Induction of poxviral immunity by synthetic MVA-based dual-antigen COVID-19 vaccine COH04S1

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.

COVID-19 vaccination recruits and matures cross-reactive antibodies to conserved epitopes in endemic coronavirus Spike proteins

The COVID-19 pandemic has triggered the first widespread vaccination campaign against a coronavirus. Most vaccinated subjects are naive to SARS-CoV-2, however almost all have previously encountered other coronaviruses (CoVs) and the role of this immunity in shaping the vaccine response remains uncharacterized. Here we use longitudinal samples and highly-multiplexed serology to identify mRNA-1273 vaccine-induced antibody responses against a range of CoV Spike epitopes and in both phylogenetically conserved and non-conserved regions. Whereas reactivity to SARS-CoV-2 epitopes showed a delayed but progressive increase following vaccination, we observed distinct kinetics for the endemic CoV homologs at two conserved sites in Spike S2: these became detectable sooner, and decayed at later timepoints. Using homolog-specific depletion and alanine-substitution experiments, we show that these distinctly-evolving specificities result from cross-reactive antibodies as they mature against rare, polymorphic residues within these epitopes. Our results reveal mechanisms for the formation of antibodies with broad reactivity against CoVs.