Single-dose Efficacy of a Next-Generation Mpox Vaccine Harnessing an Immunomodulatory Peptide

Rapidly deployable, single-dose vaccines that maintain durability under operational constraints remain an unmet need in outbreak preparedness. Live viral vectors such as Modified Vaccinia Ankara (MVA) offer strong safety profiles, yet their suboptimal immunogenicity often requires multidose regimens, reducing flexibility during emergency response. To address these limitations, we developed a modular vaccine platform that leverages immune checkpoint modulation to enhance immune cell priming without compromising the established safety profile of MVA. This platform, exemplified by the recombinant virus MVA-X, was engineered to express a peptide-based PD-1 antagonist (LD10) that provides localized, transient checkpoint blockade during early antigen presentation. The approach requires no external adjuvants, is compatible with lyophilization and stockpiling, and is readily adaptable to diverse antigens and pathogens. A single immunization with MVA-X produced durable protection that matched or exceeded that of a conventional two-dose MVA regimen against the prototypic orthopoxvirus vaccinia virus. Despite modest and contracting antibody titers, single-dose MVA-X vaccination conferred complete survival following both lethal and high-dose viral challenge at early (Day 55), intermediate (Day 90), and long-term (Day 150) time points. MVA-X also restricted viral replication at the primary site of infection, reduced systemic dissemination, and preserved lung architecture during peak disease. Importantly, MVA-X maintained efficacy in the highly susceptible CAST/EiJ mouse model following challenge with highly pathogenic Clade I monkeypox virus (MPXV). Together, these findings demonstrate that vaccine-intrinsic checkpoint modulation provides a modular strategy for enhancing the potency and durability of attenuated viral vectors while preserving their favorable safety profile, supporting broader application to emerging infectious diseases beyond Mpox.