Host determinants of inactivated COVID-19 vaccine responses

Inter-individual variation in immune responses and reactogenicity after inactivated COVID-19 vaccination remains incompletely understood. Here, we investigated the host genetic basis of vaccine-response heterogeneity in 2299 Chinese recipients of CoronaVac or BBIBP-CorV, examining phenotypes related to humoral immunity, cellular immunity, and common adverse reactions. We identified 13 fine-mapped variants associated with adaptive immune responses or reactogenicity, and estimated a positive SNP-based heritability point estimate for NAb responses (33.4%). To place these associations in an immunological context, we integrated GWAS signals with time-resolved single-cell ATAC and RNA co-assay profiles generated across baseline and post-vaccination timepoints. Variants associated with neutralizing antibody responses were enriched in post-vaccination accessible chromatin in regulatory T cells, whereas MAIT and NKT cells emerged as recurrent enrichment contexts, including neutralizing antibody responses, T helper 1 responses, B cell memory, fatigue, and muscle pain. These findings link host genetic variation to dynamic immune-cell regulatory states and provide a framework for prioritizing candidate loci, genes, and cellular contexts involved in responses to inactivated COVID-19 vaccination.