A mpox quadrivalent mRNA vaccine protects mice from a lethal vaccinia virus challenge

Abstract The outbreak of 2022 mpox virus (MPXV) infection in nonendemic regions is a global public health concern. A highly effective and safe MPXV vaccine that is available to the general public is urgently needed to control the MPXV pandemic. Here, we developed a polyvalent mRNA vaccine candidate, MPXV-1103, which expresses full-length B6R, A35R, A29L and M1R antigens with flexible linker-(G4S1)3 in a single sequence. Compared to the monovalent mpox mRNA vaccine candidates, MPXV-1103 elicits a stronger robust humoral response and MPXV-specific T-cell response and protects mice from a lethal vaccinia virus challenge with no live virus detected in the nasal and lungs even at dosages as low as 1 µg. Furthermore, the analysis of complete blood counts and photomicrographs of tissue in the main organs from mice vaccinated with MPXV-1103 at doses of 5 µg and 20 µg showed that two doses of MPXV-1103 vaccination did not cause observable pathologic changes in mice. Collectively, our results suggest that MPXV-1103, with features of high efficacy, safety and a simplified manufacturing process, is a promising vaccine candidate to defend against MPXV infection.