For two years, coronavirus variants emerged, one by one, sweeping the globe.
But this fall and winter are expected to be different: Instead of a single ominous variant lurking on the horizon, experts are nervously eyeing a swarm of viruses - and a new evolutionary phase in the pandemic.
This time, it's unlikely we will be barraged with a new collection of Greek alphabet variants. Instead, one or more of the multiple versions of the omicron variant that keep popping up could drive the next wave. They are different flavors of omicron, but eerily alike - adorned with a similar combination of mutations. Each new subvariant seems to outdo the last in its ability to dodge immune defenses.
"It is this constant evolutionary arms race we're having with this virus," said Jonathan Abraham, an assistant professor of microbiology at Harvard Medical School.
The pace of evolution is so fast that many scientists depend on Twitter to keep up. A month ago, scientists were worried about BA.2.75, a variant that took off in South Asia and spawned a cloud of other concerning sublineages. In the United States, BA.4.6 and BF.7 have been slowly picking up steam. A few weeks ago, BQ.1.1 started to steal the spotlight - and still looks like a contender to take over this fall in Europe and North America. A lineage called XBB looms on the sidelines, and threatens to scramble the forecast.
To focus too much on any one possible variant is, many experts argue, missing the point. What matters is that all these new threats are accumulating mutations in similar spots in what's called the receptor binding domain - a key spot in the spike protein where virus-blocking antibodies dock. If those antibodies can't dock, they can't block. Each new mutation gives the virus a leg up in avoiding this primary line of immune defense.
Most virologists demur when asked about which variant - or variants - will be infecting people this winter. That doesn't mean they think the virus is standing still.
Much of the world's population has gained a measure of immunity because of vaccinations and infections with omicron. That protection gave us the relative freedoms of the moment - with many people returning to normal life. But protection is fleeting for two key reasons: immunity wanes and the virus is changing. And then there's this: Monoclonal antibodies, targeted drugs that can be used as a treatment or to protect immunocompromised people who don't respond well to vaccines, are likely to be knocked out by future variants.
"It's important for people to understand that the fact there's not a Greek letter name that has come out does not mean the virus stopped evolving," said Jesse Bloom, an expert on viral evolution at the Fred Hutchinson Cancer Center in Seattle, who described the evolutionary rate of SARS-CoV-2 as "strikingly rapid."
Instead of worrying about which variant will win, or even focusing on particular mutations, many scientists have shifted to watching hotspots - specific sites on the virus, known by numbers like a street address, where any change in the virus's code might allow it to slip by the neutralizing antibodies that are a first line of defense.
The coronavirus spike protein is made up of about 1,300 building blocks called amino acids, and mutations that change even a single building block can make it harder for antibodies to block the virus. Instead of a Greek alphabet, scientists are maintaining shortlists of worrisome spots for mutation: 346, 444, 445, 452, 460, 486, 490.
Seeing so many lineages of the coronavirus develop similar constellations of genetic changes at these spots is a sign of convergent evolution - when different versions of the virus have slammed into the wall of immune defenses in the human population, and then come up with similar ways to get around them. That happens with influenza but is fairly new to SARS-CoV-2. And in the case of the coronavirus, the more mutations, the bigger advantage a new variant seems to have.
Cornelius Roemer, a computational biologist at the University of Basel in Switzerland, has been ranking the new omicron sublineages by how many mutations they have in the receptor binding domain.
XBB appears to be the best at evading immunity. Researchers in China have found that XBB can elude the protective antibodies generated by a breakthrough BA.5 infection, raising concern that fall boosters engineered to target the BA.4 and BA.5 versions of omicron may be quickly outpaced. Still, those booster shots remain the best tool on the shelf.
"We do not have a better choice at the current stage," Yunlong Cao, a scientist at the Biomedical Pioneering Innovation Center in Peking University in Beijing, said in an email.
On Friday, data from the Centers for Disease Control and Prevention showed that BQ.1 and BQ.1.1 had grown to about 11 percent of the viruses sampled in the United States. Whether it is XBB, BQ.1.1, or some as yet unknown twist on omicron, most experts agree variants will help fuel a difficult fall and winter.
"These lineages are going to have a greater ability to reinfect people than what is currently circulating . . . which is very likely to drive or contribute to infection waves over the winter," Tom Peacock, a virologist at Imperial College London, said in an email.
It's a matter of debate what will happen when one or more of them gets a toehold in a population with a protective layer of underlying immunity. Protection against the worst outcomes is likely to hold up, particularly if bolstered by boosters, many scientists predict.
Cases are ticking up in Europe already. Many scientists think the upswing is driven largely by factors such as children going back to school, people spending more time indoors and the seasonality of the virus. The variants may just be starting to contribute.
"We are certainly in a better place than we were many months ago; we are still in a downward trend" in the United States, said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, who exhorted people to get an updated booster if eligible. "We need to watch and follow these things very carefully, because we want to make sure we have a good handle on what is going on with regard to the emergence of variants, and what impact they're going to have on any trends we are going to see in winter."
But the impact on society could still be considerable even with a surge in cases that doesn't lead to a massive wave of hospitalizations.
"To put it in context, the summer wasn't considered a wave - but at the same time, there were lots of issues with work absences, and that kind of thing did have an impact on the world as a whole," said Manon Ragonnet-Cronin, a scientist at the University of Chicago. "Our primary measurement of how bad these waves are tends to be hospitalizations and deaths, but those other effects shouldn't be discounted."
There's nothing certain about a late-fall wave - whether one will happen, what its magnitude might be or what could spark it. The new crop of variants clearly escapes immunity, but Justin Lessler, a professor of epidemiology at the University of North Carolina's Gillings School of Public Health, said the question will be how that advantage plays out in the world.
"A strain can have a growth advantage compared to the other strains, but still not enough of an advantage to lead to a resurgent epidemic," Lessler said.
What's more predictable: Any variant that winds up dominating in coming months will probably challenge a key line of treatment and protection for people with compromised immune systems - the drugs known as monoclonal antibodies. Evusheld is a long-acting version used to prevent illness in people with compromised immune systems. Another monoclonal, bebtelovimab, is used as a treatment.
The pharmaceutical companies making these drugs stress that they remain useful against variants that are prevalent now. But for many scientists, the writing is on the wall. The swarm on the horizon threatens to wipe out one or both of those therapies - and may even subvert the next generation of candidates yet to make it into the medicine cabinet.
Regeneron Pharmaceuticals, a major maker of monoclonal antibodies, paused start-up activities in late September on clinical trials for its new drug - pointing not to a particular new lineage of omicron but to a mutation at one of the hotspots.
"We ask that all start-up activities . . . be paused to allow Regeneron to evaluate the new variant and its potential impact to our planned clinical development trials," a company memo sent to investigators running the trials said.
Scientists are worried that Evusheld could be useless by the end of the year, as new variants take over. The Food and Drug Administration warned this month that the drug is unlikely to protect against infection from BA.4.6, a strain that represents about 12 percent of the viruses circulating in the United States.
Bebtelovimab, the monoclonal made by Lilly, could also face a ticking clock as yet other mutations threaten to undermine its effectiveness.
Companies can choose from many libraries of monoclonal antibody drugs, but questions about how to pick them, prove they work and whether they are safe have become more pressing as the drugs turned out to have a short shelf life, because of the pace of viral evolution.
In an effort to make their drugs more variant-proof, companies are trying to design antibody products that are not similar to the dominant antibodies the human body naturally creates to rout the virus.
Laura Walker, chief scientific officer of Invivyd, a biotechnology company working on monoclonal antibody drugs, described one of the compounds her company is hoping to start testing in people in January as a "freak of nature" - because it binds to an unusual spot on the virus.
"You want to try and look ahead, and the question is: How far do those headlights go?" Walker said.
Unmitigated transmission of the virus will allow it to find vulnerable people - whether because of age or medical risk factors. It could also result in the wild-card scenario that many experts fear: A new and very different variant could emerge from some other branch of the coronavirus evolutionary tree.
A leading theory of omicron's origin is that it evolved as the result of a long-term infection in an immunocompromised patient - and the possibility of a huge jump happening again can't be ignored.
"If we sit on our hands and say, 'Well, we are all fine,' and forget about the vulnerable people who don't make good immune responses, then that might increase the likelihood a new, scarier variant emerges," Abraham, of Harvard, said. "I'm not sure if it's going to happen this winter, but I think it's likely. There's still a lot of room for evolution."