Genetic Basis of Asymptomatic SARS-CoV-2 Infection: Implications for Public Health and Vaccines


The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has posed an unprecedented global health challenge, with various clinical presentations ranging from severe respiratory distress to asymptomatic cases.

Understanding the biological underpinnings of asymptomatic infection is of paramount importance for public health measures, vaccine design, and therapeutic development. In this comprehensive article, we delve into a crowd-sourced study that leveraged a vast database and mobile technology to explore the immunogenetic underpinnings of asymptomatic SARS-CoV-2 infection.

By employing cutting-edge genetic and functional studies, the researchers uncovered a strong association between HLA-B*15:01 and asymptomatic disease course, providing valuable insights into early infection and immune responses.

The Study and Its Findings

The researchers conducted a study screening nearly 30,000 individuals who had been previously genotyped for HLA for viral infection and disease course. They found compelling evidence supporting a genetic basis for asymptomatic infection with SARS-CoV-2. Among participants who tested positive for the virus, HLA-B15:01 was significantly associated with asymptomatic infection.

Notably, individuals carrying this common allele, found in approximately 10% of individuals with European ancestry, were more than twice as likely to remain asymptomatic after SARS-CoV-2 infection compared to those who did not have the allele.

Homozygosity for HLA-B15:01 further increased the chance of remaining asymptomatic by more than eight times. This finding pointed to important features of early infection with SARS-CoV-2.

Moreover, the researchers found a highly similar frequency distribution of HLA-B*15:01 in asymptomatic versus symptomatic patients in two independent cohorts. This compelling association highlights the importance of HLA variation in COVID-19 and emphasizes the significance of examining asymptomatic infection as a primary phenotype.

Pre-existing Immunity and Cross-Reactivity

Respiratory tract infections, including seasonal coronaviruses, represent a considerable public health burden. Previous studies have shown that T cells can cross-react to SARS-CoV-2 and seasonal coronavirus peptides, indicating the existence of long-lasting T cell protective immunity that can potentially limit the severity of COVID-19.

A recent study demonstrated T cell cross-reactivity to SARS-CoV-2 and seasonal coronaviruses for an HLA-B*15:01-restricted immunodominant epitope (NQK-Q8) in individuals who received two doses of the Pfizer-BioNTech BNT162b2 mRNA vaccine.

To further investigate the role of HLA-B15:01 in mediating asymptomatic disease through pre-existing T cell immunity, the researchers analyzed immunodominant epitopes in T cells from pre-pandemic healthy individuals. They observed that T cells from a subset of healthy donors carrying HLA-B15:01, who were never exposed to SARS-CoV-2, showed reactivity to the SARS-CoV-2 peptide NQK-Q8, and most of the reactive cells displayed a memory phenotype. The sequence similarity between SARS-CoV-2 and seasonal coronaviruses peptides, with only a single amino acid substitution, explained the T cell cross-reactivity.

Structural Basis of T Cell Cross-Reactivity

To corroborate their hypothesis, the researchers examined the crystal structures of the HLA-B15:01 molecule in the presence of each peptide (NQK-Q8 from SARS-CoV-2 and NQK-A8 from seasonal coronaviruses). The results demonstrated that both peptides shared a similar ability to stabilize the HLA-B15:01 molecule and were presented in a similar conformation, providing the molecular basis for T cell cross-reactivity and pre-existing immunity.

This observation aligned with previous research in uninfected individuals who could recognize SARS-CoV-2-derived peptides due to cross-reactive T cells recognizing homologous peptides from seasonal coronaviruses. This cross-reactivity was associated with less severe COVID-19 disease.

The Significance of T Cell Polyfunctionality

The researchers also explored the polyfunctionality of T cells toward the NQK-Q8 peptide in unexposed individuals. They found that both seasonal and pandemic coronavirus-derived NQK peptides led to highly polyfunctional T cell responses in the context of HLA-B*15:01. T cell polyfunctionality, which includes various effector functions (IFNγ, TNF, IL-2, MIP-1β, CD107a), is linked to superior viral-suppressive activity and predictive of protective immunity and vaccine efficacy.


In summary, this study has provided strong evidence supporting the role of HLA-B15:01 in mediating asymptomatic SARS-CoV-2 infection through pre-existing T cell immunity. The presence of cross-reactive T cells before infection may lead to a rapid and protective immune response in individuals carrying HLA-B15:01, making it a potentially more protective allele than others associated with COVID-19.

Understanding the immunogenetic underpinnings of asymptomatic infection could lay the groundwork for refining vaccine development and therapeutic options for early disease management. However, it is essential to acknowledge the limitations of the study, including self-reported data and limited analysis in diverse populations. Further research is warranted to expand our knowledge and potentially uncover additional candidate peptides underlying cross-immunity with seasonal coronaviruses. Overall, this study represents a significant step toward comprehending the complex interplay between host genetics and immune responses in the context of SARS-CoV-2 infection.

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