An HLA Association With COVID-19 Vaccine Reactogenicity Correlates With Fewer SARS-CoV-2 Infections and Monocyte Activation

Vaccination against SARS-CoV-2 has been the most effective tool in mitigating the COVID-19 pandemic. However, some individuals experience side effects that cause distress and interfere with daily activities, which can limit vaccine uptake, with important public health implications. Here, we considered the impact of HLA variation on the propensity for mild side effects with COVID-19 vaccination. We examined variation in HLA-A, -B, -C, -DRB1, and -DQB1 for association with self-reported side effects in a large cohort of U.S. Euro-ancestry vaccinated individuals (N = 50,535) and confirmed results in an independent replication cohort (N = 4,575). We found that HLA-A*03:01 was significantly associated with systemic side effects (OR = 1.36, CI = 1.31-1.41, p = 6.79×10-57) and fewer breakthrough infections, and that this phenomenon is specific to the COVID-19 vaccine. Surprisingly, we observed limited activation of CD8+ T cells in HLA-A*03:01+ samples to the Spike-derived peptides, excluding them as a likely source of the reported vaccine side effects. Rather, examination of immune cell subsets, prior and after vaccination, points to a central role for monocytes in the production of IL-6 and IL-8, which significantly correlates with the reported severity of side effects in HLA-A*03:01+ donors. Meanwhile, the large, mostly naïve, and low-affinity population of Spike-specific CD8+ T cells likely contribute to an inflammatory milieu in HLA-A*03:01 carriers through weak binding to antigen presenting cells. This work sheds light on the mechanisms underlying HLA-mediated COVID-19 vaccine reactogenicity and associated reduction in infections, providing important new insights that may support efforts to optimize vaccine efficacy and promote broader public involvement in vaccination programs.