Nature explores the factors that might drive a COVID-19 wave — and what countries can do to blunt the effects with the new generation of vaccines that target Omicron.

Will there be a COVID-19 wave this autumn and winter?

In mid-August, an effort called the COVID-19 Scenario Modelling Hub laid out several possible US scenarios for the coming months. With surges caused by the BA.5 Omicron variant in the rear-view mirror — resulting in high population immunity — the United States could be in for a relatively quiet COVID-19 season, the models suggested, so long as vaccine booster campaigns began quickly and new variants didn’t emerge. Even with a new variant, a big surge in cases wasn’t certain.

More than a month on, hospitalizations are declining in line with projections, says Justin Lessler, an infectious-disease epidemiologist at the University of North Carolina at Chapel Hill who leads the modelling effort. But other factors on the horizon could spell trouble. The rollout of new, ‘bivalent’ boosters “has been a little bit slow,” says Lessler. And there are now subtle signs that Omicron is evolving and spawning a new cast of immunity-dodging variants. “It could lead to some upswings as we go into the fall and winter months,” Lessler adds.

Some US states are already beginning to see an uptick in cases, notes epidemiologist Jennifer Nuzzo at Brown University in Providence, Rhode Island. The United Kingdom’s weekly population survey of SARS-CoV-2 infections, a gold-standard in COVID data, has also documented an increase in COVID prevalence in its past two reports. Hospitalizations of people who test positive for SARS-CoV-2 are rising quickly — although from low levels — in Britain and other European countries.

In the backdrop, a slew of immunity-dodging variants are emerging globally, and researchers think these variants will fuel an autumn–winter wave.

Are new variants behind rising case numbers?

Probably not yet, says Tom Wenseleers, an evolutionary biologist at the Catholic University of Leuven in Belgium. The current rise in SARS-CoV-2 infections is probably largely because of people’s waning immunity — which offers short-lived protection from infection — as well as increased mixing between people. In many countries including the United Kingdom, social dynamics are nearly back to pre-pandemic levels, say health officials. Factors that cause other respiratory viruses to thrive in cooler months — including extra time spent indoors — could also be at play.

Will we see a new Omicron strain this autumn?

We might see three or more. As the Omicron sub-variants that drove past waves subside — BA.2, BA.4 and BA.5 — evolutionary descendants of these lineages are gaining mutations that seem to be helping them spread.

SARS-CoV-2-watchers are tracking an unprecedented menagerie of new variants from different branches of the Omicron family tree, says Tom Peacock, a virologist at Imperial College London. Despite these variants’ distinct ancestries, they carry many of the same mutations to the SARS-CoV-2 spike protein (the virus’s bullseye, from immune systems’ perspective). “Clearly, there’s an optimal way for a variant to look going into this season,” says Peacock.

Researchers are keeping a close eye on certain sub-lineages. The United Kingdom and some other European countries, for instance, are seeing the swift ascent of BQ.1 (a descendant of BA.5 with several key changes). In India, spawn of the BA.2.75 variant that drove an infection wave several months ago are now outcompeting all others, says microbiologist Rajesh Karyakarte, the Maharashtra State Co-ordinator for SARS-CoV-2 sequencing in Pune. In samples his team sequenced in late September, a sub-variant called BA.2.75.2 was the most common (followed by a close relative). Another BA.2 offshoot, BA.2.3.20, is growing quickly in Singapore, and has turned up in Denmark and Australia.

“I’m fairly confident that at least one of these variants or a combination of them will lead to a new infection wave,” says Wenseleers. And, because they all seem to be behaving similarly, “at the end of the day it’s not that important which of these become the next big thing.”

Why are these variants on the rise?

Two words: immune evasion. All of the variants that researchers are tracking contain multiple overlapping changes to a portion of the spike protein called the receptor binding domain, which is the targeted by potent infection-blocking, or neutralizing, antibodies. That numerous different viruses are independently developing the same spike mutations suggests that these changes provide a big advantage to their ability to spread, says Yunlong Richard Cao, an immunologist at Peking University in Beijing.

In a September preprint1, Cao and his colleagues evaluated the capacity of the new crop of variants to evade neutralizing antibodies from vaccination and prior infection with different variants. They found that, of the bunch, BQ.1.1 (a member of the BQ.1 family with one extra spike change) and BA.2.75.2 were the most immune evasive, even able to dodge most neutralizing antibodies elicited by infection with BA.5. The two remaining antibody drugs that were effective against BA.2 and BA.5 are likely to lose much of their potency against many of the emerging Omicron subvariants, the study also suggests. Another team2 that includes Peacock, came to similar conclusions about BA.2.75.2. “The degree of immune escape and evasion is amazing right now, crazy,” says Cao.

How big will autumn–winter waves be?

Based on initial estimates, Wenseleers thinks that autumn–winter waves will be similar in size to BA.5 surges, at least as far as infection numbers go. What’s harder to predict is the effect on hospitalizations. The build-up of population immunity from vaccination and previous infection is likely to keep admissions lower than past COVID-19 waves, say researchers, but how low is unclear. “While a completely different game than it would have been in 2020 or 2021, a surge still would probably be associated with an increase in deaths and an increase in hospitalizations,” says Lessler.

But even a relatively muted COVID-19 wave could put strain on hospitals, which are facing backlogs and other conditions that put a heavy burden on health systems in the winter. Influenza, which has barely registered the last two winters, is likely to come back with a vengeance in the northern hemisphere this season, stoking fears of a ‘twindemic’ of influenza and COVID-19. “In a bad flu year hospital systems get pretty stressed,” says Lessler.

What about the new vaccines?

Boosters, including new bivalent vaccines that target Omicron lineages, are likely to offer some protection against infection with emerging variants. But this might not last long, say scientists. One part of the bivalent vaccines is based on an Omicron subvariant — BA.1 in UK-approved vaccines and BA.5 in the United States. But there are signs that the vaccines tend to stimulate the production of neutralizing antibodies that best recognize the ancestral virus — on which the first vaccines were based — instead of Omicron. A second dose of these vaccinesmight be needed to generate high levels of Omicron-specific neutralizing antibodies, says Cao.

Fortunately, all evidence suggests that COVID vaccines old and new still remain highly effective at preventing severe disease, which Nuzzo argues should be the main goal of countries’ autumn and winter booster programmes. This means concentrating booster campaigns on those at the highest risk of severe disease, including older people and people with underlying health conditions, who benefit the most from the added protection. “We need a laser focus on protection against severe illness,” she says.