Baseline interferon signaling in monocytes and antibody-mediated innate activation at injection site shape mRNA vaccine reactogenicity [NanoString nCounter dataset]

Through longitudinal immune profiling of vaccinated individuals and mechanistic studies in mice, we identified key immunological determinants of reactogenicity induced by mRNA vaccines. Systemic adverse events were associated with stronger interferon and pro-inflammatory responses following the second dose of COVID-19 vaccine, which were also correlated with the magnitude of the antigen-specific adaptive responses.

This heightened inflammation occurred within 24 hours of vaccination and originated primarily from the injection site and was characterized by enhanced recruitment and activation of myeloid cells, particularly monocytes. Two mechanisms contributed to this response: (1) early interferon production by muscle T cells generated after the first dose and (2) FcγR-dependent chemokine induction by antigen-specific antibodies. Consistently, serum antibody levels prior to vaccination correlated positively with reactogenicity.