Walter Barker has, since the fall of 2020, had five doses of COVID-19 vaccine. He’s already starting to ponder when he might need a sixth.
Barker, a 38-year-old office worker in New York, received his first two doses a year ago, as part of an AstraZeneca vaccine trial. But the shots, which haven’t been authorized by the FDA, couldn’t get him into some venues. Sick of having to test every time he went to a Yankees game, Barker nabbed a pair of Moderna injections in the spring. Then, when the government urged boosters, he figured he’d “rather be safe than sorry,” especially because of his Type 2 diabetes—a risk factor for severe COVID. That was vaccine No. 5. Plus, he told me, he’d also caught the actual virus between his AstraZeneca and Moderna shots.
Now Barker’s steeling himself for the possibility of “a new booster or two every year.” Inklings of such a policy are already starting to appear. Israel is debating whether to offer fourth shots to higher-risk groups, including people over 60 and health-care workers. Some physicians are arguing that certain Americans should dose up again as well. And vaccine makers have long insisted that we’ll likely need annual shots at least. Given the clip at which the coronavirus seems to change, “I do think we’ll have to keep updating the vaccine,” Katie Gostic, an infectious-disease modeler at the University of Chicago, told me.
At this point in the pandemic, though, there’s no consensus on the number of shots we’ll need in the long term; plenty of the world’s leading COVID-vaccine experts have shifted their stance in just the past few weeks. Back in the summer, Ali Ellebedy, an immunologist at Washington University in St. Louis, thought, “There is no way we will need annual vaccinations,” he told me. “I am [at] 50 percent now.”
A future of annual vaccinations would almost be a relief. In the past year, the U.S. government has recommended that almost everyone eligible be COVID-vaccinated three times over, and the possibility of an Omicron-focused shot now looms. But the sweet spot for boosting frequency isn’t all that easy to find—both undervaccinating and overvaccinating have downsides—and the narrative is definitely not as simple as more is more. Maybe we’ll luck out, and finagle some truly durable protection out of our current shots. Or perhaps we’re just at the start of what could be the world’s most intense and widespread repeat-vaccination campaign to date.
There are two main reasons to vaccinate the already vaccinated: a substantial drop in our body’s defenses or a huge hike in the virus’s offenses.
We’re still, for instance, working to understand how well our immune systems cling to the intel offered by our shots. For months, scientists have been monitoring the lift and drop in protection from asymptomatic infection and milder forms of COVID-19, dynamics that seem tightly tethered to antibodies, the molecules that can waylay viruses outside of cells. Antibodies always decline in the months after infection or vaccination, for any pathogen, Rafi Ahmed, an immunologist at Emory University, told me. But boosters can lift their levels back up, sometimes to new heights; the triply dosed are better at fending off the virus, even dueling new variants that they’ve never encountered before. (Protection against severe disease and death is less capricious, thanks to defenders such as B and T cells, which stick around long-term.)
After people’s first two mRNA shots, levels of neutralizing antibodies ticked down about five- to tenfold from their peak in about six months. Now immunologists are monitoring what happens after the third dose—where antibody levels will stabilize, and how long reaching that plateau will take. The lower it is, or the steeper the downslope, the sooner we might be asked to vaccinate again. In a nonideal scenario, we’d see something of an up-and-down “sawtooth” trend, John Moore, a vaccine expert at Cornell University, told me, with a similarly steep decay after every dose. (Some researchers are starting to wonder whether we’re seeing the beginnings of this now—and durability may differ by vaccine brand.)
Then again, maybe the drop will be less pronounced, or at least more gradual, after the third shot. There’s reason to hope that might be the case. Post-boost, we pump out more antibodies than we did after the first shots; they’ll naturally take longer to dip below a protective threshold. Repeat exposures to a vaccine can also up the quality of antibodies, which get iteratively better at sniping SARS-CoV-2 down. “That means it takes way fewer of them to protect you,” Deepta Bhattacharya, an immunologist at the University of Arizona, told me. If that process keeps chugging along after the third shot, or perhaps the fourth, we might be able to get away with vaccinating much less often than we are now. The final pace of vaccination will also depend on what we want our shots to achieve. Blocking severe disease requires fewer shots; trying to suppress most infections and transmission means more. And we’ll need to set our expectations reasonably. Indefinitely preventing infections “is a bar that vaccinology, historically, has not been able to really meet,” Kizzmekia Corbett, an immunologist and COVID-vaccine developer at Harvard, told me recently.
All this gets more complicated, though, if the coronavirus itself keeps metamorphosing. Solid protection against one variant might not be enough to thwart another. Already, Omicron is so heavily mutated that many of our vaccine-trained antibodies don’t recognize it very well. That puts people who are far out from their first doses in a more vulnerable spot: Their defensive walls are low, and the variant’s genetically primed to jump extra high. Our current boosters still help in this scenario—the original virus and Omicron are similar enough that, given a glut of antibodies, some will still meet their mark. But even weirder versions of the virus are almost certainly on their way. Viral switcheroos are a huge part of why we offer annual flu vaccines. Coronaviruses don’t shape-shift as swiftly, but experts such as David Martinez, a vaccinologist at the University of North Carolina at Chapel Hill, think “our policy to boost is going to be driven by how much the virus is changing.” The more variants we’re troubled by, and the more often we collide with them, the more doses we’ll need.
Just as important as sussing out our need for shots is determining how many our immune systems (and psyches) can handle. At a certain point, yet another exposure to the exact same vaccine just won’t do the body’s defenses much good. Our current vaccination regimens aren’t running this risk yet. But repeatedly dosing every few months may rack up unnecessary costs.
Some are logistical. The more vaccines we need, the more we’ll have to manufacture, and the more often public-health officials will have to convince communities to accept them. Side effects can keep people out of school or work, and researchers don’t yet know to what extent boosting might raise the risk of rare, serious events such as heart inflammation. Faced with an unending series of shots, some people might stop getting them, or never start the vaccine series at all. Cumbersome dosing regimens could also exacerbate vaccine inequities, as countries with fewer resources struggle to administer repeat shots.
There’s good reason to wait between doses, too. A stretched-out interval can give antibodies more time to mature. Ellebedy’s team, which has been tracking this prolonged antibody coming-of-age, has found that, half a year out from the second mRNA dose, many molecules are still on their self-improvement kick. Waiting at least a few months could help ensure that the mediocre antibodies get weeded out, leaving only the best to be called into action. “If you wait to boost, the antibodies should be more durable, and peak at a higher level,” Martinez told me. And redosing prematurely, into a body still teeming with antibodies, might also mean that the molecules “wipe out the vaccine” before it can teach cells anything new, Marion Pepper, an immunologist at the University of Washington, told me.
Right now, though, case rates are shattering records; people can’t afford to wait very long for immune cells to stew, or for antibodies to chill. Even super-strong immune defenses can be overwhelmed by sheer quantity of virus. The United Kingdom and Israel recently halved the dosing interval between second and third injections, from five or six months to three, so more people could shore up their defenses sooner. “The TL;DR is for everyone to get a booster now,” the University of Chicago’s Gostic told me. If cases drop to less worrisome levels in a few months, maybe most of us can take our time with dose No. 4.
And someday there probably will be a fourth dose, if not more, experts told me. (Many immunocompromised people, who don’t respond well to vaccines, already need them.) We might, for instance, pivot to an Omicron-specific vaccine in a few months. If Delta’s still around in the spring, though, we’ll have to verify that Omi-vax works against both variants, especially for people who haven’t yet gotten shots. We’ll also need to prepare for the possibility of a new variant that could oust Delta, Omicron, or both.
No matter what, our next dose probably shouldn’t be an exact repeat of the ones we’ve been getting, modeled on the original SARS-CoV-2’s spike. It might not be ideal for the immune system to be told, yet again, This is the version of spike to pay attention to. That spike’s pretty much defunct; such a tactic would be like asking students to study a decades-out-of-date textbook before a grueling final exam. Immune cells could, in a sense, get hung up on ideas that are no longer terribly useful. A version of this phenomenon, called imprinting, happens with flu viruses. It’s not necessarily catastrophic, but Gostic and her colleagues have recorded some instances of people’s bodies getting so distracted by old flu strains that they don’t steel themselves properly against new ones, even when given updated vaccines.
But SARS-CoV-2’s biology is very different from that of flu viruses, and this new coronavirus just hasn’t been around that long. Experts think that this sort of skew is quite unlikely to dent our defenses anytime soon. Even if a few people’s bodies do get stuck on old variants because they’ve been vaccinated or infected multiple times with the same thing, there’s probably a fix, Ahmed said. Bodies might let go of their biases if we dose them a couple of times with new, unfamiliar recipes—effectively persuading them to overcome their inertia, and reinvest in the foreign matter they see. “We should definitely get boosted right now, but that’s a short-term strategy,” he told me. “Hopefully, the next boost we get matches the circulating strain.”
Martinez agrees—and is trying to think big. His team at UNC is one of several groups chasing a universal coronavirus vaccine that might fend off a panoply of variants (and perhaps, in certain cases, some of their more distant cousins—SARS-1, MERS, and the like). That way, we’re not just “playing whack-a-mole with variants,” Martinez told me. Other researchers are feeling optimistic about nasal-spray vaccines that could tickle out airway-specific immune responses.
Even if these newfangled formulations are better at kicking the virus to the curb, they won’t necessarily be panaceas. We’d still have to figure out a way to coax the body into remembering the doses long-term, and maybe stay flush with enough antibodies to keep most sickness at bay. But the hope is that they’d keep vaccine regimens trimmer and, by extension, more practical for the people running them and receiving them. Such a strategy could pay dividends: Durable vaccine protection might mean fewer infections among the inoculated, and fewer opportunities for SARS-CoV-2 to further mutate. More people might get the shots. Population immunity would grow. Our vaccines would gain an even stronger edge; they could reinforce their own success.