Genetic architecture of adaptive immune responses and adverse reactions to inactivated COVID-19 vaccine

Host genetic determinants influence vaccine efficacy. The majority of participants in current COVID-19 vaccine genetic studies are of European ancestry, and the basis for individual differences in cell phenotypes is largely unclear. Here, we report a genome-wide association study (GWAS) of comprehensive vaccine response, encompassing humoral immunity, cellular immunity and adverse reactions, in 2,299 Chinese individuals vaccinated with CoronaVac or BBIBP-CorV. We identify 14 fine-mapped genetic variants significantly associated with adaptive immune response and reactogenicity. Among them, 12 represent previously unreported loci and 2 (rs140176526 and rs11262794) are putative regulatory variants by Bayesian colocalization. SNP-based heritability is substantial for humoral immunity (33.4%). Integrating GWAS data with single-nucleus ATAC-seq (snATAC) and single-nucleus RNA-seq (snRNA) co-assay profiles across 10 time points identifies trait-associated immune cell types. Notably, MAIT and NKT show significant partitioned heritability enrichments across all phenotypes including neutralizing antibody (NAb) responses, T-helper 1 (Th1) cells responses, B cell memory, fatigue and muscle pain. Our findings unveil previously unrecognized genomic factors and epigenomic regulatory mechanisms underlying individual variability in vaccine responses at high resolution.