MAX BARNHART, REGINA G. BARBER · JULY 20, 2023

Do you know someone who tested positive for COVID but never felt a darn thing? Or who says they never caught the virus – even when their partner was sick in bed.

Scientists estimate that over 20% of people who get infected with COVID never have any symptoms – and a portion of them never even know they were infected. Now a new study published in Nature on July 19 says their genetics might be why the virus didn’t make them sick.

Some people have a version of a gene in their immune system called HLA-B that protects them from feeling the effects of the virus. The study found that people with this special HLA-B variant are 2 to 8 1/2 times more likely to be asymptomatic than those without the variant.

Goats and Soda covered an early version of this study last year. Since then, the scientists have found out how this genetically enhanced protection works – it’s because of immune cells that remember infections from other seasonal coronaviruses, i.e. many common colds, and thus know how to attack COVID-19 too.

Bone marrow donors were key to the study

Jill Hollenbach, an immunologist at the University of California, San Francisco who led the research described in the new study, didn’t have a mild COVID experience.

“I had COVID. I was sick for about a week. I didn’t love it.”

Hollenbach had a common kind of COVID experience, moderate symptoms and eventually a full recovery. But in her research, she says she’s most interested in those with extreme cases.

“One extreme is very severe disease [leading to hospitalization or death]. And the other end of that spectrum is you didn’t have any symptoms. We really haven’t understood what’s driving that,” she says.

The new findings are thanks, in part, to the Good Samaritans who signed up to donate bone marrow through the Be The Match program. Some people who had provided a DNA sample to the program also signed up to participate in Hollenbach’s COVID-19 Citizen Science Study.

“We simply asked people who were registered donors to track their COVID experience through a smartphone app and consented to let us look at their genetic data and link it to their answers,” Hollenbach says.

Hollenbach thought that the same HLA genes used to find bone marrow matches could also be involved with COVID outcomes. “There’s more diseases and conditions associated with variation in the HLA genomic region than any other genomic region. And that’s by a wide margin,” she says.

HLAs are a class of genes involved in the immune system that sit on the surface of our cells. When we’re infected by a virus, HLAs will hold out a piece of that virus like a flag, telling the immune system to kill the infected cell.

There are hundreds of different HLA variants. Hollenbach found that one of them, HLA-B*15:01, was associated with asymptomatic COVID.

“To be fair, not everybody that has [HLA-B*15:01] will be asymptomatic,” Hollenbach says. “But it was a really clear, robust and replicable association.”

They call it ‘cross-reactive immunity’

So how does this protection work?

The research shows that people with HLA-B*15:01 have an enhanced protection against COVID after being exposed to closely related common cold viruses. That’s the result of a process called cross-reactive immunity.

“The thinking is that your exposure to some seasonal cold viruses, that in some cases share a lot of similarities with parts of SARS-CoV-2, gave you some existing immunity,” Hollenbach says.

This is similar to how many vaccines, including the COVID vaccine, work. If you show the immune system a piece of a virus, it can use that as a template to create “Memory T cells.” which can recognize viruses in future infections that match the template and start an immune response.

So when people with HLA-B*15:01 are exposed to the common cold, they create Memory T cells from a template that’s so similar to COVID. And this template gives them enough protection from the virus that if infected they might never show any symptoms.

Hollenbach and her team demonstrated this by turning to samples of T cells from people with HLA-B*15:01 that were taken before the pandemic and then exposing those cells to COVID. Lo and behold, the T cells could react to the COVID virus.

The study doesn’t have all the answers but could hold clues to better COVID treatments

The scientific community is raving about the new study.

“Well, it’s a breakthrough,” says Dr. Eric Topol, a physician-scientist at the Scripps Research Institute who wasn’t involved in the study. “I think it may wind up giving us a whole new map for what to do in terms of drugs and vaccines, which is really notable.”

While Topol is overall very enthusiastic about this research, he does have some concerns. “The main limitation is [the study] has three cohorts that were almost all European ancestry,” he says.

This type of limited ethnic pool is an unfortunately common problem in disease research and means that this research might not apply to broad swaths of people.

The other main limitation of the study, Topol says, is that symptoms were self-reported, meaning that some people who reported as asymptomatic might have had a late onset of symptoms or mild symptoms that they didn’t record in the app. But he says that the research team “did a really good job to deal with that” by making sure no symptoms were reported both 2 weeks before and after a positive test.

And there’s the caveat that this research doesn’t fully explain the mystery of asymptomatic COVID infections. “The genetic association that we found in this study explains some but not all asymptomatic disease,” Hollenbach says. “So surely there are other genetic and non-genetic factors that are important in asymptomatic infection.”

The paper says that only one of every five people in the study who reported being asymptomatic for COVID had the HLA-B*15:01 variant.

So those lucky enough to be born with HLA-B*15:01 might have some built-in protection against COVID. There might even be other versions of HLA that protect people too.

And what does this research mean for those without the Memory T cell protection?

“I think that it gives us an opportunity to think about potentially developing vaccines and therapeutics that are aimed not at preventing infection but preventing symptoms,” Hollenbach says.

Those kinds of developments based on this research are a long way off but could lead to substantive breakthroughs in treatment down the road.

“If you can find a path so that people don’t get sick from COVID. That’s extraordinary,” Topol says. 

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