Pre-Clade IIb Mpox Virus Exposure in Ghana: A Retrospective Serological Analysis

<i>Monkeypox virus</i> (MPXV), a zoonotic Orthopox virus endemic to West and Central Africa, causes mpox disease. Although Ghana had no confirmed human cases before 2022, the 2003 U.S. mpox outbreak was traced to rodents exported from Ghana, suggesting potential undetected exposure in the local population. This study assessed mpox exposure prior to the emergence of Clade IIb in humans. We tested 457 serum samples collected across 14 regions of Ghana using a commercial anti-MPXV IgG ELISA. These samples comprised 365 archived sera from 2021 SARS-CoV-2 surveillance and 92 sera from suspected mpox cases during the 2022 outbreak. Multivariable logistic regression was performed to examine 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%. Participants from the Western Region had significantly increased odds of seropositivity (aOR = 6.70, 95% CI: 1.75-25.62, <i>p</i> = 0.005), whereas those from Greater Accra had decreased odds (aOR = 0.28, 95% CI: 0.09-0.90, <i>p</i> = 0.033). The findings suggest localized MPXV circulation or repeated zoonotic spillover may have occurred undetected, challenging the prevailing assumption that Ghana was unaffected by human mpox prior to 2022, underscoring the importance of strengthened surveillance and preparedness in Ghana.