Genetic differences in the HLA region contribute to the variability in SARS-CoV-2 vaccine responsiveness of older persons: the Doetinchem Cohort Study

Objectives: Older persons generally have weaker antibody responses to vaccines than younger individuals, but heterogeneity is large. We aimed to identify genetic variants associated with primary SARS-CoV-2 vaccine-induced antibody responses in older persons that might contribute to this heterogeneity. Methods: Demographic and genotype data were collected in the Doetinchem Cohort Study prior to the COVID-19 pandemic. Antibody responses were measured 1 month after the first and second SARS-CoV-2 vaccinations, and genome-wide association analysis was performed in 842 and 890 individuals respectively. Polygenic scores were calculated and tested in an independent sample, and the variance explained by the scores was estimated using a bootstrap procedure. Genes were mapped to genome-wide suggestive (P < 1 × 10⁻⁵) loci, and gene set enrichment was performed using the hypergeometric test. Results: Antibody responses 1 month after the first and second SARS-CoV-2 vaccinations were linked to genome-wide significant (P < 5 × 10⁻⁸) loci on Chromosome 5. Polygenic scores related to these antibody responses could explain 9% (95% CI P1: [−4% to 21%], 95% CI P2: [−4% to 24%]) of the variance. Genome-wide suggestive loci related to the responses after two vaccinations could be mapped to several genes in the human leukocyte antigen (HLA) region on chromosome 6p21. Conclusion: Genetic variation is suggested to play a role in the primary vaccine-induced IgG antibody responses to SARS-CoV-2 in older persons. The most prominent source of variation was found to lie in HLA genes, which are enriched in several immune pathways and immune-mediated diseases.