Study details

For the study, researchers enrolled almost 30,000 people from a database of bone-marrow donors. More than 1,400 participants tested positive for COVID-19 during the 15-month study span — which was conducted before COVID-19 vaccines were widely available — and 136 were asymptomatic.

The researchers then looked for a link between people who were asymptomatic and any variations in HLA genes — genes that encode proteins found on the surface of almost all cells in the body, which display fragments of potential invaders to the immune system, triggering an immune response from T cells.

They found a link between asymptomatic infection and an HLA mutation called HLA-B*15:01, which was carried by about 10% of the study's population. Those with the mutation were twice as likely to remain asymptomatic after being infected with SARS-CoV-2 than those without the mutation. In addition, those with two copies of the mutation — one from each parent — were more than eight times as likely to remain asymptomatic post-infection.

According to the researchers, the T cells collected had no "memory" of SARS-CoV-2, but still attacked the virus' "spike" protein once the HLA protein presented them with a fragment of it. That fragment is structurally similar to fragments from the spike proteins of the coronaviruses that cause the common cold, leading the researchers to hypothesize that previous exposure to common cold coronaviruses may allow T cells to recognize and mount an immune response against SARS-CoV-2 quicker than other cells would.

The researchers noted their main analysis was conducted on white participants, as they didn't have enough people from other ethnic and racial backgrounds to analyze. However, the authors found evidence for the genetic mutation link in Black study participants, but found less clear results among Asian and Hispanic study participants.

Discussion

Jill Hollenbach, a co-author of the study and a neurology professor at the University of California, San Francisco, noted that this study is "the first time where, in a really rigorous and robust way, anybody has shown that there is a clear, definitive genetic underpinning to asymptomatic disease [from the coronavirus] — not all asymptomatic disease, but some subset of people who stay asymptomatic."

Hollenbach added that she's been researching HLA disease association for her entire career, and her team was "pretty stunned" at the study results. "That was a really strong effect," she said.

"Folks with this B*15:01, for whatever reason, some of them have this preexisting immunity after exposure to seasonal cold viruses that happens to be just remarkably effective at dealing with the virus," Hollenbach said, adding that having this version of the gene "is the key element to having this very effective preexisting immunity."

The study "deserves a round of applause," said Jean-Laurent Casanova, a pediatric immunologist at Rockefeller University. The researchers showed a "modest" link but it's "stronger than any other association for a common gene published" on COVID-19, Casanova said.

Mary Carrington, an immunogeneticist at the Frederick National Laboratory for Cancer Research, said the finding is something of a "smoking gun," and that it could help vaccinologists develop next-generation COVID-19 vaccines that might be able to prevent symptoms as well as tamp down on disease severity.

Paula Cannon, a professor of molecular microbiology and immunology at the Keck School of Medicine at the University of Southern California, said the study is "not saying that if you have this, you don't have to worry. But honestly, I'd like to have these genes. I'd sleep better at night if I did." (Kozlov, Nature, 7/19; Lin, Los Angeles Times, 7/19; Abbott, Wall Street Journal, 7/19)

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