Sterilized protective immunity induced by DAM and DAMin mouse models for both VACV and MPXV.

Abstract

The increasing prevalence of mpox calls for the development of safer and more accessible next-generation vaccines. Based on a structure-guided "two-in-one" immunogen design strategy, we have previously developed an innovative protein-based monkeypox virus (MPXV) vaccine, DAM (Double A35 and M1), which addresses the issues of imbalanced bioavailability associated with cocktail vaccines and elicits superior antiviral immunity with a safety profile. In this study, we iteratively designed two "four-in-one" chimeric immunogens, DAMs, using four MPXV antigens, M1, A29, A35, and B6. Although DAMs elicited broader immune responses against four antigens, no additional benefit in either in vitro neutralization or in vivo protection against poxviruses was detected compared to DAM. Notably, vaccination-related tissue damage was observed in the live virus vaccine group, whereas all protein-based vaccines showed better safety and protection against lethal vaccinia virus (VACV) challenge. Together, these further demonstrate that DAM, with a minimal protein subunit of two components, is a promising immunogen to be further clinically developed.