An mRNA vaccine confers enhanced protection against herpes simplex virus through an IFN-I-dependent pathway

Herpes simplex virus (HSV) types 1 and 2 cause widespread oral or genital infections, but no prophylactic or therapeutic HSV vaccine has been approved to date. In this study, we developed three mRNA vaccine candidates expressing key viral glycoproteins: monovalent gD2, bivalent gD2-gC1, and bivalent gD2-gE1. We assessed their immunogenicity and protective efficacy in a murine model. All candidates elicited robust humoral and cellular immunity and provided significant protection against intravaginal HSV challenge. Notably, the gD2-gE1 vaccine induced markedly stronger immune responses. Mechanistically, its superior immunoprotective efficacy was associated with the stronger IFN‑I response, which thereby enhanced the adaptive immune response. Collectively, our findings provide a scientific rationale and valuable insights for the future development of HSV vaccines.