Seriously, Why Not Get a Fourth Shot?

The risks from over-boosting are very small.

The FDA and CDC have cleared the way for Americans older than 50 to get a second booster shot—but they don’t quite suggest that everyone in that age group should do so. Like masking and many other pandemic-control measures, a fourth dose (or third, for the J&Jers in the back) is now a matter of personal judgment, even as another wave of COVID cases seems poised to break. That leaves millions of Americans and their doctors to perform their own risk-benefit analysis.

Or perhaps it’s just a risk analysis. The upsides of a fourth shot are indeed uncertain: The best we can say right now is that its protective effects are probably modest and temporary (with greater benefits for older people). But a modest, temporary boost is still better than nothing—so why not go ahead and get one, just in case? What, if any, risks would that actually entail?

The potential downsides of an extra boost have so far been described in rather vague, confusing terms. A New York Times article published Tuesday, “Should You Get Another Booster?,” warned that repeated boosting “offers diminishing results.” (Again: Sounds better than nothing!) The article also said that getting too many original-vaccine doses could make your body less responsive to an improved formula, and that it might be worse for your longer-term immunity than waiting. Céline Gounder, a former member of President Joe Biden’s COVID transition team, pointed out on Twitter yesterday that repeated boosting could pose certain “psychological risks,” including “vaccine fatigue and skepticism”—but these are more relevant to public-health officials than individual Americans seeking shots.

For those seeking clarity, here’s what we know for sure. A second round of boosters will come with two cons: They’ll cause side effects such as fever and body aches, probably at about the same level as side effects from a first booster, and they’ll be expensive for uninsured Americans, thanks to the government’s rejecting billions in COVID spending this month. Beyond that, the risks are only theoretical. “There’s no good data in humans yet for SARS-CoV-2 that boosting too frequently is going to cause damage to the system,” John Wherry, an immunologist at the University of Pennsylvania, told me.

A couple of potential drawbacks can be ruled out right away. According to one idea, too many boosters could lead to something called “immune exhaustion,” in which a person’s relevant T cells, after trying to fight off an intruder for years on end, begin to wear down. They “become literally exhausted; they are no longer functional,” Akiko Iwasaki, an immunologist at Yale, told me. This can affect people with chronic infections such as HIV, or even tumors. But vaccines involve limited, not chronic, exposure to the coronavirus’s spike protein, and there’s no evidence that boosters spaced four months apart would exhaust anyone’s immune system, Iwasaki said—although “if you’re giving it every week, that’s a different story.”

Another virtually moot risk is one floated in the Times: that repeated exposure to a vaccine designed around the original SARS-CoV-2 virus could train a person’s immune system (through a process called imprinting) so narrowly that it won’t recognize new variants. Such an effect is theoretically possible, but not supported by evidence and not worth worrying about at this point, Marion Pepper, an immunologist at the University of Washington, told me.

Getting an unnecessary shot could, in theory, put you at an immunological disadvantage in another way, by interfering with your immune response to a previous COVID shot or infection. One recent study, set to be published in Cell in April, found that people who received three shots saw their antibody levels rise by a factor of up to 100. But among people who had also gotten COVID—that is, those for whom the booster represented a fourth exposure, rather than a third—the increase was much smaller. That’s an example of the “diminishing returns” problem, which wouldn’t really matter if you cared only about your antibody levels. (A lot plus a little is still more than a lot.) But Wherry, who led the Cell study, told me that the smaller increase might have knock-on effects in other parts of the immune system, and end up limiting the B cells that will react to the virus the next time you encounter it.

Here’s how that works: When you get a booster shot or become sick with COVID after being vaccinated, some of your B cells will enter a structure in the lymphoid tissue called a germinal center, a sort of training camp that produces other, more diverse B cells that can respond to all sorts of invaders. If you leave those training camps alone for long enough, they’ll also produce long-lived plasma cells, which hang out in your bone marrow and manufacture antibodies all the time. But an extra booster shot could interrupt that process, Pepper told me, leaving you without the full, long-term benefit of those plasma cells.

All of this means that the longer you wait between shots, the more durable the protection you get. In animals, Wherry said, the benefits of waiting start to plateau after about six months, but in humans, the optimal delay isn’t known. Pepper doesn’t think this drawback would come into play for those who got their third shot at least four months ago, as the CDC recommends. “I don’t think getting a booster is going to disrupt anything,” she said. She also recommended that people wait at least four months after their most recent infection for the same reason. But if you get two boosters within, say, a month, Pepper suspects that you’d end up with less protection in the long run than if you’d gotten only one.

Wherry is more inclined to see a possible trade-off, albeit a small and uncertain one. Even if it’s been at least four months since your last booster or infection, choosing whether to get a shot could mean balancing some short-term protection against infection (largely conferred by antibodies) with some long-term protection against severe disease and death (the domain of B and T cells), he told me. Wherry said that older people should give more weight to the former, because as we age, our B- and T-cell responses tend to slow down. Still, everyone should make that decision with their doctor, taking their own health into account. “A 67-year-old marathon runner with no comorbidities, no health issues, is going to be a very different scenario than a 72-year-old lymphoma patient on immune-modifying drugs.”

What about the risk of getting a booster now, and therefore missing out on the full effects of some new and better COVID vaccine in the next four months? For now, this doesn’t seem like a significant concern. New vaccines that have been tailored to the altered spike proteins of the Omicron variant so far don’t appear to work any better than the original formulas. And any new vaccine based on something other than the spike protein won’t be affected by an encounter with our existing shots, Wherry said. Yale’s Iwasaki, who works on mucosal vaccines, said that many designs might even be made stronger by a recent vaccination or infection. If we do get a truly unfamiliar variant and need a truly new vaccine to combat it, producing and distributing one would probably take more than four months anyway.