From BQ.1.1 to XBB and beyond: How the splintering of Omicron variants could shape Covid’s next phase

The United States is in a (relative) Covid-19 lull, with cases and hospitalizations falling as the wave driven by the BA.5 lineage of the Omicron variant recedes. But as if we needed a portent of an anticipated fall and winter wave, Covid is on the rise in some European countries.

What’s different, at least for now, is that there’s not one variant pushing the wave. Rather, scientists are tracking a bevy of new forms of Omicron, which are jockeying with each other as they compete to become the next dominant strain. Scientists are monitoring more than 300 sublineages of Omicron, World Health Organization officials said this week.

To get a sense of what’s happening right now with the evolution of the SARS-CoV-2 virus, STAT spoke with Tom Peacock, a virologist at Imperial College London.

The strains virologists are tracking — from BA.2.75.2 to BQ.1.1 to XBB and beyond (“The names are getting ridiculous,” Peacock said) — are themselves descendants of earlier forms of Omicron, such as BA.2 and BA.5. It’s an example of how, since Omicron emerged nearly a year ago, the coronavirus’s evolution has been more akin to the “drift” seen with influenza, rather than the earlier succession of very different variants, from Alpha to Delta to the original Omicron.

“It’s a little bit like what we would expect to see over a couple years of flu, but crammed into about three months with SARS-CoV-2,” Peacock said.

But even as the Omicron lineages continue to splinter, scientists have found the different sublineages are picking up some of the same mutations — what’s called “convergent evolution.” That pattern suggests that those mutations confer an evolutionary advantage, one that would allow the virus to continue to spread among people who have different layers of protection, from vaccination and infections from earlier Omicron lineages.

Just how big and damaging of a wave the emerging subvariants will drive can’t be predicted. In the U.S., whatever wave comes will build on a baseline of, as of now, some 390 people dying on average a day. It’s also not clear if one variant will outcompete its cousins, or if different combinations will get footholds in different parts of the world. (We’ll note here that the new subvariants don’t seem to completely reset the pandemic: The immunity people have built up from vaccinations and infections will likely continue to offer strong protection against severe outcomes for most, particularly if they’ve stayed up-to-date with boosters.)

But the concern about these newest sublineages is not just that they could drive up cases once more. Already, some monoclonal antibody treatments were rendered useless and had to be abandoned as the virus evolved. And in some lab experiments, the remaining antibody therapies — bebtelovimab, as well as Evusheld — can’t stand up to some of the new variants. (Just on Monday, the Food and Drug Administration warned that Evusheld, which is given to immunocompromised people to bolster their protection as a pre-exposure therapy, can’t neutralize certain SARS-2 variants.) That could leave people at high risk for severe Covid even more vulnerable.

Peacock added one note: While it’s possible that the future SARS-2 strains we’ll be dealing with will continue to be descended from Omicron, another Omicron-like event could occur. That is, a variant from a distant part of SARS-2’s family tree could appear suddenly and outcompete everything else in the landscape, just as the original Omicron did last year around Thanksgiving.

“We’re also coming up to the one-year anniversary of Omicron, so something else could come and just make everything else extinct,” Peacock said. “We should never forget that SARS-CoV-2 has done that once, and can absolutely do it again. Everyone’s looking at these minute changes in all these sublineages and suddenly Pi comes through and torpedoes the whole lot,” Peacock said, referring to the next letter in the Greek alphabet, which would presumably be given to whatever major variant appears next.

Below are excerpts from STAT’s conversation with Peacock, lightly edited for clarity.

Generally, what’s happening with the evolution of SARS-2 right now?

We’re seeing a fairly unprecedented amount of — not for other viruses, but for SARS-CoV-2 — convergent evolution. In other words, although stuff started off in different places — some BA.2, some BA.5 — everything’s going back in the same direction. They’re getting the same mutations, which implies there’s a very strong selective pressure in the environment right now, which of course is people’s immunity, or that’s what everyone is assuming it is.

One thing people might have heard when new variants emerge is that they’re the “most immune evasive yet.” Wouldn’t by definition any variant that emerges and spreads well in our current immune landscape have to be able to evade all that immunity to circulate? Isn’t this what should we expect?

Yeah, it is absolutely expected. It’s how drift happens.

If it’s expected, is it reason for concern? On top of the impact on therapies, is there any sense yet of what kind of impact these sublineages might have on vaccine effectiveness? Countries in Europe and the U.S. are rolling out these bivalent boosters, which account for Omicron, but earlier forms of Omicron. 

It’s very hard to say because we don’t really know what the vaccine efficacy is going to be against a completely matched virus. That data takes a while. But it’ll probably be similar to how it’s always been, in that there will be some level of drop of protection against infection and symptomatic disease, because you’ve got a mismatch now. But things like severe disease and death will hold up much better, and there will be a much less dramatic drop and or maybe even not much of a drop at all.

Is it surprising that for all the evolution this virus has undergone, it’s still finding room to pick up new mutations and still be able to infect, and replicate, and things like that? I remember earlier in the pandemic hearing experts talk about how there were only so many mutations a virus could tolerate before losing some function. Are we just not there yet?

People have gone back and looked at some of the seasonal coronaviruses and you do see that they have a lot of tolerance for mutations, and SARS-CoV-2 is showing to have a lot of tolerance as well, clearly.

At least in parts of Europe right now you’re starting to see some resurgence of cases, but it’s not as if there’s some brand new variant driving it. So what’s happening now with transmission, and what might happen as these new variants snowball and BA.5 keeps receding?

People are saying that maybe some of the variants that are less good at spreading than some of the new sublineages but that still have some antigenic mutations — so BA.4.6, BF.7, for example, which are quite high in a few European countries — they may be the vanguard of this variant wave that we’re going to get over the winter, but that the really nasty ones are still at, what, a percentage point or a couple percentage points in prevalence. So you have the first ones that will get replaced as the wave comes through by these nastier ones that are currently at lower prevalence. We could end up with a mix, and different countries end up with different mixes.

This is on top of schools going back across Europe, a sudden cold wave — so maybe there’s some seasonality — and waning immunity. It’s just everything at once, and it’s unclear what each contribution is. But if variants aren’t driving it now, they will be in a few weeks time, we think.

Get your daily dose of health and medicine every weekday with STAT’s free newsletter Morning Rounds. Sign up here.