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

The 2022 monkeypox virus (MPXV) outbreak has 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 vaccine (MVA)-BN or an experimental MVA-HIVB vaccine. The frequency of neutralizing antibody (NAb) 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 five 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by INSERM and the Investissements d Avenir program Vaccine Research Institute (VRI) managed by the ANR under reference ANR-10-LABX-77-01 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the appropriate ethics committee (CPP Ile de France VII and IX), with approval reference 10 023 (infected patients) and ID RCB 2018 A01610-55 CPP:18.09.09 (vaccinated patients) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes