HLA Genetics and Immune Response in COVID-19

The human leukocyte antigen (HLA) system underpins cellular immunity by presenting viral peptides to T lymphocytes and orchestrating adaptive responses. In COVID-19, variation at HLA class I and II loci has been linked to differences in susceptibility, severity and vaccine responsiveness. Certain alleles enhance presentation of SARS-CoV-2–derived peptides, promoting rapid T cell activation and viral clearance, while others confer poorer epitope binding and may predispose to more severe disease. Beyond T cells, natural killer (NK) cells interpret HLA class I downregulation on infected cells and can eliminate cells that evade cytotoxic T lymphocytes. Genetic influences on B cell–mediated antibody production have also emerged, with HLA polymorphisms modulating the magnitude and durability of vaccine-induced serological responses. Together, these findings illuminate how HLA diversity shapes individual and population-level outcomes, informing strategies for personalised risk assessment, vaccine design and public health interventions.

Research from Nature Portfolio

Recent studies have revealed a strong association between the HLA-B*15:01 allele and asymptomatic SARS-CoV-2 infection. Individuals carrying this allele demonstrate pre-existing memory T cells cross-reactive to conserved peptides shared with seasonal coronaviruses, providing a structural basis for rapid viral clearance and symptomless infection. In parallel, large-scale analyses of vaccinated cohorts have identified multiple HLA alleles that govern antibody titres and breakthrough risk. One study confirmed that variants within the HLA-DQB1*06 group enhance spike-specific antibody responses, while six additional class I and II alleles independently influence both serological levels and the likelihood of breakthrough infection. Complementing these findings, investigation of mRNA vaccine recipients showed that HLA-A*03:01 and several other class I and II alleles are significantly associated with the magnitude of anti-SARS-CoV-2 antibody production, underscoring the role of HLA genotype in modulating vaccine efficacy across diverse populations.

HLA Genetics and Immune Response in COVID-19 publication trend

The graph below shows the total number of articles in hla genetics and immune response in covid-19 across all publications each year (not limited to Nature Index journals).

Technical terms

HLA (Human Leukocyte Antigen): A set of highly polymorphic genes encoding molecules that present peptide antigens to T cells.

Epitope: A specific peptide fragment of a pathogen that is recognised and bound by an HLA molecule for T cell activation.

Breakthrough infection: Occurrence of SARS-CoV-2 infection in an individual despite complete vaccination.

Natural Killer (NK) cell: An innate lymphocyte that detects and kills cells displaying abnormal or reduced HLA class I expression.

Killer Immunoglobulin-Like Receptor (KIR): A family of receptors on NK cells that interact with HLA class I ligands to modulate cytotoxic activity.

Genotyping: Laboratory determination of an individual’s specific genetic variants, including HLA alleles.

References

1. A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection. Nature (2023).
2. Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes. Nature Communications (2024).
3. Human leukocyte antigen variants associate with BNT162b2 mRNA vaccine response. Communications Medicine (2024).
4. Genetic determinants of IgG antibody response to COVID-19 vaccination. American Journal of Human Genetics (2024).
5. A bioinformatic analysis of T-cell epitope diversity in SARS-CoV-2 variants: association with COVID-19 clinical severity in the United States population. Frontiers in Immunology (2024).
6. HLA-Bw4 in association with KIR3DL1 favors natural killer cell-mediated protection against severe COVID-19. Emerging Microbes & Infections (2023).