Robust Adaptive Immunity to MPXV in Older People Who Received Childhood Vaccinia Vaccination

Monkeypox virus (MPXV) is a zoonotic <i>Orthopoxvirus</i> responsible for Monkeypox (Mpox), historically associated with sporadic zoonotic transmission but increasingly characterised by sustained human-to-human spread. While vaccinia-based vaccination is known to confer cross-protection against MPXV, the durability of such immunity over a human lifetime remains incompletely characterised. Here, we assessed humoral and cellular immune responses to MPXV in octogenarians and nonagenarians vaccinated against smallpox during childhood. Twenty-three adults aged 79-94 years (median 83), who self-reported childhood vaccinia vaccination between 1925 and 1940, were recruited. MPXV-specific antibody responses were evaluated using ELISA, targeting homologous vaccinia and MPXV proteins, and live-virus neutralisation assays. Cellular immunity was assessed by IFN-γ ELISpot following stimulation with peptide pools derived from highly conserved vaccinia antigens. Responses were also obtained from younger, recently MVA-BN-vaccinated and unvaccinated control donors. All historically vaccinated participants exhibited MPXV-reactive IgG responses, with antibody binding and neutralisation levels comparable to recently vaccinated individuals. Functional neutralising activity against MPXV was detected in all donors, with ≥50% neutralisation observed in 78% of participants. Antibody concentrations correlated strongly with neutralisation capacity. T-cell responses were detectable in all historically vaccinated donors, most prominently against the major core protein A10L, although reduced magnitudes were observed in participants over 90 years of age. No MPXV-specific humoral or cellular responses were detected in unvaccinated controls. These findings demonstrate that childhood vaccinia vaccination induces durable humoral and cellular immunity against MPXV persisting for over seven decades. Historical smallpox vaccination status may therefore remain a relevant determinant of protection against Mpox.