ABSTRACT:
Monkeypox virus (MPXV), a zoonotic Orthopoxvirus endemic to West and Central Africa, poses an emerging global health threat with clear implications for pandemic preparedness. Although Ghana reported no confirmed human mpox cases prior to 2022, the 2003 mpox outbreak in the United States was linked to rodents exported from Ghana, suggesting the possibility of undetected exposure and silent transmission. To generate preparedness-relevant evidence, this study assessed population-level MPXV exposure in Ghana prior to the emergence of human Clade IIb infections. We tested 457 serum samples collected across 14 regions using a commercial anti-MPXV IgG ELISA, including 365 archived sera from 2021 SARS-CoV-2 surveillance and 92 sera from suspected mpox cases during the 2022 outbreak. Multivariable logistic regression was used to evaluate associations between MPXV seropositivity and demographic factors, including age, sex, region, urban–rural status, and inferred smallpox vaccination status. Overall MPXV seroprevalence was 6.6%, indicating prior exposure in the population. Significantly higher odds of seropositivity were observed in the Western Region (aOR = 6.70, 95% CI: 1.75–25.62, p = 0.005), while lower odds were identified in Greater Accra (aOR = 0.28, 95% CI: 0.09–0.90, p = 0.033). These findings provide evidence of localized MPXV circulation or repeated zoonotic spillover events preceding recognized outbreaks, highlighting critical surveillance gaps. The study underscores the importance of integrating sero-epidemiology into routine surveillance systems to support early detection, risk assessment, and pandemic preparedness for emerging zoonotic pathogens in Ghana and similar settings.