We’re Zeroing In On the ‘Holy Grail’ of COVID-19 Immunity

There’s no good way of measuring whether your vaccine worked—yet.

Getty; The Atlantic

When Kishana Taylor welcomes her twins into the world this December, she’ll be pretty confident that they won’t be carrying the virus that causes rubella, an infection that can be disastrous in infants. Thanks to a vaccine she received as a child, Taylor, a virologist at Carnegie Mellon University, is still immune to the pathogen decades later.

She was able to confirm that in June through a simple test that searched her blood for antibodies that recognize the rubella virus, and then added them up. If her antibody counts were above a certain level, called a correlate of protection, she and her babies would be considered well shielded from disease. “You are considered immune with a titer of 9.9 to rubella,” she tweeted last month, referring to her antibody levels. “My titer? 116. I love my immune system sometimes.”

The term correlate of protection doesn’t exactly roll off the tongue, but it’s one of the sexiest concepts in the field of vaccinology. Correlates are biological benchmarks—measurements of a single immune molecule or cell—that can show that a vaccine is achieving its desired effect. With a correlate in hand, researchers can confirm how well a shot is working and identify the rare individuals in whom it doesn’t take; they can suss out the need for boosters and fast-track the development of new vaccines. At their most powerful, correlates of protection boil down the complexities of an immune response to a single value—one that can confidently affirm that a person won’t get infected or seriously sick. “It’s kind of a magic number,” Ali Ellebedy, an immunologist at Washington University in St. Louis, told me. “It’s the big holy grail,” Emory University’s Sri Edupuganti says. “It’s what we dream about,” Cornell’s Sallie Permar told me last month.

In recent weeks, the correlate community has been buzzing louder than ever. Scientists are on the cusp of confidently defining some correlates of protection against symptomatic disease for the COVID-19 vaccines. If confirmed, these correlates could revolutionize the way we tackle SARS-CoV-2 immunization: Vaccine makers testing a new inoculation may no longer need to follow tens of thousands of people for many months to test their product’s protection. Instead, they could inject just a few hundred people, snag some drops of blood, and see if the elusive correlate is met. That’s how we tee up new flu vaccines every year without the rigmarole of gargantuan clinical trials.

But for all their apparent simplicity, correlates of protection are devilishly hard to come by. Try as researchers might, capturing the oomph of vaccine-induced immunity in one number—or several—isn’t always possible. Even as scientists chase them, correlates are a reminder of just how inscrutable our own bodies can be.

Even our best vaccines start out as educated guesses. Researchers study people who have recovered from a particular infection, and then try to cook up an inoculation that will prompt protection that’s similar to or better than natural immunity. What ends up entering people is simple—a harmless pantomime of the pathogen. But it leads to a tortuously complex response that marshals the immune system’s many defensive players, including antibodies, B cells, T cells, and more.

Finding a correlate means cleaving a single variable out of this mess to act as an envoy for the rest of the immune system. That’s a heavy lift for a single cell or molecule, especially when people react in such different ways to the same pathogen. And not all immune responses can be easily measured. Some of the vaccines we’ve been using for decades still don’t have a concrete correlate, including the shots for mumps, rotavirus, and tuberculosis.

That probably won’t be the case for the COVID-19 vaccines. Since the pandemic’s early days, experts have had their eye on neutralizing antibodies, sometimes nicknamed “neuts,” which can glom on to the outside of viruses and block them from entering cells. Neuts that recognize the coronavirus teem in the bodies of people and laboratory animals that have successfully fought off coronavirus infections. The molecules’ disease-fighting powers have made them the workhorses of antibody-based treatments, such as convalescent plasma and monoclonals. Levels of these neuts also soar after vaccination, and seem especially high in people who don’t come down with COVID-19 after getting all their shots. By now it’s clear that neut numbers do correspond pretty well with protection—the more neuts someone has, the more likely it is that they’re safe from disease. “As far as I’m concerned, the data are clear,” Stanley Plotkin, a vaccine expert at the University of Pennsylvania, told me. “Neutralizing antibodies are it.”

Establishing that this trend exists, though, isn’t the same as zeroing in on a cutoff for protection, above which most vaccinated people would likely be guarded from illness. “We know lower neutralizing titers predict more infection,” Taia Wang, an immunologist at Stanford, told me. “What we’re looking for now is a little more precision.” To suss out a more specific set of numbers, researchers need to repeatedly sample the blood of shot recipients, some of whom have to get sick so researchers can get a sense of what falls below the threshold they’re looking for. “The more breakthroughs you have, the easier it is to determine,” Katy Stephenson, a physician and vaccine expert at Beth Israel Deaconess Medical Center, in Boston, told me. A great irony of vaccinology is that it’s easier to define the success of a vaccine that’s prone to regularly fail—one of the only downsides of our extraordinary shots.

Another hurdle that correlate chasers need to clear is a lack of consistency across vaccine trials, which were conducted at different times in different populations using different inoculation recipes, different criteria for defining COVID-19 severity, and different brands of antibody tests. Aggregating and analyzing all the evidence to produce one unifying correlate requires some serious statistical gymnastics.

By now, though, enough people have been vaccinated, and enough blood samples drawn, that preliminary numbers are starting to emerge. One group of researchers in the United Kingdom has proposed a correlate of protection against COVID-19 for AstraZeneca’s vaccine; two others, one in Australia and another in the United States, have taken a stab at pinpointing measurements that will hold true across several different shots, including the three available to Americans. (Representatives from Moderna, Pfizer, and Johnson & Johnson told me that they didn’t yet have their own correlates to report, but were continuing to investigate.)

But the case isn’t closed. “We have some strong leads, but I would not say we have a correlate yet,” Holly Janes, a biostatistician at the Fred Hutchinson Cancer Research Center, in Seattle, told me.

While neuts have certainly hogged the spotlight so far, they could still be unseated by another molecule or cell. And even if neuts are the real deal, having one correlate doesn’t preclude defining another that captures an additional element of the immune system. Flu vaccines, for instance, seem to come with a bunch of measurable metrics of success, some of which are still being confirmed in research labs. Other, non-neutralizing antibodies exist, and their levels also seem to ratchet up in lockstep with COVID-19 vaccine efficacy.

Many researchers are hoping for more data on T cells, immune cells that support the production of antibodies or annihilate virus-infected cells on their own. Compared with antibodies, T cells are fragile, reclusive, and a pain to measure, Smita Iyer, an immunologist at UC Davis, told me. But they seem fundamental to the success of well-established vaccines, including those for chicken pox and tuberculosis. Against the coronavirus, T cells are known to pick up the protective slack when neuts and other antibodies fail. “There’s not only one immune response that protects you, which is good,” Florian Krammer, a vaccine expert and virologist at the Icahn School of Medicine at Mount Sinai, told me. “If one fails, another can take over.” That redundancy is great for us, but frustrating for researchers looking for a simple portrait of protection.

Things could get even thornier. As is the case with any vaccine, the success of a COVID-19 shot hinges on a multitude of factors—including the strength of the immune system it’s bolstering, the mutability of the virus it’s counteracting, and the exact ingredients in the shot itself. Kids, whose immune systems are still finding their footing, might need correlates of their own; so might older adults and immunocompromised people, whose immune systems are less easily marshaled by vaccines. The numbers we settle on could also vary among vaccine brands because different shots rile up different subsets of immune cells.

Then there’s the biggest wild card of all: the coronavirus itself. It’s continuing to splinter into new variants, some of which have already revealed themselves to be quite capable of dodging certain antibody-based defenses. A neut level that keeps us safe from Alpha won’t necessarily thwart Beta or Delta to the same extent. (There’s at least good news on T cells, which are much harder to stump with mutations—another reason these cells are looking so attractive to some scientists.) “We’re starting to get numbers now, but there are going to be asterisks because of the variants,” Lisa Gralinski, a virologist at the University of North Carolina at Chapel Hill, told me. Because correlates take so long to determine, “whatever number we come up with today is really talking about the past,” Stephenson, of Beth Israel, said. SARS-CoV-2 will always mutate far faster than humans can conjure new correlates. We may well end up with an entire menagerie of correlates against COVID-19, each tailored to its own combination of population, variant, and vaccine. (And that’s all just in the realm of blocking COVID-19 disease; stopping asymptomatic infection would require its own set of correlates as well.)

But the mere possibility of hitting protection pay dirt is reason enough to keep plugging away. Having a strong correlate of protection against COVID-19 would allow researchers around the world to more quickly bring new vaccines to market in countries where they are sorely needed. A correlate would also give scientists the chance to monitor the natural wane of immune responses and deploy boosters that could rapidly buoy those defenses, if need be. It could act as a guidepost for new shots that fight specific variants before they outsmart the jabs we already have.

The need for correlates is so urgent, the FDA has already gambled that antibodies are the answer: In recent guidance, the agency noted that it would consider green-lighting updated, variant-specific versions of vaccines if they’re able to prompt the production of adequate levels of neuts. It’s a hastier move than some researchers would like. But with variants such as Delta surging amid a largely unvaccinated global population, the shortcut offered by these correlates has never been more appealing. The big hope, researchers told me, is that COVID-19 vaccines will be able to follow in the footsteps of flu shots, which are reformulated seasonally to keep pace with the strains du jour. Vaccine makers can debut new vaccines by simply checking inoculated people’s blood for the telltale markers of protection, rather than waiting to see how these individuals fare against the virus itself.

Spinning the idea of correlates into a personal guarantee of immunity is tempting, especially with antibody tests so readily available. But correlates are just that—correlates, patterns gleaned from large groups of people. Levels of certain immune fighters could track with protection against disease without being directly responsible for our vaccines’ success on a person-by-person basis. “We’re talking about measurements that apply better to populations than to individual people,” Plotkin said.

Some correlates can be tested in individuals, such as in the case of the rubella-antibody test that Taylor took in June, after discovering she was pregnant. But these tests don’t offer absolute certainty. Every trend will have exceptions—some people whose SARS-CoV-2 antibody levels are bonkers-high may still end up getting sick; others with low titers will stay safe. Antibody stocks, after all, naturally dwindle over time, but the body retains the ability to replenish them. Thresholds aren’t hard lines between unprotected and protected; everyone always carries some relative risk, especially amid a pandemic this devastating. “There are no sharp edges in biology,” Iyer told me. Correlates, while useful, can’t actually encompass everything our immune systems are capable of. Without the right amount of nuance, they risk making black-and-white out of a situation that operates entirely in shades of gray.