The recent resurgence of Mpox in central Africa has been declared again a Public Health Emergency of International Concern (PHEIC) requiring coordinated international responses. Vaccination is a priority to expand protection and enhance control strategies, but the vaccine's need exceeds the currently available doses. Intradermal administration of one-fifth of the standard Modified-Vaccinia-Ankara (MVA-BN) dose was temporarily authorized during the 2022 PHEIC. Studies conducted before 2022 provided evidence about the humoral response against the Vaccinia virus (VACV) after vaccination but not against the Mpox virus (MPXV). Moreover, no data are available on the T-cell response elicited by MVA-BN administered subcutaneously or intradermally. Here, we compare the two vaccine administration routes according to reactogenicity and immunogenicity based on data from 943 vaccine recipients during the 2022 vaccination campaign in Rome, Italy. We found that the intradermal route elicited slightly higher titers of MPXV-specific IgG and nAbs than the subcutaneous one. At the same time, no differences in cellular response were detected. MVA-BN was globally well tolerated despite higher reactogenicity for the intradermal than the subcutaneous route, especially for the reactions at the local injection site. The intradermal dose-sparing strategy was proven safe and immunogenic and would make vaccination available to more people.

AA received a grant from Bavarian Nordic for participation in conferences. The other authors declared no conflicts of interest.

The study was supported by the National Institute for Infectious Disease Lazzaro Spallanzani <IRCCS Advanced grant 5x1000, 2021> and by the Italian Ministry of Health <Ricerca Corrente Linea 2> INMI Spallanzani IRCCS

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The INMI Lazzaro Spallanzani Ethical Committee gave ethical approval for this work.

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