Tag: Kanta Subbarao

Flu Shots Need to Stop Fighting ‘Something That Doesn’t Exist’

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In Arnold Monto’s ideal vision of this fall, the United States’ flu vaccines would be slated for some serious change—booting a major ingredient that they’ve consistently included since 2013. The component isn’t dangerous. And it made sense to use before. But to include it again now, Monto, an epidemiologist and a flu expert at the University of Michigan, told me, would mean vaccinating people “against something that doesn’t exist.”

That probably nonexistent something is Yamagata, a lineage of influenza B viruses that hasn’t been spotted by global surveyors since March of 2020, shortly after COVID mitigations plummeted flu transmission to record lows. “And it isn’t for lack of looking,” Kanta Subbarao, the director of the WHO’s Collaborating Centre for Reference and Research on Influenza, told me. In a last-ditch attempt to find the missing pathogen, a worldwide network of monitoring centers tested nearly 16,000 influenza B virus samples collected from February to August of last year. Not a single one of them came up Yamagata. “The consensus is that it’s gone,” Cheryl Cohen, the head of South Africa’s Centre for Respiratory Diseases and Meningitis, told me. Officially removing an ingredient from flu vaccines will codify that sentiment, effectively publishing Yamagata’s obituary.

Read: The flu may never be the same

Last year around this time, Subbarao told me, the WHO was already gently suggesting that the world might want to drop Yamagata from vaccines; by September, the agency had grown insistent, describing the ingredient as “no longer warranted” and urging that “every effort should be made to exclude it as soon as possible.” The following month, an advisory committee to the FDA unanimously voted to speedily adopt that same change.

But the switch from a four-flu vaccine to a trivalent one, guarding against only three, isn’t as simple as ordering the usual, please, just hold the Yams. Trivalent vaccines require their own licensure, which some manufacturers may have allowed to lapse—or never had at all; manufacturers must also adhere to the regulatory pipelines specific to each country. “People think, ‘They change the strains every season; this should be no big deal,’” Paula Barbosa, the associate director of vaccine policy at the International Federation of Pharmaceutical Manufacturers and Associations, which represents vaccine manufacturers, told me. This situation is not so simple: “They need to change their whole manufacturing process.” At the FDA advisory-committee meeting in October, an industry representative cautioned that companies might need until the 2025–26 season to fully transition to trivalents in the Northern Hemisphere, a timeline that Barbosa, too, considers realistic. The South could take until 2026.

In the U.S., though, where experts such as Monto have been pushing for expedient change, a Yamagata-less flu vaccine could be coming this fall. When I reached out to CSL Seqirus and GSK, two of the world’s major flu-vaccine producers, a spokesperson from each company told me that their firm was on track to deliver trivalent vaccines to the U.S. in time for the 2024–25 flu season, should the relevant agencies recommend and request it. (The WHO’s annual meeting to recommend the composition of the Northern Hemisphere’s flu vaccine isn’t scheduled until the end of February; an FDA advisory meeting on the same topic will follow shortly after.) Sanofi, another vaccine producer, was less definitive, but told me that, with sufficient notice from health authorities, its plans would allow for trivalent vaccines this year, “if there is a definitive switch.” AstraZeneca, which makes the FluMist nasal-spray vaccine, told me that it was “engaging with the appropriate regulatory bodies” to coordinate the shift to a trivalent vaccine “as soon as possible.”

Quadrivalent flu vaccines are relatively new. Just over a decade ago, the world relied on immunizations that included two flu A strains (H1N1 and H3N2), plus one B: either Victoria or Yamagata, whichever scientists predicted might be the bigger scourge in the coming flu season. “Sometimes the world got it wrong,” Mark Jit, an epidemiologist at the London School of Hygiene & Tropical Medicine, told me. To hedge their bets, experts eventually began to recommend simply sticking in both. But quadrivalent vaccines typically cost more to manufacture, experts told me. And although several countries, including the U.S., quickly transitioned to the heftier shots, many nations—especially those with fewer resources—never did.

Now “the extra component is a waste,” Vijay Dhanasekaran, a virologist at the University of Hong Kong, told me. It’s pointless to ask people’s bodies to mount a defense against an enemy that will never attack. Trimming Yamagata out of flu-vaccine recipes should also make them cheaper, Dhanasekaran said, which could improve global access. Plus, continuing to manufacture Yamagata-focused vaccines raises the small but serious risk that the lineage could be inadvertently reintroduced to the world, Subbarao told me, as companies grow gobs of the virus for their production pipeline. (Some vaccines, such as FluMist, also immunize people with live-but-weakened versions of flu viruses.)

Some of the researchers I spoke with for this article weren’t ready to rule out the possibility—however slim—that Yamagata is still biding its time somewhere. (Victoria, a close cousin of Yamagata, and the other B lineage that pesters people, once went mostly quiet for about a decade, before roaring back in the early aughts.) But most experts, at this point, are quite convinced. The past couple of flu seasons have been heavy enough to offer even a rather rare lineage the chance to reappear. “If it had been circulating in any community, I’m pretty sure that global influenza surveillance would have detected it by now,” Dhanasekaran said. Plus, even before the pandemic began, Yamagata had been the wimpiest of the flu bunch, Jit told me: slow to evolve, crummy at transmitting, and already dipping in prevalence. When responses to the pandemic starved all flu viruses of hosts, he said, this lineage was the likeliest to be lost.

Read: The pandemic broke the flu

Eventually, companies may return to including four types of flu in their products, swapping in, say, another strain of H3N2, the most severe and fastest-evolving of the bunch—a change that Subbarao and Monto both told me might actually be preferable. But incorporating a second H3N2 is even more of a headache than returning to a trivalent vaccine: Researchers would likely first need to run clinical trials, experts told me, to ensure that the new components played nicely with each other and conferred additional benefits.

For the moment, a slimmed-down vaccine is the quickest way to keep up with the flu’s current antics. And in doing so, those vaccines will also reflect the strange reality of this new, COVID-modified world. “A whole lineage of flu has probably been eliminated through changes in human behavior,” Jit told me. Humanity may not have intended it. But our actions against one virus may have forever altered the course of another.

Katherine J. Wu

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February 5, 2024
What Should Go Into This Year’s COVID Vaccine?

This fall, millions of Americans might be lining up for yet another kind of COVID vaccine: their first-ever dose that lacks the strain that ignited the pandemic more than three and a half years ago. Unlike the current, bivalent vaccine, which guards against two variants at once, the next one could, like the first version of the shot, have only one main ingredient—the spike protein of the XBB.1 lineage of the Omicron variant, the globe’s current dominant clade.

That plan isn’t yet set. The FDA still has to convene a panel of experts, then is expected to make a final call on autumn’s recipe next month. But several experts told me they hope the agency follows the recent recommendation of a World Health Organization advisory group and focuses the next vaccine only on the strains now circulating.

The switch in strategy—from two variants to one, from original SARS-CoV-2 plus Omicron to XBB.1 alone—would be momentous but wise, experts told me, reflecting the world’s updated understanding of the virus’s evolution and the immune system’s quirks. “It just makes a lot of sense,” said Melanie Ott, the director of the Gladstone Institute of Virology, in San Francisco. XBB.1 is the main coronavirus group circulating today; neither the original variant nor BA.5, the two coronavirus flavors in the bivalent shot, is meaningfully around anymore. And an XBB.1-focused vaccine may give the global population a particularly good shot at broadening immunity.

At the same time, COVID vaccines are still in a sort of beta-testing stage. In the past three-plus years, the virus has spawned countless iterations, many of which have been extremely good at outsmarting us; we humans, meanwhile, are only on our third-ish attempt at designing a vaccine that can keep pace with the pathogen’s evolutionary sprints. And we’re very much still learning about the coronavirus’s capacity for flexibility and change, says Rafi Ahmed, an immunologist at Emory University. By now, it’s long been clear that vaccines are essential for preventing severe disease and death, and that some cadence of boosting is probably necessary to keep the shots’ effectiveness high. But when the virus alters its evolutionary tactics, our vaccination strategy must follow—and experts are still puzzling out how to account for those changes as they select the shots for each year.

In the spring and summer of 2022, the last time the U.S. was mulling on a new vaccine formula, Omicron was still relatively new, and the coronavirus’s evolution seemed very much in flux. The pathogen had spent more than two years erratically slingshotting out Greek-letter variants without an obvious succession plan. Instead of accumulating genetic changes within a single lineage—a more iterative form of evolution, roughly akin to what flu strains do—the coronavirus produced a bunch of distantly related variants that jockeyed for control. Delta was not a direct descendant of Alpha; Omicron was not a Delta offshoot; no one could say with any certainty what would arise next, or when. “We didn’t understand the trajectory,” says Kanta Subbarao, the head of the WHO advisory group convened to make recommendations on COVID vaccines.

And so the experts played it safe. Including an Omicron variant in the shot felt essential, because of how much the virus had changed. But going all in on Omicron seemed too risky—some experts worried that “the virus would flip back,” Subbarao told me, to a variant more similar to Alpha or Delta or something else. As a compromise, several countries, including the United States, went with a combination: half original, half Omicron, in an attempt to reinvigorate OG immunity while laying down new defenses against the circulating strains du jour.

And those shots did bolster preexisting immunity, as boosters should. But they didn’t rouse a fresh set of responses against Omicron to the degree that some experts had hoped they would, Ott told me. Already trained on the ancestral version of the virus, people’s bodies seemed to have gotten a bit myopic—repeatedly reawakening defenses against past variants, at the expense of new ones that might have more potently attacked Omicron. The outcome was never thought to be damaging, Subbarao told me: The bivalent, for instance, still broadened people’s immune responses against SARS-CoV-2 compared with, say, another dose of the original-recipe shot, and was effective at tamping down hospitalization rates. But Ahmed told me that, in retrospect, he thinks an Omicron-only boost might have further revved that already powerful effect.

Going full bore on XBB.1 now could keep the world from falling into that same trap twice. People who get an updated shot with that strain alone would receive only the new, unfamiliar ingredient, allowing the immune system to focus on the fresh material and potentially break out of an ancestral-strain rut. XBB.1’s spike protein also would not be diluted with one from an older variant—a concern Ahmed has with the current bivalent shot. When researchers added Omicron to their vaccine recipes, they didn’t double the total amount of spike protein; they subbed out half of what was there before. That left vaccine recipients with just half the Omicron-focused mRNA they might have gotten had the shot been monovalent, and probably a more lackluster antibody response.

Recent work from the lab of Vineet Menachery, a virologist at the University of Texas Medical Branch, suggests another reason the Omicron half of the shot didn’t pack enough of an immunizing punch. Subvariants from this lineage, including BA.5 and XBB.1, carry at least one mutation that makes their spike protein unstable—to the point where it seems less likely than other versions of the spike protein to stick around for long enough to sufficiently school immune cells. In a bivalent vaccine, in particular, the immune response could end up biased toward non-Omicron ingredients, exacerbating the tendencies of already immunized people to focus their energy on the ancestral strain. For the same reason, a monovalent XBB.1, too, might not deliver the anticipated immunizing dose, Menachery told me. But if people take it (still a big if), and hospitalizations remain low among those up-to-date on their shots, a once-a-year total-strain switch-out might be the choice for next year’s vaccine too.

Dropping the ancestral strain from the vaccine isn’t without risk. The virus could still produce a variant totally different from XBB.1, though that does, at this point, seem unlikely. For a year and a half now, Omicron has endured, and it now has the longest tenure of a single Greek-letter variant since the pandemic’s start. Even the subvariants within the Omicron family seem to be sprouting off each other more predictably; after a long stint of inconsistency, the virus’s shape-shifting now seems “less jumpy,” says Leo Poon, a virologist at the University of Hong Kong. It may be a sign that humans and the virus have reached a détente now that the population is blanketed in a relatively stable layer of immunity. Plus, even if a stray Alpha or Delta descendant were to rise up, the world wouldn’t be caught entirely off guard: So many people have banked protection against those and other past variants that they’d probably still be well buffered against COVID’s worst acute outcomes. (That reassurance doesn’t hold, though, for people who still need primary-series shots, including the kids being born into the world every day. An XBB.1 boost might be a great option for people with preexisting immunity. But a bivalent that can offer more breadth might still be the more risk-averse choice for someone whose immunological slate is blank.)

More vaccination-strategy shifts will undoubtedly come. SARS-CoV-2 is still new to us; so are our shots. But the virus’s evolution, as of late, has been getting a shade more flu-like, and its transmission patterns a touch more seasonal. Regulators in the U.S. have already announced that COVID vaccines will probably be offered each year in the fall—as annual flu shots are. The viruses aren’t at all the same. But as the years progress, the comparison between COVID and flu shots could get more apt still—if, say, the coronavirus also starts to produce multiple, genetically distinct strains that simultaneously circulate. In that case, vaccinating against multiple versions of the virus at once might be the most effective defense.

Flu shots could be a useful template in another way: Although those shots have followed roughly the same guidelines for many years, with experts meeting twice a year to decide whether and how to update each autumn’s vaccine ingredients, they, too, have needed some flexibility. Until 2012, the vaccines were trivalent, containing ingredients that would immunize people against three separate strains at once; now many, including all of the U.S.’s, are quadrivalent—and soon, based on new evidence, researchers may push for those to return to a three-strain recipe. At the same time, flu and COVID vaccines share a major drawback. Our shots’ ingredients are still selected months ahead of when the injections actually reach us—leaving immune systems lagging behind a virus that has, in the interim, sprinted ahead. Until the world has something more universal, our vaccination strategies will have to be reactive, scrambling to play catch-up with these pathogens’ evolutionary whims.

Katherine J. Wu

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May 26, 2023
The Strongest Signal That Americans Should Worry About Flu This Winter

Sometime in the spring of 2020, after centuries, perhaps millennia, of tumultuous coexistence with humans, influenza abruptly went dark. Around the globe, documented cases of the viral infection completely cratered as the world tried to counteract SARS-CoV-2. This time last year, American experts began to fret that the flu’s unprecedented sabbatical was too bizarre to last: Perhaps the group of viruses that cause the disease would be poised for an epic comeback, slamming us with “a little more punch” than usual, Richard Webby, an influenza expert at St. Jude Children’s Research Hospital, in Tennessee, told me at the time.

But those fears did not not come to pass. Flu’s winter 2021 season in the Southern Hemisphere was once again eerily silent; in the north, cases sneaked up in December—only to peter out before a lackluster reprise in the spring.

Now, as the weather once again chills in this hemisphere and the winter holidays loom, experts are nervously looking ahead. After skipping two seasons in the Southern Hemisphere, flu spent 2022 hopping across the planet’s lower half with more fervor than it’s had since the COVID crisis began. And of the three years of the pandemic that have played out so far, this one is previewing the strongest signs yet of a rough flu season ahead.

It’s still very possible that the flu will fizzle into mildness for the third year in a row, making experts’ gloomier suspicions welcomingly wrong. Then again, this year is, virologically, nothing like the last. Australia recently wrapped an unusually early and “very significant” season with flu viruses, says Kanta Subbarao, the director of the WHO Collaborating Centre for Reference and Research on Influenza at the Doherty Institute. By sheer confirmed case counts, this season was one of the country’s worst in several years. In South Africa, “it’s been a very typical flu season” by pre-pandemic standards, which is still enough to be of note, according to Cheryl Cohen, a co-head of the country’s Centre for Respiratory Disease and Meningitis at the National Institute for Communicable Diseases. After a long, long hiatus, Subbarao told me, flu in the Southern Hemisphere “is certainly back.”

Read: The pandemic broke the flu

That does not bode terribly well for those of us up north. The same viruses that seed outbreaks in the south tend to be the ones that sprout epidemics here as the seasons do their annual flip. “I take the south as an indicator,” says Seema Lakdawala, a flu-transmission expert at Emory University. And should flu return here, too, with a vengeance, it will collide with a population that hasn’t seen its likes in years, and is already trying to marshal responses to several dangerous pathogens at once.

The worst-case scenario won’t necessarily pan out. What goes on below the equator is never a perfect predictor for what will occur above it: Even during peacetime, “we’re pretty bad in terms of predicting what a flu season is going to look like,” Webby, of St. Jude, told me. COVID, and the world’s responses to it, have put experts’ few forecasting tools further on the fritz. But the south’s experiences can still be telling. In South Africa and Australia, for instance, many COVID-mitigation measures, such as universal masking recommendations and post-travel quarantines, lifted as winter arrived, allowing a glut of respiratory viruses to percolate through the population. The flu flood also began after two essentially flu-less years—which is a good thing at face value, but also represents many months of missed opportunities to refresh people’s anti-flu defenses, leaving them more vulnerable at the season’s start.

Some of the same factors are working against those of us north of the equator, perhaps to an even greater degree. Here, too, the population is starting at a lower defensive baseline against flu—especially young children, many of whom have never tussled with the viruses. It’s “very, very likely” that kids may end up disproportionately hit, Webby said, as they appear to have been in Australia—though Subbarao notes that this trend may have been driven by more cautious behaviors among older populations, skewing illness younger.

Interest in inoculations has also dropped during the pandemic: After more than a year of calls for booster after booster, “people have a lot of fatigue,” says Helen Chu, a physician and flu expert at the University of Washington, and that exhaustion may be driving already low interest in flu shots even further down. (During good years, flu-shot uptake in the U.S. peaks around 50 percent.) And the few protections against viruses that were still in place last winter have now almost entirely vanished. In particular, schools—a fixture of flu transmission—have loosened up enormously since last year. There’s also just “much more flu around,” all over the global map, Webby said. With international travel back in full swing, the viruses will get that many more chances to hopscotch across borders and ignite an outbreak. And should such an epidemic emerge, with its health infrastructure already under strain from simultaneous outbreaks of COVID, monkeypox, and polio, America may not handle another addition well. “Overall,” Chu told me, “we are not well prepared.”

Read: The most important vaccine I’ll get this fall

At the same time, though, countries around the world have taken such different approaches to COVID mitigation that the pandemic may have further uncoupled their flu-season fate. Australia’s experience with the flu, for instance, started, peaked, and ended early this year; the new arrival of more relaxed travel policies likely played a role in the outbreak’s beginning, before a mid-year BA.5 surge potentially hastened the sudden drop. It’s also very unclear whether the U.S. may be better or worse off because its last flu season was wimpy, weirdly shaped, and unusually late. South Africa saw an atypical summer bump in flu activity as well; those infections may have left behind a fresh dusting of immunity and blunted the severity of the following season, Cohen told me. But it’s always hard to tell. “I was quite strong in saying that I really believed that South Africa was going to have a severe season,” she said. “And it seems that I was wrong.” The long summer tail of the Northern Hemisphere’s most recent flu season could also exacerbate the intensity of the coming winter season, says John McCauley, the director of the Worldwide Influenza Centre at the Francis Crick Institute, in London. Kept going in their off-season, the viruses may have an easier vantage point from which to reemerge this winter.

COVID’s crush has shifted flu dynamics on the whole as well. The pandemic “squeezed out” a lot of diversity from the influenza-virus population, Webby told me; some lineages may have even entirely blipped out. But others could also still be stewing and mutating, potentially in animals or unmonitored pockets of the world. That these strains—which harbor especially large pandemic potential—could emerge into the general population is “my bigger concern,” Lakdawala, of Emory, told me. And although the particular strains of flu that are circulating most avidly seem reasonably well matched to this year’s vaccines, the dominant strains that attack the north could yet shift, says Florian Krammer, a flu virologist at Mount Sinai’s Icahn School of Medicine. Viruses also tend to wobble and hop when they return from long vacations; it may take a season or two before the flu finds its usual rhythm.

Another epic SARS-CoV-2 variant could also quash a would-be influenza peak. Flu cases rose at the end of 2021, and the dreaded “twindemic” loomed. But then, Omicron hit—and flu “basically disappeared for one and a half months,” Krammer told me, only tiptoeing back onto the scene after COVID cases dropped. Some experts suspect that the immune system may have played a role in this tag-team act: Although co-infections or sequential infections of SARS-CoV-2 and flu viruses are possible, the aggressive spread of a new coronavirus variant may have set people’s defenses on high alert, making it that much harder for another pathogen to gain a foothold.

Read: Don’t worry, it’s not the flu

No matter the odds we enter flu season with, human behavior can still alter winter’s course. One of the main reasons that flu viruses have been so absent the past few years is because mitigation measures have kept them at bay. “People understand transmission more than they ever did before,” Lakdawala told me. Subbarao thinks COVID wisdom is what helped keep Australian flu deaths down, despite the gargantuan swell in cases: Older people took note of the actions that thwarted the coronavirus and applied those same lessons to flu. Perhaps populations across the Northern Hemisphere will act in similar ways. “I would hope that we’ve actually learned how to deal with infectious disease more seriously,” McCauley told me.

But Webby isn’t sure that he’s optimistic. “People have had enough hearing about viruses in general,” he told me. Flu, unfortunately, does not feel similarly about us.

Katherine J. Wu

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September 7, 2022