Associations between genetic variations of HLA and IGHV, vaccination schedule, and COVID-19 vaccine immunogenicity

Interindividual genetic variations significantly influenced SARS-CoV-2-specific immunogenicity after vaccination, particularly for human leukocyte antigen (HLA) alleles. However, the mechanisms of different HLA alleles with varying immunogenicity and additional genetic factors related to immunogenicity remained unexplored. This population-based study utilized data of 180,580 vaccinated individuals from the UK Biobank. A genome-wide association study was conducted to identify significant single nucleotide polymorphisms (SNPs) associated with COVID-19 vaccine immunogenicity, identified by immunoglobulin antibody result. We found that SNPs significantly associated with immunogenicity of COVID-19 vaccines were located near the HLA-DQ and IGHV1-69. We further determined HLA-peptide-binding affinities and found that HLA-DQ alleles were significantly associated with immunogenicity due to variations in HLA-peptide binding affinities. Functional genomics data was applied to assess regulatory mechanisms of significant variants near IGHV1-69. Moreover, we employed Mendelian randomization and found that SNPs near IGHV1-69 were associated with immunogenicity by influencing IGHV1-69 expression. Besides, both genetic factors had interactive effects on immunogenicity. These genetic factors modulated the immune response among recipients with different vaccination interval schedules. Furthermore, we observed an interval of five to six weeks that consistently yielded optimal immunogenicity among population, regardless of genetic factors. This study comprehensively demonstrated how interindividual genetic variations affected immunogenicity of COVID-19 vaccines, suggesting the potential for personalized vaccination and administration strategies.