Synthetic modified vaccinia Ankara vaccines confer potent monkeypox immunity in non-human primates and healthy adults

Summary The recent outbreak of monkeypox (MPXV) outside its endemic boundaries has attracted global attention and prompted world leaders to reserve millions of doses of the only approved third-generation smallpox/MPXV vaccine, Jynneos, which is based on the highly attenuated modified vaccinia Ankara (MVA) vector. We previously developed COH04S1, a multiantigen SARS-CoV-2 vaccine built on a synthetic MVA (sMVA) platform. COH04S1 was extensively tested for efficacy and immunogenicity in animal models, including non-human primates (NHP), and was found to be safe and to induce SARS-CoV-2-specific immunity in a Phase 1 clinical trial in healthy adults. Here we demonstrate that one or two vaccinations of NHP with either COH04S1 or sMVA elicit robust othopoxvirus-specific binding and neutralizing antibody responses. Furthermore, healthy adults vaccinated with COH04S1 at different dose levels develop robust othopoxvirus-specific humoral and cellular immune responses that are durable for over six months post-vaccination. Importantly, both COH04S1 and sMVA vaccinations induce elevated and sustained antibody responses to MPXV-proteins that are major targets of protective neutralizing antibodies. These results demonstrate that COH04S1 and sMVA are valuable vaccine candidates to stimulate robust orthopox/MPXV-specific humoral and cellular immunity.