If you want to know if you’ve ever been infected with SARS-CoV-2, the natural thing to do is to get a blood test. These look for antibodies—proteins that signal your body has encountered a virus, and could perhaps be protected from catching it again. But recently, a study published in Nature Medicine introduced a worrying complication. Researchers in Chongqing, China, followed 37 people who had tested positive for the virus but didn’t show symptoms during their illness—in other words, who were asymptomatic—and tested their blood regularly. They found those antibodies didn’t always last for long: In some cases, after two to three months, they were barely detectable. Thought a positive antibody test was your ticket out of this thing? It’s not so simple. Simple, after all, is not a word immunologists would ever use to describe their field.
Marcus Buggert, an immunologist at the Karolinska Institute in Sweden, had noticed a similar pattern among patients there: cases where people who tested positive for the virus quickly lost their antibodies or never appeared to muster those forces at all. That wasn’t a big surprise—antibodies had also waned in patients who recovered from SARS. But to Buggert, who studies T cells—part of an orchestra of cells that perform in the body’s immune response—the symphony appeared incomplete. Research from SARS offered hints that, even if antibodies faded, some people retained immune cells that recognized the virus. Sometimes, those responses could last for years. For SARS-CoV-2, similar dimensions of the immune response could have bearing on how immunity works and how to design a vaccine. “Just because you can’t detect antibodies in their blood doesn’t mean there’s no immune response,” Buggert says.
Antibodies are a critical component of immunity—especially the ones that “neutralize” the virus by homing in on the proteins that comprise it. They glom onto their target and prevent the virus from infecting cells. A good vaccine will try to replicate that kind of natural protection. “Neutralizing antibodies are the holy grail,” says Sallie Permar, a vaccine researcher at Duke University. “There are few to no viral vaccines where we’re not shooting for that as an end point.”
But antibody levels are only part of the immunity story. While antibodies may wane past the limit of detection, that doesn’t mean they go away entirely. And even a very low level could be protective. “What‘s important when you’ve been exposed to the virus is how quickly you can ramp up those antibodies,” Permar says. That involves a whole army of cells, which store knowledge of each new pathogen they encounter. There are B cells, which help coax those virus-specific antibodies into existence, plus killer T cells, which can learn to obliterate infected cells. Helper T cells help orchestrate the whole process. “You have multiple arms of the immune response,” says Donna Farber, an immunologist at Columbia University who studies respiratory viruses. “It’s like the Army, the Navy, and the Air Force.” If one branch stands down, the body hasn’t necessarily lost its germ-fighting capacity.
For vaccine researchers, those helper T cells are of particular interest. They’re the ones that rally the troops, kicking off the process that leads to antibody production. But so far, there hasn’t been evidence that that’s how the body is actually primed to fight SARS-CoV-2, says John Wherry, an immunologist at the University of Pennsylvania. That’s because T cell responses are much harder to measure than antibody levels, requiring a lot of blood and fine-tuned instrumentation to wrangle the right kinds of immune cells. “We’ve lacked data on which cells—especially B and T cells—are truly recognizing the virus,” Wherry says. “There’s a lot of noise.”