The Genetic Advantage: Revealing the Mystery of Asymptomatic COVID-19 Individuals
A recent discovery by researchers at UC San Francisco has shed light on why some individuals who contract COVID-19 remain symptom-free. The key appears to be a genetic mutation known as HLA-B*15:01, which enhances the immune response against the virus. This breakthrough, stemming from a study involving the National Marrow Donor Program, offers valuable insights into the genetic underpinnings of asymptomatic COVID-19 and opens up new possibilities for vaccine and drug development.
Intriguingly, scientists have pinpointed a specific gene variant, HLA-B*15:01, that is strongly associated with asymptomatic COVID-19 cases, thereby presenting promising avenues for novel treatments and vaccines.
Termed “super dodgers,” individuals who contract COVID-19 but never exhibit symptoms may owe their resilience to a genetic advantage. According to the research conducted by UC San Francisco, these super dodgers are over twice as likely as symptomatic individuals to carry the HLA-B*15:01 variant, which empowers their immune system to mount a robust defense against the virus.
Published recently in the prestigious journal Nature, this groundbreaking study provides the initial evidence of a genetic basis for asymptomatic SARS-CoV-2 infections, solving the enigma of why some remain unscathed by COVID-19.
The Role of HLA Genetic Variation
The secret behind this genetic advantage lies within the human leukocyte antigen (HLA), a set of protein markers that signal the immune system. A mutation in one of the genes responsible for HLA appears to enhance the ability of virus-killing T cells to recognize SARS-CoV-2 and launch a swift counterattack. Remarkably, even in individuals who have never encountered the virus before, the T cells carrying this variant can identify the novel coronavirus due to its structural resemblance to familiar seasonal cold viruses. This discovery offers a fresh perspective on potential targets for pharmaceutical interventions and vaccine development.
Prevalence and Impact of the HLA-B*15:01 Mutation
The HLA-B*15:01 mutation, relatively common, is present in approximately 10% of the study’s population. Importantly, it does not prevent the virus from infecting cells but rather prevents the development of any symptoms, including mild ones like a runny nose or a barely noticeable sore throat.
The research from UCSF reveals that among individuals who remained asymptomatic after COVID-19 infection, 20% carried at least one copy of the HLA-B*15:01 variant, compared to just 9% of those who experienced symptoms. Strikingly, those with two copies of the variant were over eight times more likely to remain symptom-free.
Data Collection and Analysis
Early suspicions regarding the involvement of HLA led researchers to turn to a national registry with the necessary data—the National Marrow Donor Program/Be The Match. This registry, the largest of its kind in the U.S., is dedicated to matching donors with individuals in need of bone marrow transplants.
However, to determine how these donors fared against COVID-19, researchers relied on a mobile app developed at UCSF called the COVID-19 Citizen Science Study. Nearly 30,000 participants from the bone marrow registry were recruited and tracked throughout the first year of the pandemic, a period when vaccines were not yet available, and testing was a routine part of people’s lives.
“We did not set out to study genetics, but we were thrilled to see this result come from our multidisciplinary collaboration with Dr. Hollenbach and the National Marrow Donor Program,” stated Mark Pletcher, MD, MPH, a professor of epidemiology and biostatistics at UCSF.
Limitations and Findings
The primary study group was limited to individuals who self-identified as white, primarily due to insufficient representation of other ethnic and racial groups in the final set of study respondents.
Among the 1,428 unvaccinated donors who tested positive for COVID-19 between February 2020 and the end of April 2021, only 136 remained asymptomatic for at least two weeks before and after testing positive. Notably, only one HLA variant, HLA-B*15:01, demonstrated a strong association with asymptomatic COVID-19 infection, and this correlation was confirmed in two independent cohorts. Traditional risk factors for severe COVID-19, such as age, weight, and chronic diseases like diabetes, did not appear to influence who remained asymptomatic.
Martin Maiers, vice president of research at the National Marrow Donor Program/Be The Match, expressed pride in the research partnership, highlighting the potential of leveraging a national registry to combat diseases and prevent future pandemics.
Understanding the Immune Response
To decipher how HLA-B*15:01 effectively combats the virus, researchers collaborated with experts from La Trobe University in Australia. Their focus centered on T-cell memory, the mechanism by which the immune system retains information about past infections.
Through their investigation, the researchers observed that T cells from individuals carrying HLA-B*15, even without prior exposure to SARS-CoV-2, could still recognize a specific segment of the novel coronavirus known as the NQK-Q8 peptide. This indicates that exposure to certain seasonal coronaviruses, which share a similar peptide called NQK-A8, equipped the T cells of these individuals to swiftly identify SARS-CoV-2 and mount a more potent and efficient immune response.
Stephanie Gras, a professor and laboratory head at La Trobe University, emphasized the potential of studying this immune response to identify innovative approaches for enhancing immune protection against SARS-CoV-2, which could be instrumental in the future development of vaccines and drugs.
Reference: “A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection” by Danillo G. Augusto, Lawton D. Murdolo, Demetra S. M. Chatzileontiadou, Joseph J. Sabatino Jr, Tasneem Yusufali, Noah D. Peyser, Xochitl Butcher, Kerry Kizer, Karoline Guthrie, Victoria W. Murray, Vivian Pae, Sannidhi Sarvadhavabhatla, Fiona Beltran, Gurjot S. Gill, Kara L. Lynch, Cassandra Yun, Colin T. Maguire, Michael J. Peluso, Rebecca Hoh, Timothy J. Henrich, Steven G. Deeks, Michelle Davidson, Scott Lu, Sarah A. Goldberg, J. Daniel Kelly, Jeffrey N. Martin, Cynthia A. Vierra-Green, Stephen R. Spellman, David J. Langton, Michael J. Dewar-Oldis, Corey Smith, Peter J. Barnard, Sulggi Lee, Gregory M. Marcus, Jeffrey E. Olgin, Mark J. Pletcher, Martin Maiers, Stephanie Gras, and Jill A. Hollenbach, 19 July 2023, Nature. DOI: 10.1038/s41586-023-06331-x.
Co-authors: Additional authors at UCSF include Mark J. Pletcher, MD, MPH; Jeffrey E. Olgin, MD; Gregory M. Marcus, MD, MAS; Sulggi Lee, MD, PhD; Jeffrey N. Martin, MD, PhD; J. Daniel Kelly, MD, PhD, MPH; Sarah A. Goldberg, MAS; Scott Lu, MD; Michelle Davidson, MD
Table of Contents
Frequently Asked Questions (FAQs) about Genetic Advantage
What is the main discovery in this research?
The main discovery in this research is the identification of a specific genetic mutation, HLA-B*15:01, strongly associated with asymptomatic COVID-19 cases.
How common is the HLA-B*15:01 mutation?
The HLA-B*15:01 mutation is relatively common, found in approximately 10% of the study’s population.
What does HLA-B*15:01 do in relation to COVID-19?
HLA-B*15:01 enhances the immune response against the SARS-CoV-2 virus, allowing individuals carrying this mutation to effectively combat the virus without developing symptoms.
How was this research conducted?
The research involved a collaboration with the National Marrow Donor Program/Be The Match and the use of the COVID-19 Citizen Science Study app to track nearly 30,000 participants during the early stages of the pandemic.
What are the potential implications of this discovery?
This discovery opens up new possibilities for the development of treatments and vaccines targeting asymptomatic COVID-19 cases, and it sheds light on the genetic basis of resilience to the virus.
Are there any limitations to this study?
One limitation is that the primary study group primarily consisted of individuals who self-identified as white, limiting the representation of other ethnic and racial groups. Additionally, the research focused on unvaccinated individuals during the early stages of the pandemic.
More about Genetic Advantage
- UC San Francisco Research
- Nature Journal Article
- National Marrow Donor Program/Be The Match
- COVID-19 Citizen Science Study
