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

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 published last week and a large household study from Denmark posted as a preprint today make it clear BA.2 is inherently more transmissible than BA.1, leaving scientists to wonder which of the former’s distinct mutations give it 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 is lifting 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 appears to be stalling the rapid decline in new infections seen after the country’s Omicron wave peaked in December 2021.

Although BA.2 represents less than 3% of all Omicron sequences in the leading global virus database, it has been identified in 57 countries—the earliest documented case so far dates back to 17 November in South Africa. It likely now dominates in India, according to Bijaya Dhakal, a molecular biologist at Sonic Healthcare 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 was available to make an assessment. UKHSA data also show that in late December 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 a sample from virtually every person who gets COVID-19, paints a more dramatic picture. In households where the first case was a BA.1 infection, 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. Preliminary U.K. data, however, showed vaccinated and boosted people 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 reinfections with BA.2. “To what extent does a BA.1 infection protect you against reinfection with BA.2?” asks  Zeller. “From what I have seen in Denmark, it’s not going to be 100%.”

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 provocatively think BA.2 shouldn’t even be considered an 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.

Not so similar

As this depiction of the SARS-CoV-2 evolutionary tree suggests, the BA.1 and BA.2 strains of the Omicron variant are about as genetically distinct as earlier variants Alpha, Beta, and Gamma are from each other.

depiction of the SARS-CoV-2 evolutionary tree showing BA.1, BA.2, Alpha, Beta, and Gamma variants
GISAID/Nextstrain/NCO, adapted by K. Franklin/Science

Although BA.2 doesn’t have all the BA.1 mutations that help the original Omicron avoid immune detection, it may have new ones. Thomas Peacock, a virologist at Imperial College London, notes that most of the differences between the strains 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—comes from a mutation that scientists can use to distinguish the strains in the current, nearly all-Omicron environment.  SARS-CoV-2 polymerase chain reaction tests detect 3 genetic sequences of the virus but the BA.1 mutation eliminate one of those targets. They do pick up all three sequences if a sample is BA.2, providing a useful proxy for the strain when it’s not possible to fully sequence a virus.  

How the sister strains were born is also preoccupying scientists. 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.” Other scientists have suggested that after human-adapted SARS-CoV-2 spread back into animals, Omicron, perhaps both strains, evolved in them—and then jumped back into people.

 Why BA.2 is emerging now, given that it’s more transmissible than BA.1, is one more mystery, Hodcroft says. She speculates that a factor as simple as which virus 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.”

With reporting by Kai Kupferschmidt.