Genetic cheat code might explain why some people catch Covid but never get sick

In the earliest days of the Covid-19 pandemic, when the new coronavirus still appeared to be confined to China, public health authorities were divided over whether to declare the outbreak a global emergency. That changed once it became clear that the virus was silently spreading farther and faster than anyone realized — fueled by transmission among contagious people who didn’t feel sick.

Some viruses, like the original SARS, can only be passed when a person is showing symptoms. Others, like the flu, can be spread a day or two before symptoms appear. Studies from the first (vaccine-free) year of the pandemic suggested that more than half the cases of Covid-19 were caused by infected people who didn’t have any symptoms when they passed on the virus. Among these symptom-free spreaders, some later experienced fever, cough, and other symptoms, but about 40% never got so much as a sniffle.

What makes people able to clear SARS-CoV-2 out of their systems before it gains a foothold has been one of the enduring mysteries of the pandemic. Now, a group of scientists from the University of California, San Francisco, believes it has found an answer: It’s in their genes.

In a study published Wednesday in Nature, the team identified a mutation that increases a person’s chance of being asymptomatic by nearly tenfold. “It’s just one of these natural lucky breaks,” said immunogeneticist Jill Hollenbach, who led the research.

Hollenbach’s UCSF lab focuses on human leukocyte antigen, or HLA — a molecule that helps the immune system surveil every cell of the human body and is critical during the earliest stages of infection. HLA proteins are constantly grabbing bits of chopped-up proteins they find inside or around their cells and bringing them to the surface to display them to immune cells passing by.

Most of the time, these proteins are just harmless bits of healthy cells. Like a biometric scanner, the immune cells read this as “self” and ignore them. But sometimes, HLA molecules hold up something unrecognizable — a piece of a bacterial protein or a part of a virus. That should set off alarm bells in the immune system, mobilizing the production of antibodies and sending troops of T cells to storm the area.

But not all HLA molecules are created equal — some are better at grabbing different kinds of proteins than others. And HLA genes are some of the most diverse in the human genome. Hollenbach had a hunch that some of the variety in people’s immune responses to SARS-CoV-2 could be coming from their particular HLA. To find out if that was true, she turned to the National Marrow Donor Program, the largest database of people who have had their HLA genes decoded, totaling around 13 million individuals. (HLA genes are the ones that have to be matched for people receiving an organ or bone marrow transplant to not reject the foreign tissue.)

Hollenbach’s team was able to recruit about 30,000 people from that registry to be a part of The Covid-19 Citizen Science Study, a project launched by her UCSF colleagues Jeffrey Olgin, Mark Pletcher, and Gregory Marcus to track people’s Covid exposures, infections, and symptoms through a smartphone app. From the time they began tracking this data until April 2021 — when vaccines became widely available — more than 13,000 tested positive. Among that group, 10% remained completely symptom-free.

When Hollenbach’s team looked at what those individuals had in common, they found that about 1 in 5 shared a common mutation in their HLA gene, known as HLA-B*15:01. That suggested this version of HLA was especially potent at clearing SARS-CoV-2. To understand why, they tracked down frozen samples of T cells from individuals carrying the B*15:01 mutation — T cells that had been harvested long before the Covid-19 pandemic — and exposed them to SARS-CoV-2. They saw that the majority of these T cells recognized the virus immediately.

Further experiments found the likely reason for that: This version of HLA is good at grabbing the bits of other coronaviruses — the ones that cause seasonal colds — that look the most like SARS-CoV-2. So if you’ve got this HLA and you’ve been exposed to those viruses (which most people have), when SARS-Cov-2 shows up, your body doesn’t need time to make specifically targeted T cells to fight it off. They’re already there.

“Individuals with this B*15:01 mutation who have these cross-reactive T cells seem to be particularly effective, very early in infection, at nuking — for lack of a better word — the virus before these folks experience any symptoms at all,” Hollenbach said. Her team’s work did not address whether such individuals clear SARS-CoV-2 fast enough so as to not acquire the viral loads necessary to be contagious.

But Hollenbach is hopeful the discovery might aid efforts to design even more effective vaccines in the future. “We now know some of the immunological characteristics for people to have this very favorable outcome.” she said. “They don’t prevent infection entirely, but not having symptoms is still a win health-wise.”

“Their approach is quite clever and the paper is very exciting,” said Jean-Laurent Casanova, who studies the genetics of viral resistance at Rockefeller University and was not involved in the new research. The effect of the B*15:01 mutation was significant, especially when people had two copies, he said, “which gives weight to these important findings.”

He added that the explanation they provided still left some room for doubt, however, because in a perfect world the cryopreserved T cells from pre-Covid would have come from the same HLA-genotyped donors who participated in the UCSF study. It’s a question he’s hoping his own group might be able to help answer in the coming months.

Casanova is one of the co-leaders of the COVID Human Genetic Effort, an international consortium that has collected and sequenced the genomes of thousands of individuals, many of whom seem to be completely resistant to SARS-CoV-2 infection. He and his colleagues are in the process of analyzing their DNA to uncover rare variants that may be playing a role in preventing people who’ve had repeated exposures — health care workers, spouses of infected individuals — from ever testing positive for the virus. Studying these so-called super-dodgers is just one aim. They’re also investigating the genetic differences involved in the most severe cases of Covid pneumonia, neurological complications, and long Covid.

Previously, they have found individuals on the opposite end of the immunological luck spectrum. In a paper published in 2021, the consortium discovered that in 10% of the most severe cases of Covid, people had preexisting autoantibodies that turned against some of the body’s key immune defenses, dooming their chances of fighting off the infection.

Casanova and his collaborators didn’t set out specifically to study silent spread — people who are infected but without symptoms. But they are now in a position to go back to their cohort and look at their HLA genes to see how people with the B*15:01 mutation tended to fare in terms of infection and symptoms.