Last June, as the Delta variant sat poised to take the globe by storm, Pfizer’s CEO, Albert Bourla, promised the world speed. Should an ultra-mutated version of SARS-CoV-2 sprout, he said, his company could have a variant-specific shot ready for rollout in about 100 days—a pledge he echoed in November when Omicron reared its head.
Now, with the 100-day finish line fast approaching and no clinical-trial data in sight, the company seems unlikely to meet its mark. (I asked Pfizer about this super-speedster timeline; “when we have the data analyzed, we will share an update,” the company responded.) Moderna, which started brewing up an Omicron vaccine around the same time, is eyeing late summer for its own debut.
Not that an Omicron vaccine would necessarily make a huge difference, even if Pfizer had made good. In many parts of the world, the variant’s record-breaking wave is receding. Having a bespoke vaccine in 100 days would have been an unprecedented accomplishment, but Omicron was simply “too fast” for a cooked-to-order shot to beat it, says Soumya Swaminathan, the chief scientist at the World Health Organization. This time, all things considered, we got lucky: Our original-recipe vaccines still work quite well against the variant, especially when they’re delivered as a trio of jabs—enough that some researchers have wondered whether we’ll ever need the elusive Omivax.
But Omicron won’t be the last antibody-dodging variant that splinters off of the SARS-CoV-2 tree—which means the vaccines, too, will need to keep coming. Tough decisions are ahead about what triggers might prompt a whole new variant-specific vaccine campaign, and how we’ll manage the shift in time. That said, we don’t have to resign ourselves to a bleak future of infinite catch-up, with shots always lagging strains. Vaccine updates might not be that necessary that often, and when they are, we can poise ourselves to rapidly react. Rather than scrambling to sprint after SARS-CoV-2 every time it surprises us, we could watch the virus more closely, and use the intel we gather to act more deliberately.
To vaccinate properly against a variant, we must first detect it. That means keeping tabs on the coronavirus and rooting out the places where it likes to hide and transform.
Flu presents an excellent template for this sort of viral voyeurism. The viruses that cause that disease also shape-shift frequently enough to elude the immune system’s grasp. For decades, scientists have been maintaining a massive, global surveillance network, now made of some 150 laboratories, that each year amasses millions of samples from sick people and susses out the genetic sequences of the viruses that linger within. That information then goes to the WHO, which convenes two meetings each year—one per hemisphere—to decide which strains should be included in next winter’s vaccine.
A watchdog system for SARS-CoV-2 could piggyback off of flu’s. The symptoms of the two diseases overlap; hospitals are “already collecting those samples,” says Richard Webby, the director of the WHO Collaborating Center for Studies on the Ecology of Influenza in Animals and Birds. “You’d just test them for two agents now.” Scientists could scour coronavirus genomes for little red flags—big-deal changes in the spike protein, say, that might befuddle antibodies—then shuttle the most worrisome morphs to a high-security lab, where they could be pitted directly against immune molecules and cells. Based on flu’s model, ideal candidates for a vaccine revision might meet three criteria: They’re riddled with unusual mutations; they’re recognized poorly by antibodies; and they’re spreading at least somewhat rapidly from one person to the next. A variant so heavily modified that it “overcomes our immunity enough” to make even healthy, vaccinated people quite sick would make the clearest-cut case for editing a shot’s recipe, Swaminathan told me.
In September, the WHO formed a new technical advisory group that’s been tasked with recommending ingredient adjustments to COVID vaccines as needed; Swaminathan envisions the committee operating parallel to one that calls the shots for flu. But over time, the conditions that demand we take quick action for COVID vaccines might not arise all that often. At least some coronaviruses are thought to metamorphose more slowly and less dramatically than flu viruses, once they settle into a population, which could mean a less frantic variant pummel than what we’ve experienced so far. Some experts also hope that as the world continues to rack up infections and vaccinations, our immunity against this new coronavirus will hold better. Our defenses against flu have always been a bit brittle—vaccine effectiveness for these shots doesn’t start terribly high, then drops rather rapidly. If our shields against SARS-CoV-2 are more stalwart, and the virus genetically quiets, perhaps we will need to rejigger COVID vaccines less often than we do for flu.
Even against Omicron, the most heavily altered variant of concern identified to date, vaccine protection against severe disease seems extraordinarily sturdy. “I don’t think the entire population is going to need annual vaccines,” Swaminathan told me. (The important exceptions, she noted, might be vulnerable populations, among them immunocompromised people and older individuals.) And when we do need vaccine revamps, the blistering speed at which mRNA shots can be switched up will be an advantage. Because most flu vaccines need about six months to slog through the production pipeline, vaccine strains are selected at the end of winter and injected into arms the next fall. That leaves a gap for the viruses to morph even more. mRNA shots like Pfizer’s and Moderna’s, meanwhile, could—Omicron saga notwithstanding—zing from conception to distribution in about half the time, and eliminate a good chunk of the guesswork.
Some parts of this relatively rosy future may not come to pass—or at least, they could be a long way off. We just don’t understand SARS-CoV-2 as well as we do flu viruses. In most of the world, flu viruses tend to wax in the winter, then wane in the warmer months, giving us a sense of the optimal time to roll out vaccines. And flu evolution occurs in a linear, ladderlike fashion; last year’s major strains tend to beget this year’s major strains. That makes it reasonably straightforward to “predict the direction that flu viruses are going in” and design our vaccines accordingly, says Emma Hodcroft, a molecular epidemiologist at the University of Bern.
The evolution of SARS-CoV-2, meanwhile, so far looks “more radial,” Webby told me, with new variants erupting out of old lineages rather than reliably riffing on dominant ones. Omicron, for instance, wasn’t an offshoot of Delta. “If we saw ladderlike evolution, we would know we need an Omicron vaccine now,” Florian Krammer, a flu-virus expert at the Icahn School of Medicine at Mount Sinai, told me. “That’s not what we have seen.” The coronavirus has also so far been serving up new variants at an absolutely staggering clip—far faster than virologists expected it to at the pandemic’s start—and scientists are unsure whether that churn will stop.
The coronavirus may eventually settle into more flu-like patterns—trending its evolution to be more stepwise than starburst, or sticking to winter waves—as population immunity grows and it learns to better coexist with us. Host defenses, when they’re strong and abundant enough, have a way of constraining which paths a virus can take; perhaps they will slow the speed at which new variants arise and take over. “The hope is that we head toward seasonality and stability,” Helen Chu, a flu-vaccine researcher at the University of Washington, told me.
But there’s no telling how long that transition will take, or how bumpy it will be, or if it will occur at all. Chu also worries that we don’t yet have the proper infrastructure to pinpoint variants that gain steam in places where they can mutate unusually quickly: people with weakened immune systems, perhaps, or animals that can contract the pathogen and boomerang it back. (Similar events for flu, wherein other species pass a foreign version of the virus to us, can cause pandemics.) SARS-CoV-2 is unlikely to prefer exactly the same real estate that flu viruses do, and so our surveillance strategies will need to look different too. Even flu monitoring has notable holes: It still lags, for instance, in low-resourced parts of the globe. “We need eyes and ears everywhere,” Swaminathan told me.
For at least the short term, our COVID-vaccine-update process is likely to remain a bit plodding; variants will crop up, and our shots will pursue them. Even late-arriving shot rewrites aren’t necessarily useless, Hodcroft pointed out. Say our next variant is an Omicron descendant; dosing people up with Omivax could still prep the body for what’s up ahead, even if the shot arrives too late to prevent past surges. That said, we’ll also have to be careful about going all in on Omicron; several experts recently warned me that it’s probably premature to totally trash our original-recipe shots. “If we went straight for an Omicron vaccine and stopped the others, that could potentially open up an immunity gap for the ancestral strains” to mutate, and their descendants to roar back, says Cheryl Cohen, a member of the WHO’s technical advisory group on COVID-19 vaccines and an epidemiologist at the National Institute for Communicable Diseases, in South Africa.
The pitfalls of pivoting from one spike version to the next are part of why this “whack-a-mole approach” of chasing single variants must end, says Raina MacIntyre, a member of the WHO’s technical advisory group on COVID-19 vaccines and a biosecurity expert at the University of New South Wales, in Australia. Ideally, future vaccines should protect, with a single injection, against multiple variants at once. An easy first step would be to combine multiple spikes into one shot—an Omicron-original combo, say, or an Omicron-Delta-original triple threat. Eventually, we might hit upon a universal formula that guards against all variants, including ones we “don’t know about yet,” Hodcroft said. If the flu’s any indication, that could be an enormous challenge: Even after many years of study, we’ve struggled to find a catch-all shot for that disease. With SARS-CoV-2, we don’t yet have a strong enough sense of all the evolutionary paths the virus could take; we may not be able to execute a wider-range shot until we understand our enemy better. Still, with so many efforts in the vaccine pipeline, Swaminathan is optimistic. “I am fairly confident it is scientifically feasible,” she said. “It is no longer, ‘Can we do it?’ It is, ‘We can.’”