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Interpretation: Our data showed the immunological signature of monkeypox virus infection, characterised by an early expansion of activated effector CD4 and CD8 T cells that persisted over time. Almost all patients, even regardless of HIV infection, developed a poxvirus-specific Th1 cell response. These results might have implications on the expected immunogenicity of monkeypox vaccination, suggesting that it might not be necessary to vaccinate people who have already been infected.