By Deborah Borfitz 

September 19, 2023 | Vaccine developers may want to consider designing formulations intended to prevent symptoms rather than infection, which the COVID-19 pandemic has demonstrated can be hard to do with any long-lasting effect. Clues may exist in the human leukocyte antigen (HLA) system, the largest cluster in the human genome that is already known to be associated with hundreds of diseases and conditions, according to Jill Hollenbach, Ph.D., MPH, professor of neurology and epidemiology and biostatistics at the University of California, San Francisco. 

In her most recently published research study, appearing in Nature (DOI: 10.1038/s41586-023-06331-x), she and her colleagues discovered that HLA-B15:01—an allele carried by an estimated 10% of the population—appears to help virus-killing T cells identify SARS-CoV-2 and launch a counterattack. A strong association between the variant and asymptomatic infection was observed in two independent cohorts of individuals who had a confirmed infection and were unvaccinated at the time, and the protective effect didn’t seem to be countered by known risk factors such as older age and obesity. 

About 20% of people in the study who remained asymptomatic after infection carried at least one copy of the HLA-B15:01 variant, compared to 9% of those who reported symptoms. Those who carried two copies of the variant were more than eight times more likely to avoid feeling sick. 

The findings were only momentarily surprising, says Hollenbach. COVID-19 research leans heavily toward seriously ill patients with a long list of co-occurring risk factors. But the individuals in this study fell on the opposite end of the spectrum in that they became infected and quickly cleared the virus before symptoms had a chance to develop, making any comorbidities potentially irrelevant.   

Hollenbach’s lab has long been interested in the influence of HLA genes in health and disease, so it wasn’t much of a leap to think there might likewise be some kind of relationship with COVID outcomes. In the study, protection was conferred in participants carrying the HLA-B15:01 variant because their T cells could identify the novel coronavirus based on its resemblance to previously encountered seasonal cold viruses, she explains. 

The study recruited nearly 30,000 people in the National Marrow Donor Program’s Be The Match registry of HLA-typed volunteer donors in the U.S. Researchers identified 1,428 unvaccinated donors who tested positive between February 2020 and the end of April 2021, 136 of whom remained asymptomatic for at least two weeks before and after testing positive. Findings were originally published last October to the medRxiv preprint server.  

It is not unexpected that people would be genetically predisposed to different outcomes from COVID-19 or any other disease, notes Hollenbach. “But genetics is not destiny, and we have many tools at our disposal to make us safer in the face of the virus and number one is vaccination.” 

The beneficial role of HLA-B15:01 is less important than what is being learned about the early immune response to the SARS-CoV-2 virus and “what particular conditions are perhaps necessary for an individual to be able to very quickly and efficiently deal with the virus and not experience any ill effect,” she says. Many people would likely consider that a “good outcome” and thus a reasonable and perhaps easier place to direct vaccine design and development energies than in trying to prevent infection from happening in the first place. 

It is also hard to know when infection has been prevented, given the possibility of dodging all the telltale symptoms, adds Hollenbach. This is especially true now people are no longer testing themselves unless they have symptoms, or they’ve been exposed to someone who became ill. 

Citizen Science 

HLA genes are the most variable genes in the human genome, and the most medically important, Hollenbach says, noting that this includes matching organ donors to transplant recipients. “They encode extremely important immune system molecules whose job is to present antigens to T cells for inspection to elicit an immune response,” which gets at their pivotal role in determining individual variability in generating neutralizing antibodies. 

Many ongoing studies are attempting to discover what’s special about people seemingly unaffected by SARS-CoV-2, she says, but they are inherently challenging to conduct. “It is not easy to collect biological samples on people who are healthy because they are not interacting with the healthcare system, so we need to go out and find them.” 

Fortunately, a national registry existed containing the genetic information needed by Hollenbach and her team. They have been collaborating with Be The Match for many years and it is home to existing data on millions of individuals. “It’s this tremendous public resource that allows us to do studies on HLA without having to do any sequencing or going to a lab,” she says. 

The original thought was to survey the donors and ask about their experiences, as was previously done with other large registries such as the UK Biobank, 23andMe, and Ancestry.com. “The problem is that’s kind of a one-time deal, and you don’t have what is happening [after] that point, says Hollenbach. 

As luck would have it, colleagues across campus in the department of medicine (study co-authors Mark Pletcher, Jeffrey Olgin, and Gregory Marcus) who had developed a health-tracking app for individuals with heart disease had just adapted the smartphone technology for COVID-related purposes. It became the basis of what became known as the COVID-19 Citizen Science Study, the source of the 30,000 individuals also in the Be The Match registry who were reporting their symptoms and outcomes, including self-reported positive tests for SARS-CoV-2 infection.  

Data collection on participants continues to this day.  

Ongoing Work 

The 10% prevalence rate of the HLA-B15:01 allele is specific to individuals with European ancestry, Hollenbach says, since not enough eligible people from other ethnic and racial groups opted to participate in the study by downloading the smartphone-based app. She and her team are now working on correcting that imbalance via additional outreach to the donor registry focused on underrepresented population groups, as well as through other collaborations underway worldwide. 

In terms of the underlying immunology behind symptom-free SARS-CoV-2 infection, Hollenbach reports a research partnership with her co-senior author on the paper—Stephanie Gras, associate professor of biochemistry and molecular biology at Monash University (Australia)—focused on the role of HLA in vaccine side effects. “There seems to be a clear association there,” Hollenbach says, noting that this provides a window into what’s producing the side effects (e.g., fever, chills, and headache) people are finding most troublesome and have been a barrier to vaccine uptake.