Characterization and comparison of immunity against MPXV for individuals infected with MPXV or vaccinated with modified vaccinia Ankara vaccines

The 2022 Mpox virus (MPXV) outbreak revitalized questions about immunity against MPXV and vaccinia-based vaccines (VAC-V), but studies are limited. We analyzed immunity against MPXV in individuals infected with MPXV or vaccinated with the licensed modified vaccinia Ankara (MVA) Bavarian Nordic or an experimental MVA-HIVB vaccine. The frequency of neutralizing antibody responders was higher among MPXV-infected individuals than MVA vaccinees. Both MVA vaccines induced similar and strong humoral responses. Similarly, we show a higher frequency and magnitude (5-fold) of T cell responses, mainly mediated by CD8+ T cells, against a peptide pool containing selected sequences from MPXV, variola, and VAC-V in MPXV-infected individuals than MVA vaccinees. We describe a hierarchy of cross-reactive T cell responses against 5 peptide pools that are highly homologous between VAC-V and MPXV 2022, with the highest frequency of responders against MVA-121L and MVA-018L proteins. Both vaccines stimulated a notable frequency of polyfunctional CD4+ and CD8+ T cell responses, with a subset of CD4+ T cells showing a mixed cytokine profile. Finally, we found that smallpox vaccination in childhood positively affected humoral but not T cell vaccine responses, whereas these responses were not affected in people living with HIV. These findings contribute to deciphering and monitoring the profile of immunity to MPXV and MVA. In the context of a potential threat of the reemergence of smallpox following bioterrorism, the diversification and availability of potent vaccines is crucial. The comparable immunogenicity of both MVA vaccines emphasizes the potential utility of MVA-HIVB as a valuable new tool for controlling MPXV outbreaks.