Immune cells can learn the vagaries of a particular infectious disease in two main ways. The first is bona fide infection, and it’s a lot like being schooled in a war zone, where any lesson in protection might come at a terrible cost. Vaccines, by contrast, safely introduce immune cells to only the harmless mimic of a microbe, the immunological equivalent of training guards to recognize invaders before they ever show their face. The first option might be more instructive and immersive—it is, after all, the real thing. But the second has a major advantage: It provides crucial intel in the absence of risk.
Some pathogens aren’t memorable to the body, no matter the form in which they’re introduced. But with SARS-CoV-2, we’ve been lucky: Both inoculation and infection can marshal stellar protection. Past tussles with the virus, in fact, seem so immunologically instructive that in many places, including several nations in the European Union, Israel, and the United Kingdom, they can grant access to restaurants, bars, and travel hubs galore, just as full vaccination does.
In the United States, conversely, only fully vaccinated Americans can wield the social currency that immunity affords. The policy has repeatedly come into heated contention, especially as the country barrels forward with plans for boosters and vaccination mandates. No one, it seems, can agree on the immunological exchange rate—whether a past infection can sub in for one inoculation or two inoculations, or more, or none at all—or just how much immunity counts as “enough.”
Even among the nation’s top health officials, a potential shift in the social status of the once-infected remains “under active discussion,” Anthony Fauci, President Joe Biden’s chief medical adviser, told me. For now, though, he reiterated, “it still is the policy that if you’ve been infected and recovered, that you should get vaccinated.” And in the United States, which is awash in supplies of shots, some version of that policy is likely to stick. Infections and vaccinations, down to a molecular level, are “fundamentally different” experiences, Akiko Iwasaki, an immunologist at Yale, told me. Surviving a rendezvous with SARS-CoV-2 might mean gaining some protection, but it’s no guarantee.
What the experts do converge on is this: Opting for an infection over vaccination is never the right move. An unprotected rendezvous with SARS-CoV-2 ultimately amounts to taking a double gamble—that the virus won’t ravage the body with debilitating disease or death, and that it will eventually be purged, leaving only immune protection behind. Questions linger, too, about how long such safeguards might last, and how they stack up against the carefully constructed armor of inoculation. Vaccines eliminate the guesswork—a fail-safe we’ll need to keep relying on as the coronavirus persists in the human population, threatening to invade our bodies again, and again, and again.
There’s a reason many of our best vaccines—measles shots, smallpox shots—are near-perfect pantomimes of the pathogens they guard against. The whole point of immunization is to recapitulate infection in a safer, more palatable package, like a driver’s-ed simulation, or a practice quiz handed out in advance of a final exam.
That means there will usually be big overlaps in how infections and inoculations rouse the immune system into action. COVID-19 vaccines and SARS-CoV-2 infections each elicit gobs of virus-trouncing antibodies, along with a long-lasting supply of the plucky B cells that manufacture them; they each rouse lingering hordes of T cells, which blow up virus-infected cells and coordinate other immune responses. SARS-CoV-2 reinfections and breakthroughs do happen. But they’re uncommon and tend to be milder than the norm, even symptomless. Early evidence in several countries suggests that the two types of immunity are blocking illness at roughly similar rates. “The reality is, both are exceptionally good,” Rishi Goel, an immunologist at the University of Pennsylvania, told me. (One caveat: There’s a paucity of data on how the one-shot Johnson & Johnson vaccine stacks up, though it’s definitely very good at staving off severe disease.)
Infection arguably delivers a more comprehensive lesson on the virus, introducing the body to the entirety of its anatomy. Most COVID-19 vaccines, meanwhile, focus exclusively on the spike protein, the molecular lock pick the coronavirus uses to break into cells. And while SARS-CoV-2 first infiltrates the moist mucosal linings of the nose, mouth, and throat, where it can tickle out airway-specific immune defenses, typical COVID-19 shots are blitzed into the arm, mostly marshaling all-purpose antibodies that bop through the blood. That makes it tough for vaccinated bodies to waylay viruses at their point of entry, giving the invaders more time to establish themselves.
Some of these differences might help explain the results of a recent, buzzy study out of Israel, in which researchers reported that previously infected individuals were better protected than people who had been fully vaccinated with the Pfizer shots, including against severe cases of COVID-19. “As soon as that paper came out,” Fauci told me, “we obviously discussed the inevitable issue”—whether infection should be enough to exempt someone from a shot.
But Fauci, as well as most of the other experts I talked with, cautioned against overinterpreting the results of a single study, especially one documenting only a snapshot in time. Even taken at face value, the “better” defenses offered by post-infection immunity come at a massive potential cost, said Goel, of the University of Pennsylvania. Cells and molecules are scrambling to learn the traits and weaknesses of a foreign invader while their home is being attacked; any infection bears some risk of hospitalization, long-term disability, or death. The virus can also interfere with the immune response, muffling antiviral defenses, severing the ties among disparate branches of immune cells, and, in some cases, even duping the body into attacking its own tissues. And unlike the vaccines, infections are, well, infectious, turning each afflicted person into “a public-health threat,” Nahid Bhadelia, the founding director of Boston University’s Center for Emerging Infectious Diseases Policy and Research, told me.
Those who surface from these encounters seemingly unscathed might not have much immunity to show for it, either. Several studies have shown that a decent percentage of infected people might not produce detectable levels of antibodies, for the simple reason that “not all infections are the same,” Beatrice Hahn, a virologist at the University of Pennsylvania, told me. The immune system tends to use its own threat assessment to calibrate its memory, dismissing many brief or low-symptom encounters. That could be an especial concern for people with long COVID, many of whose initial infections were asymptomatic or mild.
At the other end of the spectrum, very severe disease can so traumatize the immune system that it fails to recollect the threat it’s fighting. Researchers have watched immune-cell training centers “completely collapse” beneath the blaze of inflammation, Eun-Hyung Lee, an immunologist at Emory University, told me. In some cases, the virus might find its prior hosts nearly as unguarded as before. “It would be dangerous to assume good immunity across all individuals in this group,” says Kimia Sobhani, who’s studying antibody responses to the virus at Cedars-Sinai Medical Center, in Los Angeles.
Vaccines strip away some of the ambiguity. For a given brand, every injection contains the same ingredients, doled out at the same dose, to generally healthy people. The shots still won’t work the same way in everyone, especially people with compromised immune systems, or certain older individuals whose defenses have started to wane. But nearly every healthy recipient of a COVID-19 shot temporarily transforms into a coronavirus-antibody factory—including many of the people for whom infection wasn’t triggering enough. “What we know is that you get a much, much better response following infection if you vaccinate somebody,” Fauci told me. “I tend to go with what’s much, much better.”
Neither immunity nor pathogenicity is static. Immune cells can experience amnesia; viruses can change their appearance and sneak by the body’s defenders. Stacking vaccinations atop prior infections, then, is an insurance policy. Post-infection shots can buoy whatever defenses are already there, likely boosting not just the quantity of protective cells and molecules, but their quality and longevity as well, John Wherry, an immunologist at the University of Pennsylvania, told me. A similar rationale backs up the two-dose mRNA shots and other multi-dose vaccines, including the ones we use for HPV and hepatitis B.
Growing evidence suggests that the combination of infection and inoculation might even be synergistically protective, outstripping the defenses offered by either alone—something the immunologist Shane Crotty calls hybrid immunity. Some reports have shown that “people who have previously been infected then get vaccinated have higher antibody levels” than people who have only one of those experiences, Jackson Turner, an immunologist at Washington University in St. Louis, told me. Antibody potency, too, seems to get souped up, potentially equipping the molecules to better grapple with a wide range of coronavirus variants, even ones they haven’t seen before. Accordingly, the hybrid-immune seem to be reinfected less often. “You basically supercharge your immune response,” Goel told me. This could all be good news for the durability of protection as well. Viruses and vaccines will inevitably prod different subsets of immune responses—a more comprehensive education than any single teacher can accomplish alone. The pairing is a good way, Wherry said, to goad immune cells into doubling down on their lessons, and acquiring more sophisticated attack plans over time.
Where experts splinter in opinion is regarding the number of COVID-19 shots to give the once-infected, at least for multi-dose vaccines. In some countries, including France, healthy people who have had SARS-CoV-2 need to get only a single shot. The strategy can, potentially, free up doses for others who remain unimmunized, among whom first injections would save more lives. So far, not much evidence suggests that adding a second shot on schedule has “benefit, quantitatively or qualitatively,” for the recovered, Wherry said. But given the unpredictability of past infections, some experts think a two-dose vaccination course is still a safer policy to ensure that no one is left with suboptimal protection. “I tend to lean toward what is prescribed, and say people should get the full two doses,” Bhadelia told me. This more conservative tactic is also an easier logistical lift, because confirming a prior brush with the pathogen can be difficult. Some experts have suggested that potential vaccine recipients could be screened for antibodies as a rough proxy for a past protective infection, but even that’s a bit of a “nightmare,” Wherry told me, especially because researchers haven’t yet pinpointed a threshold that denotes even partial immunity.
If the perfect post-infection shot combo is elusive now, that equation becomes even more complicated as third shots go on offer to those who are currently fully vaccinated. Despite calls for additional injections from the White House, many researchers are skeptical that the young and healthy need these inoculations so soon, and some are wary of the potential for overboosting, which can exhaust immune cells or stir up side effects. Still, Fauci, who’s come out strongly in favor of delivering COVID-19 vaccines in three doses, thinks a duo of shots might be necessary to clinch the protective process for most previously infected people. “To me, if you have enough vaccine, it’s worth giving a second dose,” he said. That strategy could, in theory, work especially well if the doses are spaced several months apart, giving the immune system time to recuperate and mull over the intel it’s gathered. This grace period might even help explain the strong synergy with post-infection inoculation: Most recovered people are getting their shots well after the virus has vacated their body, which means the vaccine’s lessons are being imparted to refreshed and well-rested cells.
Eventually, fewer and fewer of us will have the option of either vaccination or infection; soon, most of us will be dealing in scenarios of and. With the virus so thoroughly enmeshed in our population, the order of exposures is inevitably shifting: More and more vaccinated people are catching the coronavirus and sometimes falling ill. Arguably, all of these pathogen parleys are boosts—but whether they leave lasting impressions on our immune systems still isn’t clear. Immune responses have both ceilings and floors; it’s not always easy to know what we’re knocking up against.
The long view, then, becomes about seeing infection and inoculation not as a dichotomy but as an inevitable interaction—which is actually the point of vaccines. We immunize as a hedge, one predicated on the assumption that we could all chance upon the pathogen in question. It’s a reality our bodies have spent an eternity preparing for: that certain threats take time to abate; that some battles have to be fought over and over; that, with the right defenses in place, some enemies become less dangerous over time.