Variability in the TLR3 type I interferon pathway is predictive of RNA vaccine responses

Biological predictors of variable vaccine responses are lacking. We hypothesized that variability in prevaccine innate immune responses, specifically for type I interferons (IFN-I), is predictive of postvaccine antigen-specific responses. To test this, we assessed prevaccine immune responses at protein and transcriptomic levels following whole blood stimulation with Toll-like receptor (TLR) viral agonists in healthy adolescents and adults. Four weeks after the second vaccine dose, with either the BNT162b2 mRNA or CoronaVac inactivated virus vaccine, we assessed antigen-specific T cell cytokine responses and plasma antibody levels. BNT162b2 vaccinees had increased production of the antigen-specific T cell cytokines interleukin-2 (IL-2), interferon-γ, and IL-21 after severe acute respiratory syndrome coronavirus 2 spike stimulation, as well as increased antibody levels and serum pseudo-neutralization compared with CoronaVac recipients. In direct support of our hypothesis, we find that prevaccine poly(I:C) (polyinosine-polycytidylic acid; TLR3 viral agonist) IFN-I responses were significantly associated with the postvaccine T cell cytokine responses. In an independent cohort of 990 healthy donors, we confirmed the significant association between poly(I:C)-induced IFN-α and spike-induced cytokines in mRNA vaccine recipients. We further confirmed this specific association in a cohort of healthy Europeans and identified a common genetic polymorphism in TLR3 that affects IFN-I induction and subsequent vaccine-specific T cell responses. This study shows that preexisting innate immune variability can predict the effectiveness of vaccine responses and identifies pathways relevant to mRNA vaccination. Targeting the specific innate immune pathway relevant for a vaccine may provide a new approach for tailoring vaccines to different populations.