By Helen Branswell? June 2, 2021

In the eight years leading up to the Covid-19 pandemic, one of the subtypes of influenza A viruses started acting bizarrely. Flu viruses continuously evolve, to evade the immune defenses humans develop to fend them off. But after 2012, H3N2 started to behave differently.

It was almost as if there was a falling out within a family. The viruses formed into factions — clades, in virologists’ language — drifting further and further apart with each passing year and making the process of choosing the version of H3N2 to include in flu shots an increasingly challenging task.

The greater the genetic distance between the clades, the bigger the cost of making the wrong choice. Vaccine that protects reasonably well against one might perform poorly if the other turned out to be the dominant strain in a given winter. In fact, that’s precisely what happened in the 2017-18 season, when the flu shot failed to protect three-quarters of vaccinated people in the U.S. against the H3N2 strain in circulation.

But an unexpected upside of the Covid-19 pandemic may have solved this problem for us — or at least made flu’s diversity more manageable.

With Covid suppression measures like mask wearing, school closures, and travel restrictions driving flu transmission rates to historically low levels around the world, it appears that one of the H3N2 clades may have disappeared — gone extinct. The same phenomenon may also have occurred with one of the two lineages of influenza B viruses, known as B/Yamagata.

Neither has been spotted in over a year. In fact, March of 2020 was the last time viral sequences from B/Yamagata or the H3N2 clade known as 3c3.A were uploaded into the international databases used to monitor flu virus evolution, Trevor Bedford, a computational biologist at the Fred Hutchinson Cancer Research Center in Seattle, told STAT.

If the global pool of flu viruses has truly shrunk to this degree, it would be a welcome outcome, flu experts say, making the twice-a-year selection of viruses to be included in flu vaccines for the Northern and Southern hemispheres much easier work.

“I think it has a decent chance that it’s gone. But the world’s a big place,” Bedford said of the H3N2 clade that may have disappeared.

Florian Krammer, a flu expert at Mount Sinai School of Medicine in Manhattan, has been scouring genetic databases looking for B/Yamagata viruses. He’s hoping the viruses in this lineage are gone for good.

“Just because nobody saw it doesn’t mean it has disappeared completely, right? But it could,” Krammer said.

Flu is complex and a brief primer might be helpful here. There are two key families that cause human disease, influenza A and influenza B. Two subtypes of flu A viruses currently transmit among people, H1N1 and H3N2. Within those two subtypes are subclassifications or clades, with H3N2 viruses having more diversity than H1N1.

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Flu B doesn’t have subtypes, but its viruses divide into two “l(fā)ineages”, B/Victoria and B/Yamagata. In the not-too-distant past only one of the B viruses was included in flu shots every year, but now most brands are quadrivalent — four-in-one shots that include one version each of the H1N1 and H3N2 viruses, and both flu B viruses.

“We work so hard to get quadrivalent vaccines … and now, if really Yamagata has disappeared, then actually trivalent [vaccine] would be okay again,” said Ben Cowling, a flu expert at Hong Kong University. For the record, Cowling is among the skeptics when it comes to the question of whether B/Yamagata is actually gone.

So is Cécile Viboud, a flu epidemiologist at the National Institutes of Health’s Fogerty International Center.

“It’s hard to rule out,” Viboud said, adding these viruses could be circulating at low levels in places that didn’t use the types of non-pharmaceutical interventions like mask wearing and social distancing that other countries have employed to suppress Covid transmission. “The world is a very big place.”

The measures used to slow the spread of Covid-19 have had a dramatic impact on transmission of a number of respiratory viruses. Flu, respiratory syncytial virus — known as RSV — and many of the other bugs that afflict us during cold and flu season have been mercifully absent during the pandemic.

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During a typical year, the genetic sequences of about 20,000 flu viruses are logged into GISAID, a repository used by researchers and public health officials to monitor the evolution of influenza and coronaviruses. But in the past year, only 200 were uploaded, Bedford said.

Part of that is likely due to the fact that labs that do viral sequencing are prioritizing work on SARS-CoV-2, the virus that causes Covid. But a big factor here is that there is just a lot less flu transmission occurring, around the globe. That has led to a substantial winnowing of the pool of human flu viruses.

“There had been maybe five-ish, six-ish [H3N2] clades circulating and now there’s two or three that made it through that bottleneck,” Bedford said.

Though there’s been little flu illness globally, there are places that have seen outbreaks during the pandemic, he noted, saying China recorded flu B transmission — the Victoria lineage — and West Africa, Bangladesh, and Cambodia had H3N2 activity.

Richard Webby, director of the World Health Organization Collaborating Centre for Studies on the Ecology of Influenza in Animals and Birds, cautioned that only a portion of flu viruses ever undergo genetic sequencing, so predictions about which flu viruses may have disappeared that are based on what’s in the databases risk being wrong.

But Webby does believe there has been a large reduction in the diversity of the circulating flu viruses, saying it will be interesting to see how that plays out in coming years.

“Without doubt this is definitely going to change something in terms of the diversity of flu viruses out there. The extent to which it changes and how long it stays changed are the big question marks. But we have never seen this before,” said Webby, whose center is based at St. Jude Children’s Hospital in Memphis.

His bet is that the B/Yamagata viruses aren’t gone, noting the flu B virus lineages sometimes go quiet for a while, only to reappear later.

“But I do think we’re likely to lose a little bit of the H3N2 diversity. That’s a great thing. … Currently when we sit down to make recommendations for vaccine strains, it’s always the headache virus,” Webby said.

“If we have to pick a [subtype] to lose diversity in, that would be the one.”