Vaccination against SARS-CoV‑2 has been the most effective measure against the COVID‑19 pandemic. However, mild vaccine side effects have caused distress to individuals and could limit vaccine uptake, presenting a serious health risk. Genetically inherited Human Leukocyte Antigens (HLAs) have been linked with increased disease severity or protection against COVID‑19, and here we have studied the HLA association with COVID‑19 vaccine side effects and their impact on reinfection.
We examined variation in HLA-A, -B, -C, -DRB1, and -DQB1 for association with self‑reported mild side effects in a large cohort of U.S. individuals of European ancestry who had been vaccinated (N = 50,535), and confirmed the 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 with 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 in response to Spike‑derived peptides, excluding them as a likely source of the reported vaccine side effects. Instead, we found that high levels of IL‑6 and IL‑8 production by monocytes significantly correlate with the reported severity of side effects in HLA-A*03:01+ donors.
This work sheds light on the mechanisms underlying HLA‑mediated COVID‑19 vaccine reactogenicity, which is associated with a reduction in breakthrough infections, providing reassurance to individuals that despite the discomfort, mild vaccine side effects can be beneficial to overall protective immunity.