The Only Way We’ll Know When We Need COVID-19 Boosters

Midway through America’s first mass-immunization campaign against the coronavirus, experts are already girding themselves for the next. The speedy rollout of wildly effective shots in countries such as the United States, where more than half the population has received at least one dose of a COVID-19 vaccine, has shown remarkable progress—finally, slowly, steadily beating the coronavirus back. But as people inch toward something tantalizingly resembling pre-pandemic life, a cloud hangs over our transcendent summer of change: the specter of vaccine failure. We spent months building up shields against the virus, and we still don’t know how long we can expect that protection to last.

To keep our bodies from slipping back toward our immunological square one, where the virus could pummel the population again, researchers are looking to vaccine boosters—another round of shots that will buoy our defenses. Around the world, scientists have already begun to dole out these jabs on an experimental basis, tinkering with their ingredients, packaging, and dosing in the hope that they’ll be ready long before they’re needed.

When exactly that will be, however, is … well, complicated. Nearly all the experts I spoke with for this story said that the need for boosters is looking more and more likely, but no one knows for sure when they’ll arrive, what the best ones will look like, or how often they’ll be needed, assuming they’re part of our future at all. What underlies this uncertainty isn’t scientific ignorance: We know the signs that will portend an ebb in vaccine protection, and we’re actively looking for them. But their timing could still surprise us. The immunization process is much less akin to erecting an impenetrable fortress than it is to prepping forgetful students for an exam full of unpredictable questions. We can cram with flash cards for weeks, but to some degree we just have to cross our fingers and hope we’re still well studied when the pop quiz arrives.

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That same brand of bet-hedging is unfolding on a global scale. Around the world, researchers and vaccine manufacturers have been, for months, preparing for what seems to be an inevitable end to our immunological détente with the virus. But these experts are also playing a very hard and very necessary waiting game. The only way we’ll really know the best approach to boosters is to allow the vaccines to show their weak points, then patch them as soon as they arise.

There are at least two major ways that COVID-19 vaccines could falter. The first might best be described as a memory lapse, and it’s a bit of a flub on the human side: Left to its own devices, the immune system slowly loses its intellectual grasp on the pathogen, and is much less prepared the next time it sees it. The second is a mismatch between what immune cells studied and what ended up on the final exam: a mutation in the coronavirus that alters its appearance so significantly that it becomes unrecognizable, even if immune memory of the vaccine remains intact. Designing and deploying boosters requires keeping tabs on these two fast-changing variables at once.

Memory lapses can, in theory, be easier to detect and repair: Researchers take blood samples from vaccinated people and track the levels of different immune actors, such as antibodies and T cells. If those levels start to dip below a crucial protective threshold, it’s time to offer a booster. This approach works well in certain boosting regimens, such as the Hepatitis B vaccine for health-care workers, But sussing out this so-called correlate of protection typically takes gobs and gobs of data. For many vaccines, even ones that have been in use for decades, such as the mumps vaccine, those numbers still aren’t clear-cut. SARS-CoV-2’s correlate remains elusive.

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We do have, at least, hints about the longevity of vaccine protection. Antibodies that recognize SARS-CoV-2 are known to stick around in high numbers for at least six months after the first round of shots is administered. John Wherry, an immunologist at the University of Pennsylvania, told me that, based on the data he’s seen, he suspects that antibody levels will hold their own for at least a couple of years after vaccination, though antibodies represent just a sliver of the complex immune response to the coronavirus. There have also been encouragingly few breakthroughs, or infections in people who have been fully vaccinated. An unexpected uptick in these cases would serve as a “canary in the coal mine” for public-health experts, an indication that protection was ebbing, Sallie Permar, the chair of pediatrics at Weill Cornell Medicine and NewYork-Presbyterian Komansky Children’s Hospital, told me. (The chickenpox vaccine, originally conceived of as a one-and-done shot, became a two-doser in the U.S. in the 2000s to stamp out breakthroughs, including some potentially linked to waning antibody levels, in the years after kids got their first jab.)

Virus mutations can be even tougher to pin down and predict than immunological memory lapses. No known variants have yet managed to fully flummox our current repertoire of vaccines, and none yet seems to be disproportionately causing breakthroughs. But certain versions of the virus do seem more resistant to vaccine-driven antibodies in the lab—a hint that the pathogen is becoming more and more unfamiliar to the immune cells that studied it. Some experts are worried that, if enough alterations occur, we may need another round of mass inoculations as early as this fall, possibly with an updated vaccine recipe that accommodates the virus’s shape-shifting form—a more labor-intensive approach than simply juicing people up with more of the OG inoculation.

In a way, our vaccines’ stellar track record is an ironic hindrance to the process of improving them. Without more long-term data on their shortcomings, epidemiologists and vaccinologists are effectively trying to predict the weather in a climate they’ve only just discovered. No universal litmus test exists for making decisions about boosters—no single definition for what would constitute a “concerning” rise in cases, no flare that goes off when our immune cells are hit with microbial amnesia, no spoilers that warn of the coronavirus’s next metamorphosis. Instead, the experts are left to determine their own benchmarks for boosters, by evaluating the available information on antibody levels, breakthroughs, variant surveillance, and how different versions of the virus fare in labs and animal models, all while being mindful of the pandemic’s progress on scales both local and global.

All of this intel then gets fed into a risk-benefit analysis, to determine whether the need for boosters outweighs any possible costs, which can span the medical to the economic, says Grace Lee, a pediatrician at Stanford University and a member of the CDC’s Advisory Committee on Immunization Practices. That’s all before public-health officials have to coordinate the logistics of getting another round of vaccines into people—a campaign that will inevitably reawaken the issues about trust, equity, and access still stymieing our current rollout. And even after boosters debut, agencies like the CDC might tinker with the playbooks for years or decades to get the scheduling just right. (The CDC did not answer questions about the nature of future boosting efforts, noting only that “the need for and timing of COVID-19 booster doses have not been established.”)

Even amid all this uncertainty, the road to boosting won’t be a fumble in the dark. In the past year and a half, millions of SARS-CoV-2 genomes have been sequenced, helping researchers monitor the virus’s every genetic change; other scientists are monitoring the vaccinated, in the hope of catching or even predicting the inflection point, when our immune protection against the virus might start to drop. By the time our first round of shots starts to lose its oomph, contingency plans will have long ago been set in motion.

Some companies and researchers have already started experimentally doling out additional jabs. Johnson & Johnson representatives told me that their single-dose vaccine is being tested as a two-doser, while Moderna and Pfizer have confirmed that they’re checking whether third shots, some of which have been specially reformulated to fight worrisome variants, can better equip immune systems to tussle with new versions of the virus. The National Institutes of Health recently announced a clinical trial that will offer a Moderna booster to participants who were vaccinated three to five months prior. And researchers at Johns Hopkins are exploring whether certain immunocompromised people—a group at higher risk of not responding to standard-issue vaccines—might benefit from a third injection. These individuals and others with less exuberant immune systems, such as older people, might need boosters sooner than the rest of us, says Ali Ellebedy, an immunologist at Washington University in St. Louis.

[Read: COVID-19 vaccines are entering uncharted immune territory]

Several boosting trials will take a mix-and-match approach, offering vaccines that differ in formulation from the first COVID-19 shot people took—a Moderna boost for people who initially got Pfizer, for instance. If so-called heterologous boosting is safe and effective, future rounds of shots will be much easier to give: People won’t have to scour their neighborhood for a company-specific vaccination clinic—or waste time struggling to remember which shot they got months or years ago. Hybrid inoculations could even improve on the original plan, potentially by marshaling different branches of the immune system, as they have with vaccines against HIV, Ebola, and tuberculosis. Delivered in succession, different types of COVID-19 shots could, in theory, build a punchier and more cohesive response because of their diverse packaging—and perhaps provide more comprehensive protection when it comes to variants, Srilatha Edupuganti, an infectious-disease physician and vaccinologist at the Emory Vaccine Center, one of the sites for the NIH trial, told me.

New vaccine recipes, which haven’t yet been cleared, could also play a role in future vaccination efforts. Some researchers are looking outside the spike protein, to see whether they can build shots that contain more instructive bits of SARS-CoV-2 anatomy. A few are experimenting with delivering vaccines as oral drops or nasal sprays that might coax out an airway-specific immune response, to head off the coronavirus at its natural point of entry. This whole rigmarole will get easier if we eventually find SARS-CoV-2’s elusive correlate of protection, which will probably involve a specific kind of antibody: Instead of running long, expensive clinical trials to determine a vaccine’s efficacy, scientists can just check whether it marshals an immune response strong enough to match or exceed the threshold. “It’s what we dream about,” Permar told me. “Vaccines would be so much easier to develop and test.” There’s even talk of developing universal vaccines that could accommodate a wide range of potential variants, perhaps cutting down on the amount of mutant-specific tinkering we’ll need to do in the future, and the number of shots we’ll need to give.

Boosting in perpetuity isn’t an ideal option, if we can avoid it. For some shots, the severity of side effects can ratchet up with each additional dose. (Some evidence exists that the mix-and-match approach might come with nastier side effects as well.) Vaccinating too often is also possible: At a certain point, cells will stop learning efficiently from the material vaccines provide, and essentially “burn out” from information overload, Wherry told me. Perhaps the heaviest immunization schedule we’ll end up with is one that’s already familiar: annual shots, like those we develop for the flu, each reformulated to tackle a slightly different set of strains. But many experts think that’s not terribly likely. Flu viruses mutate faster than coronaviruses do, and hop between animals and humans much more frequently, giving them more opportunity to mutate.

The world is better served when we’re judicious with vaccines, after all, and inoculate as needed, no more, no less. A lot would feel wrong about lining people up for a second or third helping of a COVID-19 vaccine while billions around the world have yet to receive their first dose, Krutika Kuppalli, an infectious-disease physician at the Medical University of South Carolina, told me. Every unprotected person represents another potential depot for the virus to establish itself and mutate, and jump ahead of our vaccines once again. Getting more first shots into arms means slowing the virus’s spread, and limiting its costume changes. It means, perhaps, delaying our need for boosters a little while longer.