Some people have never gotten COVID-19. An obscure gene may be why

Those who’ve dodged COVID-19 for more than four years may have a newly discovered immune response to thank.

In a study that intentionally infected volunteers with the coronavirus, participants with elevated activity of a little-studied immunity gene called HLA-DQA2 didn’t get a sustained infection after exposure to SARS-CoV-2, researchers report June 19 in Nature. The study offers an unprecedentedly detailed look at how the immune system responds to the coronavirus, and how variation in that response could explain why some people get sick while others don’t.

The results stem from a challenge trial: At the height of the pandemic in 2021, scientists in the United Kingdom exposed 36 young, healthy unvaccinated volunteers who’d never gotten COVID-19 to the virus through their noses (SN: 2/18/21). While the initial goal was to establish how much virus it takes to kick-start an infection, 16 of the participants underwent more extensive testing. Researchers tracked the actions of a wide range of immunological players in the blood and lining of the nose, both before and after exposure, allowing a detailed view of when and where different players spur into action.

But there was a problem: Only six of the 16 participants got sick. 

“Initially, we were very bummed, like, we’re wasting all these experiments on people that we didn’t actually infect,” says Rik Lindeboom, a biologist at the Netherlands Cancer Institute in Amsterdam. But later, he says, he and his colleagues realized they’d stumbled across a “unique opportunity” to understand how some people who got an infectious dose of the virus managed to fend it off. It’s unclear how many people have dodged COVID-19. The most recent estimate from the U.S. Centers for Disease Control and Prevention suggested that by the end of 2022, nearly 1 in 4 Americans hadn’t caught the virus.

Challenge trials are controversial, as some experts question the ethics of deliberately infecting people with a pathogen (SN: 5/27/20). But “you can’t underplay how valuable this kind of information is,” says Jill Hollenbach, an immunogeneticist at the University of California, San Francisco who wasn’t involved in the research. “It’s so rare that we get to see a snapshot of what’s actually happening in early infection,” she says, as researchers in challenge trials can track people from the moment they encounter the pathogen. 

Participants who didn’t get sick in Lindeboom’s 2021 trial fell into two buckets. Seven individuals never tested positive for the virus, while three got transient infections in their nose that their bodies quickly shut down, so they never got sick. In the former group, researchers detected widespread, but subtle, changes in immune cells called monocytes and MAIT cells. The transiently infected individuals mounted a robust immune reaction, known as an interferon response, in their noses within a day of exposure. Interferons help signal a viral threat, attracting cells that fight the infection.

By contrast, people who got sick took about five days, on average, to marshal the same interferon response in their noses, giving the virus time to proliferate and spread. The discrepancy suggests that swift, localized activity at the site of infection may help prevent SARS-CoV-2 from getting a foothold, Lindeboom says. 

Surprisingly, sick participants’ blood showed interferon activity before their noses did. “That’s the exact opposite of what we had hypothesized,” Lindeboom says, given that the virus was delivered via the nose. “Your immune system is capable of sensing that something is happening and relaying this to the body before the cells that are actually affected know about it.”

Among those who didn’t get sick, Lindeboom isn’t sure why some got briefly infected and others didn’t. But before exposure, both groups exhibited elevated activity the gene HLA-DQA2 in specialized immune cells that help alert the immune system to pathogens, compared with people who developed symptoms. Scientists aren’t sure exactly what this gene does, though previous research linked it to milder COVID-19 outcomes. 

“We may be able to predict who is susceptible to infection just by looking at their gene signature for this particular gene,” says Akiko Iwasaki, an immunologist at Yale University who wasn’t involved in the study but wrote about it in Nature.

Of course, a lot has changed since these challenge trials were conducted in 2021. Virtually everyone has some immunity to SARS-CoV-2 from infection or vaccination, meaning most people’s immune responses would likely differ from those traced here, Iwasaki says. A larger, more diverse study population — for instance with people of different ages — could show more varied responses, too.

“For whatever reason, folks who have this different constellation of immune cells present in the [nose] prior to infection may be able to mount an immune response more quickly,” says Hollenbach. “It’s a lucky break for those people.”

In a sense, the study was also a lucky break for researchers. Subsequent challenge trials have struggled to infect volunteers, given virtually everyone has some immunity to COVID-19 now. “That’s what makes this study so unique,” says Lindeboom. “We’ll hopefully never be in the position to do this kind of study for SARS-CoV-2 again.”