Sero-genomic evidence for occult mpox exposure in healthy Nigerian adults.

The 2022 multi-country mpox (formerly monkeypox) outbreak, driven by mpox virus (MPXV) Clade IIb poses renewed threat to global public health. The cessation of smallpox vaccination has created large immunologically naïve cohorts, with uncertain implications for contemporary MPXV susceptibility. To assess whether residual vaccination-derived immunity influences exposure risk, we combine serological and phylodynamic analyses. Using a six-plex Luminex assay, we measure immunoglobulin G (IgG) binding to six MPXV antigens in 176 Nigerian adults comprising of 75 healthcare workers sampled in 2021 and 101 community volunteers sampled in 2023. At baseline, 24/176 (13.6%) were MPXV seropositive, predominantly born before 1980. Magnitude-breadth analysis scores were two-fold higher in pre-1980 cohort relative to post-1980 cohort. In 153 participants with follow-up samples (median 9 months), 5/153 (3%) showed evidence of exposure, with ≥2-fold increases in magnitude-breadth scores and antigen-specific responses against ≥4/6 antigens without reported clinical illness. Antigen-specific responses were strongest to B6R (11-fold), followed by M1R and A35R, with marked individual-level heterogeneity. Complementary phylodynamic reconstruction of 105 Nigerian MPXV genomes identified sporadic transmission against frequent dead-end infections. Together, these data show that residual smallpox immunity continues to shape mpox transmission and asymptomatic exposure contributes to under-detected spread, informing surveillance and targeted vaccination strategies.