Immune profiling of mpox survivors reveals divergent durability of antibody and T cell responses.

Despite the global spread of mpox virus (MPXV), the durability and breadth of infection-induced immunity remain incompletely defined. Here, we comprehensively characterize MPXV-specific antibody and T cell responses up to 18 months after natural infection in male individuals. Neutralizing antibodies exhibit typical acute viral kinetics, with titers peaking early and declining over time, from a mean of 328 at 12 months to 180 at 18 months post-infection. Neutralization analyses against MPXV clade Ib, clade IIb and VACV WR strains demonstrate pronounced cross-neutralization among orthopoxviruses, but with lineage-specific reductions in neutralization, indicating incomplete cross-reactivity across different lineages. In parallel, MPXV-specific CD4⁺ and Tfh cell responses remain robust and polyfunctional throughout follow-up, and CD8⁺ T cells maintain sustained responses characterized by cytokine production, together supporting durable cellular immunity. These findings offer critical insights into the durability and breadth of post-infection immunity, with implications for reinfection risk and orthopoxvirus vaccine strategies.