A swarm of covid variants could fuel a winter wave

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For two years, coronavirus variants emerged, one by one, sweeping the globe.

But this fall and winter is 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 is unlikely that we will be blocked with a new collection of Greek alphabet variants. Instead, one or more of the many versions of the omicron variant that keep popping up may power the next wave. They are different varieties of omicron, but eerily similar – adorned with a similar combination of mutations. Each new subvariant appears to surpass the last in its ability to evade immune defenses.

“It’s this constant evolutionary arms race we have with this virus,” said Jonathan Abraham, an assistant professor of microbiology at Harvard Medical School.

The pace of development is so fast that many scientists rely 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 others regarding sub-lineages. In the US, BA.4.6 and BF.7 are slowly coming up. A few weeks ago, BQ.1.1 began to steal the limelight – and still looks like a candidate to take over this autumn in Europe and North America. A genus called XBB looms large on the sidelines, threatening to upend the forecast.

To focus too much on one possible variant is, many experts argue, to miss the point. What matters is that all of these new threats accumulate mutations at similar sites in what’s called the receptor-binding domain — a key point in the spike protein where virus-blocking antibodies attach. If these antibodies cannot dock, they cannot block. Each new mutation gives the virus a leg up in avoiding this primary line of immune defense.

Most virologists are dubious when asked which variant – or variants – will infect people this winter. That doesn’t mean they think the virus is standing still.

A large part of the world’s population has acquired some degree of immunity due to vaccinations and infections with omicron. That protection gave us the relative freedoms of the moment – with many people returning to normal life. But the protection is fleeting for two key reasons: Immunity wanes and the virus changes. And then there’s this: Monoclonal antibodies, targeted drugs that can be used as treatment or to protect immunocompromised people who don’t respond well to vaccines, are likely to be knocked out of future variants.

“It’s important for people to understand that the fact that there is no Greek letter name that has come out does not mean that the virus stopped evolving,” said Jesse Bloom, an expert in viral evolution at Fred Hutchinson Cancer Research Center in Seattle, which described the evolutionary speed of SARS-CoV-2 as “strikingly fast.”

Instead of worrying about which variant will win, or even focusing on particular mutations, many researchers have switched to looking at hotspots — specific sites on the virus, known by numbers as an address, where any change in the virus’s code can allow the slipping 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 maintain shortlists of worrisome sites of mutation: 346, 444, 445, 452, 460, 486, 490.

Seeing so many lineages of coronaviruses develop similar constellations of genetic changes at these sites is a sign of convergent evolution—when different versions of the virus are beaten into the wall of immune defenses in the human population and then come up with similar ways of getting around them. It happens with influenza, but it is quite new for SARS-CoV-2. And in the case of the coronavirus, the more mutations, the greater advantage a new variant appears to have.

Cornelius Roemer, a computational biologist at the University of Basel in Switzerland, has ranked the new omicron sublineages by how many mutations they have in the receptor binding domain.

XBB seems to be the best at avoiding immunity. Researchers in China have found that XBB can evade the protective antibodies generated by a breakthrough BA.5 infection, raising concerns that knockdown boosters developed to target BA.4 and The BA.5 versions of omicron can quickly be surpassed. Still, these booster shots remain the best tool on the shelf.

“We don’t have a better choice at this time,” Yunlong Cao, a scientist at the Biomedical Pioneering Innovation Center at 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’s XBB, BQ.1.1, or an as-yet-unknown twist on omicron, most experts agree that variants will help fuel a difficult fall and winter.

“These lineages will have a greater ability to reinfect humans than what is currently circulating … which is very likely to drive or contribute to waves of infection over the winter,” Tom Peacock, a virologist at Imperial College London, said in an e -mail.

It is a matter of debate what will happen when one or more of them gain a foothold in a population with a protective layer of underlying immunity. Protection against the worst outcomes is likely to hold up, especially if boosted by boosters, many researchers predict.

Cases are already piling up in Europe. Many researchers believe the recovery is largely driven by factors such as children going back to school, people spending more time indoors and the seasonal spread of the virus. The variants may have just started to contribute.

“We are definitely 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 urged people to get an updated booster if they are eligible. “We have to watch and follow these things very carefully because we want to make sure we have a good handle on what’s going on in terms of the emergence of variants and what impact they’re going to have on all the trends, we are. see you in the winter.”

But the impact on society could still be significant, even with an increase in cases that does not lead to a massive surge in hospitalizations.

“To put it in context, the summer was not considered a wave – but at the same time there were lots of problems with absenteeism and that kind of had an impact on the world as a whole,” said Manon Ragonnet-Cronin, a scientist at the University of Chicago. “Our primary measure of how bad these waves are tends to be hospitalizations and deaths, but these other effects shouldn’t be ruled out.”

There is nothing certain about a late-autumn wave – whether one will happen, what its size might be, or what might trigger 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.

“One strain may 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 ends up dominating in the coming months will likely 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 disease in people with compromised immune systems. Another monoclonal, bebtelovimab, is used as treatment.

The pharmaceutical companies that make these drugs emphasize 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 these therapies—and may even undermine the next generation of candidates that have yet to enter the medicine cabinet.

Regeneron Pharmaceuticals, a major maker of monoclonal antibodies, put startup activities on hold in late September with clinical trials of its new drug — pointing not to a particularly new line of omicron, but to a mutation in one of the hotspots.

“We are requesting that all start-up activities … be paused to allow Regeneron to evaluate the new variant and its potential impact on our planned clinical development trials,” said a company memo sent to investigators running the trials.

Researchers are concerned that Evusheld may 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 viruses circulating in the United States.

Bebtelovimab, the monoclonal made by Lilly, may 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 choose them prove that they work and whether they are safe has become more urgent as the drugs proved to have a short shelf life due to the pace of viral evolution.

In an effort to make their drugs more variant-proof, companies are trying to design antibody products that do not resemble the dominant antibodies the human body naturally creates to clear the virus.

Laura Walker, chief scientific officer of Invivyd, a biotech company working on monoclonal antibody drugs, described one of the compounds her company hopes to begin testing in humans in January as a “freak of nature” — because it binds to an unusual place on the virus.

“You want to try to look ahead, and the question is: How far do those headlights go?” Walker said.

Unrestricted transmission of the virus will allow it to find vulnerable people – whether due to age or medical risk factors. It could also result in a wild-card scenario that many experts fear: A new and very different variant could emerge from a different branch of the evolutionary coronavirus tree.

A leading theory about omicron’s origin is that it developed as a result of a long-term infection in an immunocompromised patient – and the possibility of a big leap happening again cannot be ignored.

“If we sit on our hands and say, ‘Well, we’re all fine,’ and forget about the vulnerable people who don’t make good immune responses, then that could increase the likelihood of a new, scarier variant emerging,” Abraham said. from 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 development.”

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