Sudden rise of more transmissible form of Omicron catches scientists by surprise

2022-01-31

On 7 December 2021, as the Omicron variant of the pandemic coronavirus began to pummel the world, scientists officially identified a related strain. BA.2 differed by about 40 mutations from the original Omicron lineage, BA.1, but it was causing so few cases of COVID-19 that it seemed a sideshow to its rampaging counterpart.

“I was thinking: ‘BA.1 has the upper hand. We’ll never hear again from BA.2,’” recalls Mark Zeller, a genomic epidemiologist at the Scripps Research Institute. Eight weeks later, he says, “Clearly that’s not the case. … I’m pretty sure [BA.2] is going to be everywhere in the world, that it’s going to sweep and will be the dominant variant soon in most countries if not all.”

Zeller and other scientists are now trying to make sense of why BA.2 is exploding and what its emergence means for the Omicron surge and the pandemic overall. Already a U.K. report issued last week and a large household study from Denmark posted this week as a preprint make it clear BA.2 is inherently more transmissible than BA.1, leaving scientists to wonder which of its distinct mutations confer an advantage.

But so far, BA.2 does not appear to be making people sicker than BA.1, which itself poses less risk of severe disease than variants such as Delta and Beta. In Denmark, where by 21 January BA.2 accounted for 65% of new COVID-19 cases, “We see a continuous, steep decline in the number of intensive care unit patients and … now a decrease in the number of hospital admissions related to SARS-CoV-2,” says Tyra Grove Krause, an infectious disease epidemiologist at the country’s public health agency. In fact, the Danish government is so confident the variant won’t cause major upheaval that it lifted almost all pandemic restrictions on 1 February.

Still, some scientists predict BA.2 will extend Omicron’s impact. “I would guess we’ll see [BA.2] create a substantially longer tail of circulation of Omicron than would have existed with just [BA.1], but that it won’t drive the scale of epidemics we’ve experienced with Omicron in January,” computational biologist Trevor Bedford of the Fred Hutchinson Cancer Research Center tweeted on 28 January. In South Africa, BA.2 already may be stalling the rapid decline in new infections seen after the country’s Omicron wave peaked in December 2021.

Although BA.2 represented less than 4% of all Omicron sequences in the leading global virus database as of 30 January, it has been identified in 57 countries, with the earliest documented case dating to 17 November in South Africa. It likely now dominates in India, according to Bijaya Dhakal, a molecular biologist at the Sonic Reference Laboratory in Austin, Texas, who examined sequence data uploaded from eight large Indian states. In the United Kingdom, the proportion of likely BA.2 cases doubled from 2.2% to 4.4% in the 7 days that ended on 24 January.

In the United States, the Centers for Disease Control and Prevention is not yet tracking BA.2 separately. But Bedford estimates it accounted for 7% of new U.S. cases as of 30 January, up from 0.7% on 19 January. “In each country and across time, we see that the epidemic growth rate of Omicron BA.2 is greater than Omicron BA.1,” he says.

The report last week from the UK Health Security Agency (UKHSA) backs up that assessment in England, finding BA.2 was spreading faster than BA.1 in all regions where enough data were available to make an assessment. UKHSA data also show that in late December 2021 and early January, transmission was higher among household contacts of BA.2 cases, at 13.4%, than in contacts of other Omicron cases (10.3%).

The study from Denmark, which sequences the virus from virtually every person who gets COVID-19, paints a more dramatic picture. In households where the first case was BA.1, on average 29% of other people in the household became infected. When the first case was BA.2, 39% of household members were infected.

Omicron was already known to have mutations that help it evade antibodies, but the Danish researchers also found that BA.2 may be even better at dodging vaccine-induced immunity: Vaccinated and boosted people were three times as susceptible to being infected with BA.2 as with BA.1. Vaccinated but unboosted people were about 2.5 times as susceptible, and unvaccinated people 2.2 times as susceptible. Early U.K. data, however, showed vaccinated people, if boosted, had about the same level of protection against symptomatic infections with BA.1 or BA.2—63% and 70%, respectively.

In one hopeful and unexpected finding from Denmark, those who were vaccinated or vaccinated and boosted passed on BA.2 to household members less often, relative to BA.1. The same didn’t hold for unvaccinated people, who passed BA.2 to their household contacts at 2.6 times the rate they passed BA.1.

Much as scientists a few weeks ago wondered whether a previous infection with Delta or another variant would protect people from Omicron overall, some are now looking for data on whether Omicron’s first surge created a shield against BA.2. “To what extent does a BA.1 infection protect you against reinfection with BA.2?” Zeller asks. “From what I have seen in Denmark, it’s not going to be 100%.”

Scientists are also probing the variant’s ability to dodge vaccine-induced antibodies in lab dish studies. And drugmaker GlaxoSmithKline is testing its monoclonal antibody, sotrovimab, made with Vir Biotechnology, against BA.2 in lab studies. It’s the only widely authorized antibody that still thwarts BA.1.

Scientists note BA.1 and BA.2 are about as far apart on the evolutionary tree as earlier variants of concern—Alpha, Beta, and Gamma—are from each other (see graphic, below). Some even think BA.2 shouldn’t even be considered Omicron. “I hope in the near future that BA.2 gets its own variant of concern [label] because people assume it’s very similar which it’s not,” Zeller says.

BA.2 doesn’t have all of the mutations that help BA.1 avoid immune detection, but it has some its sibling doesn’t. Thomas Peacock, a virologist at Imperial College London, notes that most of the differences are in an area of the spike protein, called the N-terminal domain (NTD), that houses antibody targets. “What we don’t know is: Just because there are changes, are they changes that actually do something?” says Emma Hodcroft, a molecular epidemiologist at the University of Bern.

But one NTD difference—a deletion at amino acids 69 and 70 that is present in BA.1 and not in BA.2—could give researchers a tool for monitoring the spread of the up-and-coming Omicron strain. Certain SARS-CoV-2 polymerase chain reaction tests detect three genetic sequences of the virus, but the mutation in BA.1’s NTD gene eliminates one of those targets. Polymerase chain reaction tests pick up all three targets in BA.2, providing a proxy for distinguishing the Omicron strains if there is no full virus sequence.

How the sibling strains were born is also preoccupying scientists. Viral evolution in a single immunocompromised patient is one theory, says Andrew Rambaut, an evolutionary biologist at the University of Edinburgh. “It’s possible that long-term infection could produce quite a lot of diversity within a single individual. It could be compartmentalized. So different variants living in different parts of the body.” Both Omicron strains could have also evolved in animals infected with human-adapted SARS-CoV-2, then spread back into people.

Why BA.2 is emerging only now is one more mystery, Hodcroft says. She speculates that a factor as simple as which Omicron caught an earlier flight out of South Africa, where both strains were first identified, may be the explanation. “BA.2 may have just been trapped for a little bit longer. But when it did finally get out and start spreading it started to show that it can edge out its big sister.”

Science, 31 January 2022
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