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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