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

## TL;DR

Older people who were vaccinated against smallpox as children still have immune protection against Monkeypox virus decades later.

## Contribution

Demonstrates that childhood smallpox vaccination induces durable immunity against Monkeypox virus lasting over 70 years.

## Key findings

- All historically vaccinated participants had MPXV-reactive IgG and neutralizing antibodies comparable to recently vaccinated individuals.
- T-cell responses were detectable in all vaccinated individuals, primarily against the A10L core protein.
- Unvaccinated individuals showed no MPXV-specific immune responses.

## Abstract

Vaccination against smallpox provides protection from Monkeypox virus, which has recently shown an increase in cases. We assessed adults aged 79–94 years who were vaccinated against smallpox as children and showed both antibody and T-cell memory responses against Monkeypox virus. No such responses were found in unvaccinated individuals. This suggests that receiving the smallpox vaccination as a child can provide long-lasting protection against Monkeypox, decades later.

Monkeypox virus (MPXV) is a zoonotic Orthopoxvirus 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.