The Omicron Variant Has New Versions Already. What Comes Next?

The fast-moving Omicron variant is on the wane. More than half the states in the US appear to have passed a peak in cases, and global modeling predicts the wave will wash through most of the world by the end of March.

That poses the question: What comes next? SARS-CoV-2 has already provided a near-term answer. A subvariant of Omicron called BA.2 is rapidly supplanting the first version, known as BA.1. In an assessment published last Friday, the United Kingdom’s Health Security Agency said the incidence of BA.2 there doubled in seven days. A few days before that, the Statens Serum Institut, an arm of Denmark’s health ministry, said BA.2 already accounts for almost half of that nation’s Omicron cases.

Similarly quick turnovers have been reported in most of the countries maintaining good data, according to a rapid review published on Twitter by the Pandemic Prevention Institute, a project of the Rockefeller Foundation. Its staff found the same pattern of replacement in India, Germany, and Japan and other Asian nations, as well as the UK. As of January 30, according to the data dashboard Outbreak.info, BA.2 had been found in 57 countries and 29 US states.

From early findings, the BA.2 subvariant looks more transmissible than its already very infectious predecessor. There is not yet any clear signal that it causes more severe disease than BA.1 or improves on that variant’s ability to escape the immune protection created by vaccines. Even without enhancements, though, it's possible that BA.2 could do some damage. The original version of Omicron, in circulation since November, caused less serious illness than its predecessor Delta yet crushed health care systems in the US because its intense infectiousness produced so many cases in unvaccinated people.

In the US, 64 percent of the population is fully vaccinated and 26 percent have gotten boosters, which bolster immunity enough to improve defenses against the original Omicron. In the UK, the rates are 71 percent, with 55 percent boosted. But globally, only 52 percent of the world’s population is fully vaccinated, and in some countries, mostly in sub-Saharan Africa, rates of full vaccination are still in the single digits. So the longer-term answer to “What comes next?” is likely to be “more surprises,” as the coronavirus’s restless evolution presses against the incomplete protections we have distributed patchily around the world.

BA.2 isn’t new, precisely. The South African researchers who flagged the emergence of the original Omicron identified BA.2 a week later based on differences in the mutations that made Omicron so distinct from Delta. (A nomenclature note: Scientists are generally calling BA.2 a “sublineage” or “subvariant” because the World Health Organization has not classified BA.2 as a stand-alone variant earning its own Greek letter. In that early work, the South African group also identified a BA.3.)

But while the original Omicron roared around the world right away, the second version took a while to rev up. That’s puzzling to scientists, who are waiting for more data. “From a virology perspective, it's fascinating,” says Nathan Grubaugh, a viral epidemiologist and associate professor at the Yale School of Public Health. “The differences in mutations between BA.1 and BA.2 are similar to the number of differences between Alpha and Delta. There’s a lot of distance between them. So virologists and evolutionary biologists are asking: Where did this come from? How is it so divergent?”

Among the original Omicron’s key differences from Delta, the variant that emerged in the summer of 2021, are a new ability to infect cells lining the upper airway—the nose and throat, instead of the lungs—along with some enhanced facility for escaping the antibody defenses created by vaccination or prior infection. In combination, those made Omicron much more transmissible. As Omicron BA.2 takes over, suggesting it’s more transmissible still, the question becomes whether its divergence has allowed it to get better at cell entry and replication or at immune escape.

The answer could determine what the next phase of the pandemic looks like. “If BA.2 is able to escape immune responses better than BA.1—or if it's able to escape the immune responses that so many people globally just had to BA.1—then we're likely to see a resurgence in cases,” Grubaugh says. “If BA.1 infection can protect against BA.2, then we’re likely to see just a slower decline.”

That switch in Omicron’s preferred site of attack from deep in the lungs to high up in the airway—which made it easier for infected people to cough germs onto others—gave it a transmission advantage over Delta. It also may have reduced the occurrence of devastating illness that marked the earliest waves of the pandemic by keeping the virus from invading the lungs and other organs. Data published last week by the US Centers for Disease Control and Prevention shows that, even though case numbers and hospitalizations soared during the Omicron wave, health care metrics that indicate severe illness—such as the number of days patients stayed in hospitals and whether they were admitted to an ICU—actually decreased.

But whether Covid is now intrinsically a more mild disease or has been rendered that way by the blunting effect of immunity from vaccination or infection can’t yet be determined. The emergence of Omicron BA.1 and BA.2 were detected by genomic studies, but it’s too soon to have results from the kind of lab assays and population studies that will help untangle whether SARS-CoV-2 is becoming less virulent as it settles into endemicity. Many virologists are skeptical. “I can’t think of a virus in history that has evolved to mildness,” says Rick Bright, a virologist and former director of the US Biomedical Advanced Research and Development Authority. “Evolution favors transmissibility.”

Bright, who now leads the Rockefeller prevention initiative, argues the US has been missing opportunities to build tools that could detect the emergence of variants more quickly. Before Omicron arrived, the CDC switched away from studying most breakthrough infections, choosing to analyze only ones that sent people to the hospital or killed them. The Rockefeller team thinks the mild infections that the agency no longer prioritizes could hold crucial information. “That is the primordial soup, where the virus is evolving and mutating,” Bright says.

“We have to invest in sequencing the mild cases, and when we do that, we're going to light up that battlefield where this virus is changing and evolving,” he adds. “We can wait for these dangerous variants to smack us in the face, or we can look at the evolution under the surface of this virus and predict where the virus will go.”

Some of the first indications that Omicron and then BA.2 emerged in the US came from wastewater sampling, which is an inexpensive and relatively low-tech surveillance scheme compared to testing patients and reporting their results to information systems governed by state authorities and federal privacy laws. The shock of the newest variants’ arrival could be enough to drive adoption of additional data sources to flag them: passively collected mobility info, at-home rapid-test results, immunity surveys over zip codes or census tracts.

All the red flags in the world, though, won’t stop new variants from arriving. SARS-CoV-2 can’t be chased from the planet—it has found a home in multiple animal species—but we can deny it the chance to adapt to human immune systems. Protection could be conferred by prior infection, though this is not guaranteed: Omicron caused reinfections in people who had already contracted Delta and breakthrough infections in people who had taken the vaccines. And developing immunity through infection alone risks an unpredictable illness and recovery, or long Covid, or the whole-body inflammatory attack in children known as MIS-C.

The simpler answer is to distribute full courses of vaccines, including boosters, as widely as possible. “The best way to prevent more, more-dangerous, or more-transmissible variants from emerging is to stop unconstrained spread, and that requires many integrated public-health interventions, including, crucially, vaccine equity,” Aris Katzourakis, a professor of evolution and genomics at the University of Oxford, wrote in Nature last week.

Vaccine equity has consistently been where the world’s pandemic response stumbles and stops. Researchers say—and have said so often that they now sound despairing—that pandemic control can never succeed until vaccine access improves. Worldwide, more than 3 billion people have received no vaccine at all.

“There is no reason at all why the next variant—which will happen, because of the billions of people in whom billions of virus particles are replicating right now—by sheer chance, could be way more sinister than Omicron,” says Madhukar Pai, the Canada research chair in epidemiology and global health at McGill University. “There is no reason at all, from everything we've seen with this virus, to hope that the next variant will not emerge, or that Omicron will be a mass immunizing event that will see us to the end of the pandemic.”

The interplay between vaccines and new variants is visible in a preprint that Grubaugh posted online last week, containing the results of a study by Yale and University of Nebraska researchers of 37,877 PCR-positive Covid tests performed as Omicron was moving into Connecticut. The research, which has not yet been peer-reviewed, shows that two vaccine doses created some defense against Delta, forcing the positive test rate down by almost half compared to people who were unvaccinated. Adding boosters reduced the positive rate by 83 percent. But among the people who became infected with Omicron, significant protection didn’t kick in until after they received boosters—and even then, half of the participants still registered positive on their Covid tests.

The funny thing about that finding was that Grubaugh predicted it—last month, in a paper in the journal Cell written with Sarah Cobey, an associate professor at the University of Chicago. The authors envisioned that the next successful variant would leapfrog over its predecessors by combining increased transmissibility, the advantage Delta possessed, with greater facility for immune escape, the trick deployed by earlier variants. The catch: They thought a newer, more nimble variant would emerge from Delta—and not, as Omicron did, from a distant branch of the virus’s evolutionary tree.

Grubaugh acknowledges that this constitutes a lesson about the need to think through all the possibilities. “We lacked the imagination to see that there's some unknown reservoir floating around, in which this virus evolved in such a divergent way,” he says. It’s a useful reminder that as Omicron 1 and 2 and 3 gnaw at the outer edges of how transmissible a virus can become, SARS-CoV-2 can still retain the capacity to surprise.