The Best COVID Vaccine Series Will Be a Varied One

Two years into the pandemic, and two months into Omicron’s globe-crushing surgeTo counter the new variant’s uncanny knack for slipping past antibodies roused by our first-generation shots, our COVID-19 vaccines are finally on the cusp of a federally sanctioned update. Moderna and Pfizer have both kick-started clinical trials to see how Omicron-specific vaccines fare in people. Results are expected within the next few months, and if all goes well, syringes around the world could be locked and loaded with Omicron’s wonky-looking spike protein by the summer.

Omicron-izing our COVID vaccines is a good, if unfortunately timed, move, experts told me. But the same strangeness that makes an Omicron-specific vaccine wise is also a warning against trashing our original-recipe shots too soon. We don’t know what the next major variant will look like. It could be an offshoot of Omicron, something that strongly mirrors the ancestral SARS-CoV-2, or something that resembles neither variant at all.

Our vaccine regimens going forward should include Omicron “for sure,” Rafi Ahmed, an immunologist at Emory University, told me. But they should also “include one of the earlier strains,” and even leave room for a future variant, as the SARS -CoV-2 family tree continues to branch, he said. For the billions of people around the world who are still unvaccinated, including tens of millions of children under 5 in the United States—more of whom are being born every day—going all in on Omicron could backfire. The original shots, outdated as they are, likely still have a role to play.

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The shots we’re currently using give us a limited set of options for building immunity. Although vaccine makers have have cooked up Beta-and Delta-specific versions of their COVID vaccines along with Omicron-specific ones, the only formulas with an FDA green light are the ones that use a spike from a coronavirus version that hasn’t been spotted in many, many monthsThat wasn’t so bad when the most common variants were Alpha, Delta, or even the slightly immune-evasive Beta and Gamma, because they weren’t such big departures from their parent; our original-recipe vaccines still worked. Think of SARS-CoV-2 variants like breeds of house cats. Our coronavirus classic (RIP) was an American shorthair; Alpha was a British shorthair; Beta, a Siamese; Gamma, a Manx; Delta, a Maine coon. , all a pretty good match for the generic feline template that the original-recipe vaccine lays down..

Omicron, meanwhile, is a sphynx: decidedly still a cat, but wrinkly, whiskerless, and bald as a baby’s bottom. It looks looks like nothing the human immune system has been asked to deal with before. When antibodies trained on standard-issue shorthairs see the new variant’s spike, they’re thrown for a loop.

The OG shorthair spike isn’t a total tutorial flop. It can still teach feline features to T cells, which are fairly variant-proof; that’s part of why multiply vaccinated people remain remain so well protected against severe cases of COVID. Antibodies, which are more easily flummoxed by mutations, benefit as well, because even a sphynx-like variant retains many core cat characteristics: retractable claws, pointy ears, glowy eyes with slit-shaped pupils. And each time our immune cells glimpse these features, they up the quantity and quality of antibodies available for attack, Rishi Goel, an immunologist at the University of Pennsylvania, told me. Though two doses of a classic-spike mRNA vaccine are shaky against Omicron, a three-dose course still works fairly fairly well well It’s not unlike how kids learn from pets or picture books: The more cats they see, the more primed they are to recognize the next one that saunters by. When a sphynx shows up in the body, not but the ones that do—those that home in on the catlike features it’s kept—will latch on confidently.

That trend probably has a limit, Melanie Ott, a virologist at Gladstone Institutes, in San Francisco, told me. “I don’t know if it’s wise to go four, five, six, seven times with the same spike,” she said . Eventually we’ll hit the point of diminishing returnsthe body may even become too fixed on only the most common cat traits, and start to ignore what falls outside the norm. (Omicron? That’s just some giant, naked rodent.)

That’s probably reason enough to avoid boosting in perpetuity with the original recipe. For the next round of COVID shots, whenever they might be necessary, we may be better off using something else—an “insurance policy,” as Goel put it, to help Omicron would seem to be the obvious choice; ideally “we should be vaccinating with what’s reducing,” Katie Gostic, an infectious-disease modeler at the University of Chicago, told me. “That has the best chance. of protecting you today“That sort of thinking is what seems to be driving Moderna’s and Pfizer’s new trials. Both companies are revaccinating twice- and thrice-immunized people with Omicron’s spike, a strategy that should bolster the defenses already laid down by prior vaccinesBut the products won’t be available to the public for at least another couple of months, by which time Omicron may be mostly blipping off the map, or being overtaken by another variant that renders a sphynx-specific shot less useful. Some experts have even argued that there will be no point to boosting with Omicron’s spike when that shot’s ready; it’ll be too lateThat vaccine’s utility, then, hinges on what the next big move in SARS-CoV-2’s evolution might be.

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No one’s willing to put down a confident prediction on that front, but experts have tentative guesses. Taia Wang, an immunologist at Stanford, thinks that the next variant to take over will will be an Omicron descendant. (That’s generally how flu viruses work: Successful strains beget more successful strains in an almost linear, stepwise fashion.) It’s a numbers game, Wang told me, given how comprehensively Omicron is sweeping the world. Wang said she’ d even favor the notion of thereby with OG-spike vaccines entirely, and using only the Omicron recipe from now on for boosters and primary shots, should Pfizer and Moderna push it through. Of the two companies, only Pfizer’s testing this tactic directly: Some 200 people in its Omicron-vaccine trial are receiving their first three COVID shots as Omicron,, Omicron,, Omicron.

Alex Sigal, a virologist at the Africa Health Research Institute, in South Africa, told me that he’s less confident such a plan will pay off. In his mind, the next major variant will probably reap its biggest advantages from snubbing a resemblance to Omicron; that would position it to escape whatever sphynx-ish immunity the variant’s currently coaxing out. That means leaning too hard into an Omicron-specific defense now could be dicey. Sigal and his colleagues have found that Omicron infections in unvaccinated people don’t goad the immune system into churning out antibodies that recognize other variants very well. Ott’s team has shown similar patterns in mice..

Researchers are still working out the nitty-gritty of what’s behind this Omicron bias, but experts told me that they suspect the new variant’s weirdness can cut both ways: Original-recipe-trained immune fighters struggle to recognize Omicron; Omicron-trained defenders aren’ t great at homing in on variants that look like OG. When Omicron lopes into an airway that’s never seen a coronavirus spike before (either through infection or vaccination), antibody-producing immune cells seem to lock on to features that are sphynx-like— its nudity; its webbed paws; its gaunt, stern, Clint Eastwood–esque face—but that are not necessarily all that helpful for ID’ing the average cat breed“It’s just too specialized,” Sigal said. The new variant is too much of an aberration, compared with its cousins, to go all in on with our vaccination regimes; in a landscape of diversity, he said, betting on averages, rather than extremes, is safer. No one can yet say whether the myopia that unfolds after an Omicron infection will translate over to Omicron-based shots,, but if it does, unimmunized bodies pumped up only with Omicron vaccines might get hitched to the wrong wagon. “If it were me going to the vaccination station, I wouldn’t want just three doses of Omicron,” Sigal said.

That calculus might slightly shift for unvaccinated people who have had a brush with a non-Omicron flavor of the virus. For them, getting a couple of Omicron shots might still diversify But few people know what version of the virus hit them, so keeping multiple spikes in rotation in our vaccine roster is a hedge. It might also be a good way to stay one step. ahead of the virus, especially if we need to revaccinate people somewhat regularly—perhaps every year, as we do for the flu. Totally uninfected, totally unvaccinated people are also entering the population every day, as infants; when they need vaccines, a big menu of spikes might be what serves them best.

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The point, Goel said, isn’t to stubbornly latch onto the OG spike and never let go. We may ditch that iteration eventually, especially as we get a better handle on how SARS-CoV-2 will likely evolve. The point is that “It’s no secret that broad immunity is elicited with a broad strategy, ”Ott said. Vaccine makers might even be wise to toss Beta- or Delta-spike vaccines into the mix, she added, just to see what sorts of immunological oomph they offer. Several companies, including Moderna, are also testing shots that combine at least two spike flavors in one dose, which could make the logistics of multi-variant regimens easier. As research into SARS-CoV-2’s evolution continues, scientists may even glean enough intel to start to predict which variants might usurp the global throne next—and recommend that strain for use in, say, an annual shot. A massive worldwide surveillance program already makes this possible for the flu; equivalent programs for COVID are still in their infancy, but they are growing.

Tactics like these could pave the path to universal vaccines— Single shots that could teach the body to recognize a whole panoply of variants and that wouldn’t have to be updated every time the coronavirus undergoes a costume change, Padmini Pillai, an immunologist at MIT, told me. time we have a new variant of concern is not a viable strategy, ”she said. For now, though, we can achieve at least some of the same effects by mixing and matching the tools we have. The original SARS-CoV-2 may be effectively dead. But with its ghost living on in our vaccines, what it has to offer us is not.