The hunt for the next big, bad coronavirus variant is on. Scientists around the world are sampling wastewater and amassing nose swabs from the sick; they’re scouring the microbe’s genetic code for alarming aberrations. The world of outbreak surveillance “is all virus,” says Danny Douek, an immunologist at the National Institute for Allergy and Infectious Diseases. We’re laser-focused on getting eyes on a variant that would be well-equipped to wallop us, then alerting the globe. But that, Douek told me, is just one half of the infectious playing field where offense and defense meet.
The powers of pathogens change over time; so do those of the molecules and cells that our bodies use to fight them, including antibodies and T cells. Preparedness, Douek said, means keeping good tabs on both. So in the same way we survey viruses to see how they’re evolving over time, we might do well to canvass people too.
Monitoring the status of our anti-disease protection would amount to a kind of immune surveillance that could tell us “when immunity wanes, and when it needs to be augmented,” says John Wherry, an immunologist at the University of Pennsylvania. One obvious spot to start is with mass antibody testing, or serology, to figure out how drastically and quickly antibody levels are changing over time, and in whom. We could get a rough sense of which members of the population might be most susceptible in the event of another surge and prioritize them for boosters, tests, treatments, and more.
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The notion of using antibody data to identify vulnerable people (and ideal vaccination candidates) in a population isn’t new. But regularly taking those sorts of samples on a massive scale, over long periods of time, “has never been done,” Anisha Misra, a clinical microbiologist at Mayo Clinic, told me. Building such a system would require massive federal investment and a huge infrastructural overhaul. “This is much harder than virologic surveillance,” Richard Webby, a flu virologist at St. Jude Children’s Hospital, in Memphis, told me.
At its most powerful, though, a strategy like this could act as an immunological fuel gauge, sounding the alarm before our antibody tanks run dry. The alternative is simply waiting for immunized people to catch a virus, and maybe even get seriously sick, then revaccinating to fill in the defensive gaps. Although “it’s natural to just measure the cases” as they’re happening, that reactive approach can get us only so far, Jessica Metcalf, a disease ecologist at Princeton, told me. Figuring out who’s vulnerable in advance could pinpoint the cracks in our shields before the virus exploits them. It could minimize the number of people who have to fall ill at all.
The tech to manage this feat is already in hand. Even now, researchers can assess antibody levels through blood that’s collected via the prick of a finger—a procedure that some tests (not the Theranos kind) even allow folks to do at home. Wherry envisions collecting those samples every few months or so, whether at routine checkups or through a public-health campaign. Those community specimens could be supplemented with samples from blood banks. The goal would be to track antibodies by two metrics, Douek told me: durability, or the length of time that the molecules’ levels stay acceptably high, and breadth, or the degree to which they zap different variants. A shortfall in either might prompt revaccinations.
The CDC, and equivalent agencies abroad, have built up systems to scope out antibodies in the community before, including during the coronavirus pandemic. But those surveys have primarily used antibodies as a proxy for past infection. Using antibodies alone to denote immunity is a lot more fraught: Being chock-full of them is no guarantee of protection, in the same way that being somewhat low on them does not necessarily spell doom.
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Knowing what antibody levels correspond to protection against infection or disease from SARS-CoV-2 would help. When we’ve found these so-called correlates of protection for other viruses, they’ve become über useful. They can tell us when people hoping to get pregnant should nab a rubella shot, or when health-care workers low on hepatitis B antibodies should sign up for a booster, Elitza Theel, a serology expert at Mayo Clinic, told me. With the new coronavirus, we’re close to a consensus on some correlates—in “a nice ballpark,” says Akiko Iwasaki, an immunologist at Yale. We could imagine a future in which we call for boosters when, say, half the population drops below a defined threshold. But we haven’t yet nailed the inflection point between protected and not.
Even when we understand those numbers with more precision, we will face a tough decision: which correlate of protection to select as a booster cutoff. The number of antibodies necessary to stave off severe disease will be far lower than the number needed to block transmission, much less any infection at all. “We need to ask what we are trying to achieve here,” says Marc-André Langlois, a molecular virologist at the University of Ottawa. A campaign geared toward maintaining sky-high, infection-blocking levels of antibodies, for instance, could require tons and tons of shots at an unsustainable clip.
Antibodies are also finicky and super specific—ones that latch on tightly to one version of the virus might bounce uselessly off of another. Which means a level of antibody that’s sufficient to guard against, say, a variant such as Omicron, “will most likely not apply to the next one,” Langlois told me. If we had just one SARS-CoV-2 flavor, the correlates conversation would probably be done, Theel said. As things stand, though, the virus presents “a moving target.” This is why breadth of protection matters: If an antibody-dodging version of SARS-CoV-2 rears its head, everyone might need another round of doses, perhaps reformulated to account for the new variant’s quirks.
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To make things all the messier: Correlates can even differ between groups of people, based on age, immune-system health, or possibly even vaccine brand, infection history, and exposure conditions; some researchers still wonder if antibodies, as opposed to another immune defender such as T cells, will be the correct way to measure SARS-CoV-2’s correlates at all. (That’s part of why using antibody tests to measure immunity on an individual basis, as a means to guide behavior, remains dangerous; the FDA advises against it.) Which is to say, we don’t get SARS-CoV-2 immunity anywhere near as well as we could, and hopefully someday will. But maybe ultra-precise correlates of protection don’t have to make or break a program like this. While we’re still finagling those values, immune surveillance could still be valuable for sussing out antibody dynamics among subsets of the population, said Douek, who, together with colleagues at NIAID, is launching a new initiative, focused on immune surveillance for a bevy of pathogens, that he hopes will prep us for the next pandemic.
In a sense, all we really need to know is that antibody levels are dropping at all. Certain individuals, including the elderly, will inevitably experience speedier downticks than others; those are the people we’d want to prioritize for revaccination should a new wave of cases start to rise. Immune surveillance could also reveal still-unknown variables that might be tugging antibody numbers down. Tracking these sorts of trends could flash an additional warning if the virus reshapes itself or resurges: “If you’re seeing a rapid decline in antibody, and an increase in the virus in wastewater,” Wherry said, that’s a clear trigger to roll out vaccines anew for anyone whose levels are low. Keeping a close eye on community antibody levels could also tell us who doesn’t yet need to boost because their defenses remain comfortably high. In those folks, “boosting may have minimal benefit,” Wherry told me—an equally important message to send to the public when resources are scarce.
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Accumulating and storing these samples on a regular basis would also bolster the sorts of viral surveillance that many other scientists already want to be doing. When a highly mutated variant starts to spread, scientists must scramble to figure out if the antibodies raised by current vaccines can block it, using serology samples from immunized people. The system we have in place to update our flu vaccines annually, run by the World Health Organization, relies on just “a few hundred samples” collected from around the globe each year, Webby, of St. Jude, told me. With COVID, a more expansive repository, representing a much more diverse swath of the population, could give researchers and policy makers a more granular view of population risk.
We’re still figuring out which factors will most often push us to vaccinate again. Maybe the virus will mutate so quickly that we’ll need a reformulated shot every year. Or perhaps its evolution will slow, and plunges in antibody levels will dictate our boosts. Paying attention to both could help strike the right balance. We can’t just “wait for the next variant” before we decide to act, Iwasaki told me. The more we monitor our defenses, the better we can maintain them, and the tougher it will be for the virus to roar back again.
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