Trevor Bedford on Omicron and what about COVID keeps him up at night [PODCAST]

Welcome to an expedited episode of The Podcast by KevinMD. Trevor Bedford is a computational biologist and infectious disease scientist, Fred Hutchinson Cancer Research Center. He was selected as a recipient of the 2021 MacArthur Fellowship and can be reached on Twitter @trvrb.

Transcript

Kevin Pho, MD: Hi, and welcome to the show where we share the stories of the many who intersect with our health care system, but are rarely heard from. My name is Kevin Pho, founder and editor of KevinMD. Today on the show we have Trevor Bedford, he is a computational biologist and an infectious disease scientist at Fred Hutchinson Cancer Research Center in Seattle, Washington. He’s the recipient of the 2021 MacArthur Fellowship, otherwise known as the MacArthur “Genius Grant.” His Twitter feed is a must-follow during the pandemic. I follow it every day and you can find him on Twitter @trvrb. Trevor, welcome to the show.

Trevor Bedford, PhD: Thank you for having me, Kevin. It’s great to be here.

Kevin Pho, MD: Let me ask you what is a computational biologist? And can you give an example of that expertise in action during the COVID pandemic?

Trevor Bedford, PhD: So my main focus has been on viral sequence data. So before the pandemic, for flu and Ebola and Zika, and all these things, when someone is infected, you can take a swab and sequence the virus out of that, you get this genome of 10,000 or 30,000 letters, and you’re able to learn things about evolution and spread of the virus from that genome sequence. So a lot of the pure scientific output has really been focused on learning about evolution and epidemiology from this the sequence data. We do a bit of sequencing in the lab at the Fred Hutch, but mostly that what we rely on is publicly available sequence data or sequence data from collaborators to work with.

Kevin Pho, MD: We are speaking in the afternoon of Friday, December 17, and when this comes out Omicron going to take hold in the United States. How is the Omicron variant different from the prior variants of COVID?

Trevor Bedford, PhD: So Omicron took me, and I think took basically everyone by complete surprise. So we have kind of this super variance in spring 2021, Alpha, Beta, Gamma, Delta, et cetera. Delta ends up being more transmissible than the rest, it out-competes, and three weeks ago, 99% of infections, something like that, throughout the globe were Delta. And now in just a few weeks after that, we’re going to hit 50% Omicron very rapidly.

It is a very different genome of a virus so the best hypothesis I have that is still weak, but is the hypothesis, is that kind of evolved, incubated within one chronic infection in southern Africa for perhaps a year, over a year, and then accrued a number of these spike mutations that were trying to escape immunity, that wasn’t kind of fully able to clear the infection but was enough to kind of push the virus to evolve. So then when it spills out of that chronic infection, you end up with something that is quite transmissible in a large part due to escaping existing immunity because the spike protein has changed enough that existing antibodies from natural infection and from vaccination don’t don’t work as well against it.

Kevin Pho, MD: You mentioned that Omicron surprised you and other scientists. Why is that?

Trevor Bedford, PhD: I was expecting kind of now that there’s so much immunity in the global population, a switch to kind of evolution mostly for antigenic drift, that’s more flu-like, where you can have new variants, new strains emerging, that displace existing strains, you can update vaccines, and all of that was completely expected. But I was expecting something much more flu-like in that we have a new strain emerging, and then within that a few mutations, a few mutations, whereas Omicron kind of appears completely out of left field with these 30 mutations in spike protein looking like a flu that’s from 2031 in terms of kind of the amount of evolution that’s happened there. So it’s suddenly something hugely different.

Kevin Pho, MD: Well, the fact that it’s hugely different, how does that impact the trajectory of the pandemic?

Trevor Bedford, PhD: So we know that it’s spreading incredibly rapidly and basically the number that I focus on here is this Rt number, the number of secondary infections that one infection causes or cases that one case causes. Early on in February 2020, that was with the original Wuhan-like virus that was around three and a half in places like Seattle and Western Europe as it was spreading before mitigation measures really hugely brought that down. The initial Delta wave in April/May was an Rt of about one and a half, and right now for Omicron in places like Seattle and London, it’s perhaps three or four even, if not even slightly higher.

And so it’s more kind of faster spread than we’ve basically seen ever before. We can expect higher caseloads than we’ve seen throughout the entire pandemic, and so now it’s basically a question of we know at least due to prior immunity and very potentially due to actual intrinsic severity that the kind of on a per case level outcomes will be much more mild for Omicron than previous waves. And it’s just kind of how big is that big number of cases and how small is that small fraction of severe outcomes, and kind of multiplying the two together will determine how bad this actually is.

Kevin Pho, MD: So taking a look at how Omicron is spreading overseas in South Africa and Europe, when do you expect Omicron to displace Delta in the United States?

Trevor Bedford, PhD: So in Seattle, we’re about 50% Omicron as of today. New York, it looks perhaps a bit past that. Other places will take a little while to catch up, but the doubling time is every two or three days so it won’t take long. So yeah, give it a week. And displaced now is a word that I’m watching carefully in that if we look at South Africa, it’s hard to tell because Delta was starting from such a low fraction. You can actually still find Delta circulating in South Africa as of the latest genome sequences that are being provided, and so it’s not clear entirely whether Omicron has just been on top of Delta or has actually displaced Delta.

So it’ll definitely be that the vast majority of cases being detected in the U.S. and in Europe will be Omicron, but it will be … I’m not sure how much of a dent that will actually put into Delta, and I can imagine perhaps in places like London and Europe, where they might do more mitigation, more nonpharmaceutical interventions, that Delta might die. Where in the U.S. where we might have less, we might see less of an impact than Delta, but that’s something that I’ll be watching carefully.

Kevin Pho, MD: Let’s talk about the severity of infections that Omicron creates. So I’ve been seeing articles all over the place. So I guess initially in South Africa, some are saying that gives a more mild disease but now I’m seeing that other scientists are calling that in question. So what are your thoughts in terms of the severity of disease that Omicron gives?

Trevor Bedford, PhD: Yeah, this is frustratingly unresolved. I mean, and it’s only … It’s been just a few weeks and has spread so rapidly that even if this was normal clinical course of illness, we expect time for kind of the severe outcomes to accumulate. So it’s making it to be a very, very difficult question. I do think we can say for certain that a large fraction of the Omicron infections are occurring in people with some immunity, either from natural infection or from vaccination. And we know from kind of previously what we were looking at with waning immunity and booster shots and so forth that generally you’ll have this thing where if immunity is not perfect, has dropped a bit, either through waning or through viral evolution, you might lose protection against infection but you usually will retain protection against severe outcomes.

So I think a large fraction, maybe not all, but a large fraction of the reduction of severity that we have observed is due to these infections being a large fraction in South Africa and now elsewhere in people that have some prior immunity. And so that by itself will reduce, will reduce severity. And so we can have high caseloads in the U.S. and in Europe, and maybe not have as many severe … As a ratio, we won’t have as much severe outcomes as say, the Delta wave. I haven’t been able to determine, and I haven’t seen any real good evidence on this on whether there’s also some intrinsic more mild disease from Omicron. I could well imagine that being the case as well, but again, it’s like yeah, trying to dial in that exact severity number, which is still hard.

Kevin Pho, MD: So it’s certainly likely about Omicron will be the predominant strain very shortly. Is it likely that fully vaxxed is going to be defined as three vaccines?

Trevor Bedford, PhD: What do we talk about when we talk about protection? So it looks like two doses and waning since if people got their second dose of Pfizer/Moderna, say back in April, that there’d not be a lot of protection against infection from Omicron. We’re talking maybe 20%, 30% vaccine effectiveness against a symptomatic illness, whereas the third dose from work by Public Health England puts that at maybe about 70% to symptomatic illness, which is pretty good. So kind of a pretty big difference there. But we should expect that two doses will still provide some decent protection against hospitalization and death. And so perhaps seeing more of a dichotomy between people that got their third dose, not becoming symptomatically infected and people that had two doses more often becoming symptomatically infected.

Kevin Pho, MD: Put the COVID pandemic in historical context. Are there any past pandemics that can contrast with what we’re currently going through with COVID?

Trevor Bedford, PhD: I’ve been thinking about this a lot on this evolutionary front because it’s definitely my focus, where if you look at say 2009 swine flu, that infected 30% of the world and within the first year of it appearing in 2009, but we didn’t see nearly as much evolution. There weren’t like variants of swine flu in the same way that there are variants of SARS-CoV-2, and if we look at things like Ebola and Zika, yeah, the amount of kind of evolution or impactful evolution that’s seen, kind of viruses evolving all the time, sequences changing repeatedly, but of actually new novel variants having an impact, I really can’t think of an analogy here. We might have had this in 1918 when we didn’t have good sequencing, but of kind of more recent things it’s been pretty extraordinary seeing this level of evolution.

Kevin Pho, MD: Now with the trajectory of COVID hopefully becoming endemic, when do you think that time will come?

Trevor Bedford, PhD: We’re kind of approaching it very rapidly in that I’m not going to get these numbers perfect with something like 60% of the U.S. total population having been vaccinated. With something like 35% of the U.S. total population having been infected, we can expect … What is that? If we multiply this out, like 80% of the population have immunity, and at endemic state, I’m expecting basically 100% of the population have immunity. So we’re close to there. Omicron makes me more worried about what endemic state looks like if the virus can kind of … If every year or something like this were to emerge, we’re going to end up with much … Again, even if we don’t have a lot of severe outcomes, you’ll get large attack rates, large waves, due to evolution of the virus in a fashion that that will be disruptive.

Kevin Pho, MD: And is it likely then we’re probably going to be needing new Omicron specific or whatever variant specific COVID shots every six or 12 months?

Trevor Bedford, PhD: Even before Omicron, my expectation was that every September there would be a COVID vaccine that people that are interested would take just like flu vaccine because mRNA is a faster platform than the chicken eggs that flu is grown in, you could maybe have that strain selection decision made in something like June, rather than in flu, it’s made in February. And so because of seasonality and endemicity and immunity, and once things are kind of getting into the regular cycle, I’d expect like flu, like other respiratory viruses, a winter COVID season followed by not much circulation in the summer and so you time yearly vaccination to coincide.

I had been expecting that to just be a strain swap the way that we do with influenza, but I think as, yeah, just discussed, I can’t imagine that come September we’ll have both Omicron and Delta, the descendants of Omicron and the descendants of Delta co-circulating, and we might want a vaccine that has both valencies in it that should be easily doable with a mRNA vaccine, but it’s something that we’d have to be preparing that regulatory framework for now and getting … Kind of getting work on this to actually have that ready for September.

Kevin Pho, MD: I’m a primary care internal medicine physician, and in my exam room, I get a lot of questions about natural immunity. What’s the role of natural immunity in the upcoming Omicron wave?

Trevor Bedford, PhD: So basing most of this on vaccine effectiveness studies alongside virus neutralization assay work where you generally see that that natural infection has a bit more variation to it than vaccination. And some people who have an infection will have higher titers than two doses, many times lower. On average, it’s slightly lower. But it’s largely not super different. And so now the real comparison is basically two doses and some COVID and natural infection being pretty equivalent to three doses and kind of really wanting to be probably in that area versus not a lot of protection against symptomatic illness for people who’ve only been naturally infected or only had two doses.

Kevin Pho, MD: What’s something that keeps you up at night about the COVID pandemic?

Trevor Bedford, PhD: So I think with Omicron, this left-field evolution of something that’s so wildly different that if that keeps happening and if it’s different enough so it doesn’t displace Delta. So again, in September 2022, we have both Omicron descendants and Delta descendants circulating, and that happens each year, you could just kind of keep stacking up co-circulating SARS viruses. And they will provide some immunity to severe illness to each other but it would still be something where you’d expect much higher burden of disease and much higher circulation levels than in the scenario where there’s just kind of one strain that’s evolving and replacing another like we have with flu. And that would then be challenging to keep up with in terms of vaccination strategies.

Kevin Pho, MD: And my final question. What are some of your take-home messages that you want to leave with the Kevin MD audience?

Trevor Bedford, PhD: So right now, the best thing that you can do for Omicron is to get the third dose of vaccine. I hugely recommend doing that, and that would … Both to protect from symptomatic illness, but to also protect your neighbors, your community from onward spread. It won’t be perfect, but it will be kind of the easiest, best thing to do. I am kind of going back to a bit like behavior in a year ago before I was vaccinated thinking that I’m not … I go grocery shopping, I get takeout, I get coffee at coffee shops, but I don’t sit in at restaurants. Might have small gatherings with immediate rapid tests alongside, but kind of definitely modulating my behavior a bit to try to make this January wave not quite as bad for the healthcare system, even if my own personal risk having had three doses is quite low.

Kevin Pho, MD: Trevor, thank you so much for joining me and sharing your time and insight.

Trevor Bedford, PhD: Thank you so much, Kevin. Thank you for having me.

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