizing, "Well, the shape's not quite the same, but the way it moves is kind of the same, so that could be the same threat."

Dr. Goldstein: Yeah, I love that.

Interviewer: So what about symptoms? Somebody who had the original COVID-19 virus versus maybe a BA.5 virus, are they going to have different symptoms? I remember loss of smell and taste was big in the beginning. Is that still a thing?

Dr. Goldstein: I think those things are still happening. The difficulty in kind of picking that all apart is very few of us . . . If you got infected with the original version of the virus, it's the first time in your life your body and your immune response have seen that virus.

If you get it again, even with a slightly different variant . . . The immune system has a lot of different components to it, and just because the virus is maybe a little bit better at slipping past your antibodies doesn't mean it's not recognized by other parts of your immune response that can still serve to dampen the amount of symptoms you see.

So reinfections on average, on a population level, are going to be less severe than primary infections. It doesn't mean an individual person can't have it worse the second time, because we're talking about averages, or the third time. It can happen. But probably, the chances that you're going to have some particular symptoms on average become less likely as you go through more infections in your life.

So even if, say, BA.5 is just as likely to cause a loss of taste and smell the first time someone gets infected by it, it doesn't mean that if it's your fourth exposure to this virus through some combination of infection and vaccination that you're just as likely to lose your sense of taste and smell.

So a lot of that, as the immune landscape becomes more complex, the symptomology becomes more difficult to kind of tease apart.

Interviewer: And that's why you hear people that have had it a few times say, "Oh, it's just a cold this time."

Dr. Goldstein: Yeah. Sure.

Interviewer: It's not quite as bad because the immune system is getting smarter, and your body has seen it.

Dr. Goldstein: Yeah, absolutely. And I want to emphasize that that's the average scenario. For most people, that will be true, but everybody is different. There are people who are going to say, "I had it the second time and it was way worse."

Interviewer: Got it. Because we're all different.

Dr. Goldstein: When there are seven billion people in the world, you're going to have people who are worse than the . . . I mean, the average is the average for a reason. Because there are people who are worse than that, and there are people who are less. There are people who are going to have no symptoms their first time even, or their second and third time. Then there are a lot of people who are going to have mild or moderate, and then some people are going to have it worse the second time for whatever reason. In most cases, we don't understand why.

Interviewer: What about post-COVID? So long COVID, I guess, is what I'm trying to say, right? Do different variants cause different extremes of the long COVID, or is it much like what you just described with the immune response and the symptoms?

Dr. Goldstein: This is an area that is still pretty murky. I think we don't even have a really good understanding of exactly what causes long COVID yet. And long COVID is . . . if we define it very broadly as kind of any symptoms that are persisting past three months or six months, whatever date you want to pick . . .

Interviewer: And some examples of that would be shortness of breath. What are some other examples?

Dr. Goldstein: Sure. Brain fog, extreme fatigue, things like that. But we don't know if those are caused by the same thing in all people. Some people maybe are having some persistent replication of the virus in their bodies. Other people, maybe the virus is gone, but their immune response has gone haywire after their infection. So we still need to kind of pick all of that apart, in my opinion. Our knowledge is still kind of thin in that area.

And then also, again, we don't really have a great understanding of . . . My expectation would be that if you didn't get long COVID the first time, the chance of getting long COVID on the second time is probably less than the first time. But it's also complex because the more times you get COVID, the more likely you may be to . . .

Interviewer: Your odds.

Dr. Goldstein: Yeah, your odds. It's really complicated, is what I think the best answer I can give you is.

Interviewer: And I think I realized maybe a flaw in my thinking as we're having this discussion, which is I'm putting the symptoms and, "Is this going to give me long COVID?" on the disease. But it's really the individual and how they're reacting to the disease that's a big part of that equation too.

Dr. Goldstein: Yeah, I think the kind of inflammatory part of the immune response probably has a lot to do with long COVID in a lot of cases. But there's still so much that we need to learn about this.

I mean, unfortunately, this has been an area I think that largely there's been underinvestment in on the research front. Hopefully that changes.

But I think the best way to put it is probably your risk of long COVID goes down . . . For each infection, the risk of getting long COVID after that infection goes down, but every time you get COVID there's probably an additional chance. So the average risk goes down, but there is some additive effect.

Interviewer: As far as I'm aware, I have not had COVID, right?

Dr. Goldstein: Good.

Interviewer: And so then I hear about these variants, and they're like, "Oh, this variant is less severe and whatever," and I'm like, "Well, I'm not so afraid of getting that variant now because I've been vaccinated. I feel pretty healthy. I know I'm probably not going to get severely ill." But that long COVID thing scares me a little bit.

Dr. Goldstein: Yeah. I mean, my expectation is that vaccination, especially keeping up with the boosters, probably reduces your risk of getting long COVID ultimately. It's just an area we don't have a lot of hard data yet. But from an immunological standpoint, that's my expectation.

Interviewer: Now, when COVID first came out, we had one line of defense and that was social. It was wearing masks, it was keeping our distance, those sorts of things. And then we got a vaccine, and then . . . And maybe this isn't the exact chronological order, but then now we also have treatments as well, right?

Dr. Goldstein: Yep.

Interviewer: I hear these words like treatments, therapies, interventions. Are those all essentially the same thing? Give me the hierarchy of that.

Dr. Goldstein: Yeah. So treatments and therapies kind of come in two flavors. So one is antiviral drugs like Paxlovid, and that works to disrupt the actual replication of the virus. So it doesn't stop the virus from getting into your cells, but it stops it from replicating.

Then you've got these antibody therapies, and they basically work like your immune response, but they're giving it to you from kind of outside, what we would call passive immunization in a sense. But you can also do it therapeutically. It gives these antibodies . . . the virus that's in your body, it stops them from infecting new cells.

The problem with these is that a lot of these antibodies are designed against an older version of the virus and are becoming much less effective against Omicron. So we need new antibody therapies.

One way is ones that are developed specifically against different Omicron variants, but actually the better goal is to make antibody therapies that are based on what we call broadly neutralizing antibodies that show the ability to target many different versions of the spike protein. And those do exist, they've been identified, but we need to get them across the finish line as far as developing therapies based on them.

Interviewer: And in those instances, that is after somebody contracts COVID. These are tools that are used to help reduce the severity?

Dr. Goldstein: For the most part, yes. There is one antibody drug called Evusheld that's used to actually protect people. That's given every few months and it's primarily given for people who are immunocompromised to protect them preemptively or preventatively. Looks like it's not going to be working very well against the latest Omicron variant, so we do badly need an update there.

Interviewer: But that is something that, much like the vaccines, can be updated.

Dr. Goldstein: Yes.

Interviewer: It just is going to take some time.

Dr. Goldstein: Takes some time. We ideally want to develop them based on those broadly neutralizing antibodies, because then we're not chasing variants and we're cutting down the chance that we're going to get a variant that escapes that antibody therapy. We can just have ones that are based on broadly neutralizing antibodies and roll with those hopefully for a very long time.

Interviewer: And then what about home test accuracy when we're talking about the variants? I know people that said, "Oh, I'm sure I had COVID, but I kept getting negative on my tests." Are the variants not as detectable by some of those home tests? How does that work?

Dr. Goldstein: So far, we have not seen any variants that seem to have dented the accuracy of the home test, especially, I think, the most popular ones that people are using, especially in the U.S.

So these home tests, they're not designed to detect the spike protein, which is the part of the virus that changes the most. And so they're not super sensitive to the variants escaping them.

I think more of the variable performance of the home tests is people vary in the amount of virus they have in different parts of their body. So some people have a lot of virus in the lungs and maybe those are the people who get really sick, and some of them will also have a lot of virus in the nose. Some people have very little virus in the nose.

So you may have heard a story where someone got infected and their partner or wife or husband didn't get it. Why? I mean, they live together. People are often transmissible before they get symptoms. So maybe they slept in the same bed. How is that possible? It's crazy.

Interviewer: Yeah, why? I'm asking.

Dr. Goldstein: So one big reason is probably that some people just don't shed a lot of virus out of their nose or their upper airway, their trachea. And if you don't have a lot of virus coming out of your nose, the home test is not going to work as well.

Sometimes people will say, "Oh, I didn't test positive until Day 3." Well, some people, maybe the amount of virus in their nose spikes up really fast, and those are the people who are going to test positive the first day they have symptoms, like me when I had COVID.

Other people, maybe the amount of virus in their nose kind of increases much more gradually. And so maybe it's two or three days into their sickness before they have enough for the test to detect.

The final point of your question, "I'm sure I had COVID. Why did I keep testing negative?" So one possibility is you did have COVID, but you never had a lot in your nose.

The other possibility is you were infected with one of literally hundreds of other viruses that can cause a very similar respiratory disease. Maybe they're less likely, even much less likely in some cases, to cause severe pneumonia, but distinguishing between different viruses . . . If you just had essentially an upper respiratory tract infection, maybe you had a mild fever. Distinguishing between those from a clinical standpoint is impossible.

Interviewer: Give me some advice on how I should move forward. When COVID first came out, I paid very close attention to what was going on, as I would imagine a lot of people, and then it gets very fatiguing. And then I hear a news story about, "Oh, there's a new variant." But then I'm like, "Oh, I don't know if I have the wherewithal to dive into learning all about that. Where should I be in my life as far as when I hear news stories about new variants or whatnot?

Dr. Goldstein: So aside from making sure your vaccine is updated, getting the booster . . . We covered that. Definitely do that. Beyond that, I personally, even myself, and so certainly for someone who's not a coronavirus researcher, don't worry day-to-day about which variant is dominant. So I would look more at the curve, the number of cases than which variant it is. For most people, the specifics of which variant are dominant at any given time, this is not important information to me, frankly.

And I wish there was less coverage in the media of, "This variant, this variant, this variant," because the things that people can do in their day-to-day lives are the same. Get boosted, and if your risk mitigation practices are prone to change, if you're interested in changing them based on what's going on, just look at the number of cases. It doesn't matter which variant they're being caused by. Just pay attention to how much virus is transmitting in your community and react to that.

Interviewer: And that's for the average person. What about for somebody who might be immunocompromised or something like that? Same advice?

Dr. Goldstein: Well, I think someone who's immunocompromised should be taking more precautions all the time. And that still scales, I think, with the amount of virus that is going around in the community.

And another thing people who are immunocompromised should do is . . . We talked about that drug Evusheld that can be given preventively. If that continues to be recommended by the FDA, meaning that it still works against what they expect to be the variants that are circulating, get that if you're immunocompromised.

Actually, a huge problem is this drug has not been promoted well enough, and many fewer people than the number who would benefit from it are getting it. Hopefully, there'll be an update to this kind of preventative antibody therapy soon to better match the variants that are circulating. Definitely, as soon as that happens, if you're immunocompromised, if you qualify for this drug, get it. It's very effective.

Interviewer: Let's wrap it up with what should the average person take away from this conversation when it comes to COVID-19 variants?

Dr. Goldstein: Most people can just tune out the noise about what particular variant, the news stories that you're seeing every day about the newest variant and the immune escape properties of the latest variant, etc. I think it's not important for most people. I think it's drowning people in complexity that frankly is irrelevant to them.

I mean, give people the best advice. Like I said, get boosted, match your risk mitigation to the number of cases in your community, and that is literally all you need to know. You do not need to know what amino acid changes there are in the BQ.1.1 spike relative to the original BA.5 spike. There's not a separate vaccine for the two of them, so who cares? Go get the booster, for sure.

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