Immune responses don’t last forever. They’re supposed to wane, and the fact that they do works to our advantage - Katherine J. Wu
image by: Health Sciences Society
In early March, Deepta Bhattacharya, an immunologist at the University of Arizona, celebrated a milestone: hitting the point of full vaccination, two weeks after getting his second Pfizer shot. Since then, he’s been watching the number of coronavirus antibodies in his blood slowly but surely decline.
The drop hasn’t been precipitous, but it’s definitely happening—regular checkups have shown his antibody levels, also known as titers, ticking down, down, down, from spring through summer, now into fall. The slump fits the narrative that countless reports have been sounding the alarm on for a while now: In the months after vaccination, our antibodies peace out, a trend that’s often been described as a “waning” of immunity, and evidence that we’re all in dire need of boosters to shore our defenses back up.
It all sounds, quite frankly, like a tragedy. But as Bhattacharya and others assured me, it’s really, really not. “All we hear about is titers,” says Stephanie Langel, an immunologist at Duke University. That fixation “misses an entire nuance.” Antibodies are supposed to peter out; that’s why they always do. Still, even as our antibodies are dwindling in absolute quantity, these scrappy molecules are enhancing their quality, continuing to replace themselves with new versions that keep improving their ability to bring the virus to heel. Months after vaccination, the average antibody found in the blood simply has higher defensive oomph. “That’s why I hate the word waning,” Jennifer Gommerman, an immunologist at the University of Toronto, told me. “Antibody levels are declining, but something good is happening too: The immune response is evolving.”
The focus on antibody counts alone actually does a disservice to our understanding of immunity, experts told me. Like a block of wood being hewn into a sharper blade, vaccinated immune systems can hone their skills over time. Part of waning certainly does mean fewer. But it can also mean better.
A couple weeks after vaccination, a group of immune defenders called B cells starts to pump out antibodies en masse. But many of these early antibodies are, as Bhattacharya told me, “really crappy” at their jobs. Their raison d’être is to be clingy—the Y-shaped molecules hook their tips onto a specific hunk of SARS-CoV-2’s anatomy, and hang on for dear life. The better they are at glomming on, the better chance they have of waylaying the threat. Sometimes it’s a solo act: Antibodies alone can grab on so firmly that they block the virus from hacking into a cell, a process called neutralization. Or they’ll use the stems of their Ys to flag down other members of the immune system in a destructive assist.
But that’s the best-case scenario. Most of our B cells, or the antibodies they produce, won’t actually react at all to SARS-CoV-2, or a vaccine that resembles it. That’s because our bodies are always churning out B cells at random, repeatedly futzing with their genetics so that they’ll make a diverse array of antibodies—billions or trillions in total—that can collectively recognize just about any microbe they might ever see. This process is haphazard and imprecise, though: When B cells are born, “they don’t have any particular pathogen in mind,” Gabriel Victora, an immunologist at Rockefeller University, told me. Instead of gripping firmly onto the virus’s surface, many antibodies might just “bounce on and off,” giving the pathogen ample time to wrest itself free, Bhattacharya said. It’s the best defense the body can slap together on short notice, having never met the bug before. Early antibodies are sort of the immune system’s best guesses at defense—the immunological equivalent of throwing spaghetti against a wall to see what sticks—which usually means we need a lot of them to truly pen the pathogen in place. They’re also fragile. Most antibodies don’t hang around for more than a few weeks before they degrade.
Such flimsy fighters aren’t terribly good investments for the long term. So while the subpar antibodies are duking it out on the front lines, the immune system will shuttle a contingent of young B cells into a boot camp, called a germinal center, where they can study up on the coronavirus. What happens inside these training camps is a battle royal in miniature: The cells crowd together and desperately vie for access to the resources they need to survive. Their weapons are their antibodies, which they wave frantically about, trying to latch on to chunks of dead coronavirus, while a panel of other immune cells judges them from afar. Only the most battle-ready among them—the ones whose antibodies grip most tightly onto the coronavirus—move on to the next round, and the losers perish in defeat. As Gommerman put it, “If they suck, they die.”
The harrowing cycle repeats itself over and over, and only gets more grim. Survivor B cells will xerox themselves, deliberately introducing errors into their genetic codes in the hopes that some of the mutations will enhance their antibodies’ chances of gluing themselves to the virus. The entire process is downright “Darwinian,” like a super-sped-up form of natural selection, Victora said. The weaklings are weeded out, leaving just the sharpest and strongest behind. It’s also very prolonged. Researchers such as Ali Ellebedy, of Washington University in St. Louis, have found that these tournaments of culling continue for at least 12 to 15 weeks after people receive their COVID-19 vaccines, perhaps longer.
If all of this is getting a little too Squid Game, consider the much rosier upshot: At the end of this process, our bodies are left with some truly primo antibodies, well poised to take up the mantle of protection as the first waves of mediocre defenders start to fall away. This is what is happening in the immune system of those who got vaccinated months ago: An initial burst of antibody activity, followed by a gentle tapering off, as the body goes back to baseline. “Immune responses can’t just stay in your blood forever,” Langel told me. If they didn’t abate, we’d have no room or resources for the body to mount a different defense, against another threat—and our blood would be nothing more than a useless antibody sludge.
There’s another way to think about the post-vaccination dip in antibodies: taking out the trash. Early-acting B cells are, in some cases, so crummy that they’re not all that worth keeping around. Evolution, too, has clued into the perks of this pattern, which might be why the B-cell victors aren’t just higher quality, but also much longer-lived. Whereas the first B cells that rally after vaccination might live just a few days, the cohort that trounced their peers in training can post up in the bone marrow or the blood for months or years. Some will continue to squeeze out antibodies for the long term, while others drift about in quietude, ready to resume their defensive duties when they’re called upon again. “What is seen as a ‘loss’ in antibodies is actually the slow waning of the less-good, short-lived response,” Victora told me. And when antibodies are needed—say, when the actual virus infects us—veteran B cells will produce them again, in gargantuan quantities. Antibodies themselves don’t always linger. But the capacity to create them usually does.
There’s definitely a limit to how much quality can compensate for quantity—one antibody, no matter how badass, can’t do the work of hundreds. Experts don’t yet know how many antibodies (good, meh, or “crappy”) people need to have in tow to be considered well-guarded from COVID. Rishi Goel, an immunologist at the University of Pennsylvania, told me that his work has shown that, six months out from vaccination, the number of neutralizing antibodies found in people’s blood tends to drop noticeably from its peak. But he and others have also found that there’s little difference in how much neutralization the body is capable of—a strong hint that superior antibodies have since stepped up to the plate. Again, antibody levels always drop. That doesn’t mean that immune protection (which, by the way, is about more than just antibodies) disappears.
The slow trudge toward self-improvement might also be one reason to not rush into nabbing a booster shot. Boosting reminds the immune system of a threat it’s seen before. But offering up that refresher too often or too soon could be pointless, even slightly counterproductive, if active germinal centers are still doing their thing. Waiting a bit longer might help ensure that the best possible B cells are reawakened into action, to manufacture antibodies anew. Immunity, then, is much less about what’s around now, and more about what’s around when it’s needed; it’s no big deal if those defenses aren’t always visible, as long as they kick back into gear when they’re called to the fore.
All this means that a slowdown in antibody production could, in a way, be seen as comforting. It’s a sign of an immune system that’s allocating its resources wisely, rather than working itself into a constant panic. Bhattacharya, for one, hasn’t been at all fazed by what’s happening to his antibodies, which, nearly eight months out, still look pretty freaking good, despite the numerical drops—because they still seem to be walloping the virus when he tests them in his lab. Langel says that’s standard. When she sees antibodies “waning,” she shrugs. “I say, ‘Look,’” she told me, “‘that’s the immune system, doing what it does.’”
Source: Katherine J. Wu, The Good Part About ‘Waning’ Immunity, The Atlantic, October 20, 2021.