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In recent months, scientists have identified multiple new Omicron subvariants of SARS-CoV-2. First spotted in South Africa and the United States, the subvariants—BA.4, BA.2.12.1, and BA.5—have driven new upticks in cases in both nations. The new versions of Omicron are even better at evading the protection offered by vaccines, a previous infection, or a combination of the two. So far, it’s unclear whether the new subvariants will drive a spike in cases worldwide as their predecessors, the Omicron BA.1 and then BA.2 strains, did this past winter and spring, respectively. 

“We’re definitely entering a resurgence in South Africa, and it seems to be driven entirely by BA.4 and BA.5,” Penny Moore, a virologist at the University of the Witwatersrand in Johannesburg, South Africa, tells Science. “We’re seeing crazy numbers of infections. Just within my lab, I have six people off sick.”

See “Scientists Investigate Omicron Subvariant BA.2” 

Science reports that BA.4 and BA.5 first cropped up in South Africa in early January but have only recently caused a large spike in cases in South Africa, the number of which increased 10-fold (from 1,000 to 10,000 daily reported cases) between April 17 and May 7. In April, scientists first detected Omicron subvariant BA.2.12.1 in New York. It has been spreading across the US ever since.

In most cases, vaccination or prior infection still seem to provide protection from severe disease caused by the subvariants. “There’s no reason to freak out,” John Moore, an immunologist at Weill Cornell Medicine, tells Science. While he says that the new strains are “an additional hassle,” he adds that “there’s no indication that they’re more dangerous or more pathogenic” than earlier forms of Omicron. 

See “How Mild Is Omicron Really?” 

The new subvariants may complicate vaccine makers’ efforts to roll out variant-specific shots, reports Nature. Although the numbers of infections and hospitalizations in South Africa and the US caused by the variants are on the rise, researchers suggest that the waves of infection due to specific variants might be becoming more predictable, reports STAT. Here’s what we know so far: 

The BA.2 subvariant 

First detected in South Africa back in November 2021 (at the same time as BA.1) and the US in January, according to Scientific Americanthe BA.2 subvariant quickly overtook BA.1, the previous subvariant of Omicron. BA.2 shares 32 mutations with BA.1 that distinguish them from ancestral SARS-CoV-2 virus, but carries 28 other mutations that distinguish it from BA.1, including on the receptor binding domain that binds to host cells. Known as “stealth Omicron” because it’s harder to detect via standard PCR tests, BA.2 was roughly 1.5 times more transmissible that the original variant. By mid-April, BA.2 represented close to 90 percent of cases in the US but did not cause a severe wave, in part because of the protection offered by prior BA.1 infections, according to New York Magazine.

The BA.2.12 and BA.2.12.1 subvariants 

These new subvariants, first detected in New York, are closely related to BA.2 but are 25 percent more transmissible, according to US News & World Report. BA.2.12.1 now makes up 48 percent of cases in the US, according to CDC data published today (May 17). It has been detected in 23 countries, according to CNBC.

The BA.4 and BA.5 subvariants

These subvariants cropped up in South Africa in early January and are more transmissible than BA.2. Outside of South Africa, these variants are circulating at low levels, with less than 300 cases of BA.5 and 700 cases of BA.4 detected across 16 and 17 nations, respectively, CNBC reports. 

The new variants may be better at evading previous infections and vaccination

A study posted as a preprint on medRxiv on May 2 found that BA.4 and BA.5 are better at evading host immunity than Omicon BA.1, even with the immunological boost offered by vaccination or having been infected with BA.1. Researchers in South Africa collected blood samples from both vaccinated and unvaccinated patients with previous BA.1 infections between November and December 2021. Antibodies in the samples were several times less effective at neutralizing BA.4 or BA.5 than they were at neutralizing the original Omicron strain. However, antibodies from people who had been vaccinated were more potent against the new subvariants than were those of unvaccinated people who had survived a BA.1 infection. Researchers tell Science that this may be in part because immunity has waned since South Africa’s BA.1 wave peaked in December. 

See “CDC: COVID-19 Booster Effectiveness Wanes After Four Months

Another preprint study published May 2 on bioRxiv also found that antibodies from patients that had recovered from a BA.1 infection were less potent at neutralizing the BA.4, BA.5, and BA.2.12.1 subvariants in the lab than they were against BA.1. For the study, a China-based team made copies of the coronavirus spike protein based on the sequences of the new subvariants and tested how well different antibodies could prevent the proteins from binding to cells. The researchers collected blood samples from 156 vaccinated and boosted subjects, including some who had recovered from either BA.1 or severe acute respiratory syndrome (SARS), the coronavirus disease that caused deadly outbreaks two decades ago. Like the South African team, they found that blood from patients who had been infected with BA.1 had a weaker ability to neutralize BA.4, BA.5, and BA.2.12.1. Curiously, they found that blood from vaccinated participants who also recovered from BA.1 was even worse at neutralizing antibodies than blood from unvaccinated participants that had been infected with BA.1. 

Nature reports that separate work by David Ho at Columbia University in New York City also confirms these findings. (Ho hasn’t yet reported his team’s data in a preprint but has shared them with US government officials.)

How the strains dodge immunity

The bioRxiv preprint points to why the new strains might be able to escape the immune response conferred by previous vaccination and infection. The three subvariants—BA.4, BA.5, and BA.2.12.1—have mutations that alter amino acid L452, which is part of the coronavirus’s receptor-binding domain, the part of the spike protein that helps the virus lock onto and infect cells. That domain is also a key target for protective antibodies. “The independent appearance of four different mutations at the same site? That’s not normal,” preprint author and immunologist Yunlong Richard Cao of Peking University tells Science. The authors suspected it was the virus’ response to the high levels of population immunity generated by vaccination and widespread Omicron infection. The Delta variant, Science reports, also had significant mutations in L452, so many scientists have been watching the region closely. 

The emergence of these strains suggests that the Omicron lineage is continuing to develop increased transmissibility, says Ho. 

Making vaccines to combat variants

The limited protection that BA.1 infection provided against the new subvariants in lab studies has already raised questions about how useful new Omicron-specific vaccines under development by Moderna, Pfizer-BioNTech, and others might be. Linfa Wang, a bat coronavirus expert at the Duke-NUS Medical School in Singapore, tells Science that the virus is evolving too quickly for strain-specific vaccines to keep up. Instead, a broad cocktail of monoclonal antibodies targeting different strains may be the best way forward, he says.

Such a treatment could potentially prevent infections for several months in those vulnerable to severe disease, including immunocompromised people. Protecting that group is crucial, Wang tells Science, because many researchers suspect new variants emerge during long-term infections in people whose immune systems fail to clear the virus. The main hurdle is cost, Wang says. A dose of monoclonal antibodies is about $1,000 per patient, “but if someone could find a way to lower that to $50 or $100,” then it could be a more effective long-term strategy for staving off infection, he says. Additionally, the approach could be cheaper than updating vaccines. 

Predicting the next wave

Scientists tell Nature that BA.4 and BA.5 may not set off a fresh COVID-19 wave in Europe and North America, where the strains have been detected—at least not right now. The variants are closely related to BA.2, which has just finished sweeping through Europe, so the population's immunity could still be high, Tom Wenseleers, an evolutionary biologist at the Catholic University of Leuven in Belgium, tells Nature. “It gives hope that maybe in Europe it will have a smaller advantage and will cause a smaller wave.”

Nature reports that if SARS-CoV-2 continues along this path, its evolution could resemble that of respiratory illnesses that are seasonal and come in waves. The coronavirus’s pattern of infection may also become more predictable, as new mutations in the virus exploit vulnerabilities in population-wide immunity, driving periodic waves of infection. “It is probably what we should expect to see more and more of in the future,” Moore tells Nature. Scientists may get better at predicting how long immunity to COVID-19 will last and when waves will hit.   

“That is one way to read the patterns that have been observed so far,” Jesse Bloom, a viral evolutionary biologist at the Fred Hutchinson Cancer Research Center in Seattle, tells Nature. “But I think we should be cautious in extrapolating general rules from a fairly short observation time frame.”