Highlights • Mpox infection by three routes induces robust natural immunity • Natural immunity protects against mpox re-challenge • Adaptive immune responses appear critical for protection Summary The mpox outbreak of 2022–2023 involved rapid global spread in men who have sex with men. We infected 18 rhesus macaques with mpox by the intravenous, intradermal, and intrarectal routes and observed robust antibody and T cell responses following all three routes of infection.
