The Flu May Never Be the Same

In March 2020, Yamagata’s trail went cold.

The pathogen, one of the four main groups of flu viruses targeted by seasonal vaccines, had spent the first part of the year flitting across the Northern Hemisphere, as it typically did. As the seasons turned, scientists were preparing, as they typically did, for the virus to make its annual trek across the equator and seed new outbreaks in the globe’s southern half.

That migration never came to pass. As the new coronavirus spread, pandemic-mitigation measures started to squash flu-transmission rates to record lows. The drop-off was so sharp that several flu lineages may have gone extinct, among them Yamagata, which hasn’t been definitively detected in more than three years despite virologists’ best efforts to root it out.

Yamagata’s disappearance could still be temporary. “Right now, we’re all just kind of holding our breath,” says Adam Lauring, a virologist at the University of Michigan Medical School. The virus might be biding its time in an isolated population, escaping the notice of tests. But the search has stretched on so fruitlessly that some experts are ready to declare it officially done. “It’s been missing for this long,” says Vijaykrishna Dhanasekaran, a virologist at Hong Kong University. “At this point, I would really think it’s gone.”

If Yamagata remains AWOL indefinitely, its absence would have at least one relatively straightforward consequence: Researchers might no longer need to account for the lineage in annual vaccines. But its vanishing act could have a more head-spinning implication. Flu viruses, which have been plaguing human populations for centuries, are some of the most well-known and well-studied threats to our health. They have prompted the creation of annual shots, potent antivirals, and internationally funded surveillance programs. And yet, scientists still have some basic questions about why they behave as they do—especially about Yamagata and its closest kin.

Yamagata, in many ways, has long been an underdog among underdogs. The lineage is one of two in a group called influenza B viruses, and it’s slower to evolve and transmit, and is thus sometimes considered less troublesome, than its close cousin Victoria. As a pair, the B’s are also commonly regarded as the wimpier versions of flu.

To be fair, the competition is stiff. Flu B’s are constantly being compared with influenza A viruses—the group that contains every flu subtype that has caused a pandemic in our recent past, including the extraordinarily deadly outbreak of 1918. Seasonal flu epidemics, too, tend to be heavily dominated by flu A’s, especially H3N2 and H1N1, two notably tough-to-target strains that feature prominently in each year’s vaccine. Even H5N1, the flavor of avian influenza that’s been devastating North America’s wildlife, is a member of the pathogen’s A team.

B viruses, meanwhile, don’t have a particularly daunting résumé. “To our knowledge, there has never been a B pandemic,” says John Paget, an infectious-disease epidemiologist at the Netherlands Institute for Health Services Research. Only once every seven seasons or so does a B virus dominate. And although A and B viruses sometimes tag-team the winter, causing twin outbreaks spaced out by a few weeks, these seasons often open with a major flu A banger and then close out with a more muted B coda.

The reasons underlying these differences are still pretty murky, though scientists do have some hints. Whereas flu A viruses are known as especially speedy shape-shifters, constantly spawning genetic offshoots that vie to outcompete one another, flu B’s evolve at oddly plodding rates. Their sluggish approach makes it easier for our immune system to recognize the viruses when they reappear, resulting in longer-lasting protection, more effective vaccines, and fewer reinfections than are typical with the A’s. Those molecular differences also seem to drive differences in how and when the viruses spread. The A’s tend to trouble people repeatedly from birth to death, and are great at globe-trotting. But B’s, perhaps because immunity against them is easier to come by, more often concentrate among kids, many of whom have never encountered the viruses before—and who are usually more resilient to respiratory viruses and travel less than adults, keeping outbreaks mostly regional. That might also help explain why B epidemics so frequently lag behind A’s: Slower pathogen evolution facing off with more durable host immunity add up to less rapid B spread, while their A colleagues rush ahead. Our bodies also seem to mount rather fiery defenses against A viruses, steeling them against other infections in the weeks that follow and deepening the disadvantage against any B’s trailing behind. All of that means flu B has a hard time catching humans off guard.

The virus’s host preferences, too, make flu A viruses more dangerous. Those lineages are great at hopscotching among a whole menagerie of species—most infamously, pigs and wild, water-loving birds—sometimes undergoing rapid bursts of evolution as they go. But flu B’s seem to almost exclusively infect humans, igniting only the rare and fast-resolving outbreak in a limited number of other species—a few seals here, a handful of pigs there. Spillovers from wild creatures into humans are the roots of global outbreaks. And so, with its zoonotic bent, “influenza A will always be the main focus” of concern, says Carolien van de Sandt, a virologist at the Peter Doherty Institute for Infection and Immunity, in Melbourne. Even among some scientists, Yamagata and Victoria register as little more than literal B-list blips.

Plenty of other experts, though, think flu B’s relative obscurity is misguided—perhaps even a bit dangerous. Flu B’s account for roughly a quarter of annual flu cases, many of which lead to hospitalization and death; they seem hardier than their A cousins against certain antiviral drugs. And scientists simply know a lot less about flu B’s: how, precisely, they interact with the immune system; what factors influence their sluggish evolutionary rate; the nuances of their person-to-person spread; their oddball animal-host range. And that lack of intel on what has for decades been a formidable infectious foe creates a risk all on its own.

Flu lineages have dipped into relative obscurity before only to come roaring back. After the end of the H2N2 pandemic of the late 1950s, H1N1 appeared to flame out—only to reemerge nearly two decades later to greet a population full of young people whose immune systems hadn’t glimpsed it before. And as recently as the 1990s, the B lineage Victoria underwent a years-long ebb in most parts of the world, before ricocheting back to prominence in the early 2000s.

As far as researchers can tell, Victoria is alive and well; during the globe’s most recent winter seasons, the lineage appears to have ignited late-arriving outbreaks in several countries, including in South Africa, Malaysia, and various parts of Europe. But based on the viral sequences that researchers have isolated from people sick with flu, Yamagata is still nowhere to be found, says Saverio Caini, a virologist at the cancer research center ISPRO, in Italy.

The lineage was already teetering on a precipice before the pandemic began, van de Sandt told me. Yamagata and Victoria, which splintered apart in the early 1980s, are still closely related enough that they often compete for the same hosts. And just prior to 2020, Victoria, the more diverse and fleet-footed of the two B lineages, had been reliably edging out its cousin, pushing Yamagata’s prevalence down, down, down. That trend, coupled with several years of use of a well-matched Yamagata strain in the seasonal flu vaccine, meant that Yamagata “had already decreased in incidence and circulation,” van de Sandt said. With the odds so steeply stacked, the addition of pandemic mitigations may have been the final factor that snuffed the lineage out.

Recently, a few countries—including China, Pakistan, and Belize—have tentatively reported possible Yamagata infections. But there’s been no conclusive genetic proof, several experts told me. Several parts of the world, including the United States, regularly use flu vaccines containing active flu viruses that can trip the same viral tests that the wild, disease-causing pathogens do. “So the reports could be contaminations,” van de Sandt said. Scientists would need to scour the virus’s genetic sequences to distinguish infection from injection; those data, however, haven’t emerged.

Should the Yamagata dry spell continue, researchers may want to start considering snipping the lineage out of vaccines altogether, perhaps as early as the middle or end of this year. Doing so would punt the world back to the early 2010s, when flu shots were trivalent—designed to protect people against two A viruses, H3N2 and H1N1, plus either Victoria or Yamagata, depending on which lineage researchers forecasted would surge more. (They were often wrong.) Or maybe the space once used for Yamagata could feasibly be filled with another flavor of H3N2, the fastest mutator of the bunch.

But purging Yamagata from the vaccine would be a gamble. If Yamagata is not gone for good, van de Sandt worries that booting it from the vaccine would leave the world vulnerable to a massive and deadly outbreak. Even Dhanasekaran, who is among the researchers who are fairly confident that we’ve seen the last of Yamagata, told me he doesn’t want to rule out the possibility that the virus is cloistering in an immunocompromised person with a chronic infection, and it’s unclear if it could reemerge from such a hiding place. The only thing scientists can do for now is be patient, says Jayna Raghwani, a computational biologist at the University of Oxford. “If we don’t see it in successive seasons for another two to three years, that will be more convincing,” she told me.

If Yamagata’s death knell has actually rung, though, it will have reverberating effects. There’s no telling, for instance, how other flu lineages might be affected by their colleague’s supposed retirement. Perhaps Victoria, which can swap genetic material with Yamagata, will evolve more slowly without its partner. At the same time, Victoria may have an easier time infecting people now that it no longer needs to compete as often for hosts.

If Yamagata has gone to pasture, “there won’t be a ceremony declaring the world Yamagata free,” Lauring told me. And it’s easy, he points out, to forget things we don’t see. But even if Yamagata seems gone for now, the effects of its demise will be significant enough that it can’t be forgotten—not just yet.



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