COVID-19 Vaccine Reactogenicity Marks an Innate Inflammatory Response Associated With HLA Variation and Enhanced Protection.

Vaccination against SARS-CoV-2 has been central to mitigating the COVID-19 pandemic, although transient systemic side effects remain common and contribute to vaccine hesitancy. While previous studies have implicated HLA variation in COVID-19 vaccine reactogenicity, the mechanisms linking immunogenetic variation, inflammatory side effects, and protection remain poorly understood. Here, using a large deeply genotyped and phenotyped cohort, together with functional immunological analyses, we investigated the determinants of vaccine reactogenicity. In 50,535 vaccinated individuals, with replication in an independent cohort of 4,575 individuals, we confirmed a remarkably strong association between HLA-A*03:01 and systemic side effects following COVID-19 vaccination (OR = 1.36, CI = 1.31-1.41, p = 6.79 × 10-57). In contrast, HLA-B*08:01 was associated with reduced vaccine reactogenicity, that extended across both COVID-19 and influenza vaccines, suggesting separable antigen-specific and generalized determinants of vaccine reactogenicity. HLA-A*03:01 carriage was additionally associated with fewer breakthrough and recurrent SARS-CoV-2 infections, while individuals reporting stronger vaccine side effects exhibited reduced infection risk and milder disease course independent of HLA genotype. History of allergy was likewise associated with increased vaccine reactogenicity, consistent with a broader host predisposition to inflammatory responsiveness. Unexpectedly, despite the strong HLA association, we did not observe evidence of enhanced antigen-specific T-cell activation in HLA-A*03:01 + individuals. Instead, our immunological analyses pointed toward a prominent role for early inflammatory cytokine responses from monocytes, with inflammatory signatures correlating with vaccine side-effect severity selectively among HLA-A*03:01 + donors. Together, these findings support a model in which vaccine reactogenicity reflects the interaction of antigen-specific immunogenetic effects and broader innate inflammatory responsiveness. More broadly, our results suggest that transient vaccine side effects may represent a clinically observable correlate of protective immune activation.