Clade I mpox virus genomic diversity in the Democratic Republic of the Congo, 2018–2024: Predominance of zoonotic transmission

Recent reports raise concerns on the changing epidemiology of mpox in the Democratic Republic of the Congo (DRC). High-quality genomes were generated for 337 patients from 14/26 provinces to document whether the increase in number of cases is due to zoonotic spillover events or viral evolution, with enrichment of APOBEC3 mutations linked to human adaptation. Our study highlights two patterns of transmission contributing to the source of human cases. All new sequences from the eastern South Kivu province (n = 17; 4.8%) corresponded to the recently described clade Ib, associated with sexual contact and sustained human-to-human transmission. By contrast, all other genomes are clade Ia, which exhibits high genetic diversity with low numbers of APOBEC3 mutations compared with clade Ib, suggesting multiple zoonotic introductions. The presence of multiple clade I variants in urban areas highlights the need for coordinated international response efforts and more studies on the transmission and the reservoir of mpox. [Display omitted] •Two patterns of transmission contribute to human mpox cases in DRC•Mpox in DRC is predominated by clade Ia, exhibiting high genetic diversity•Low numbers of APOBEC3 mutations in clade Ia suggest multiple zoonotic introductions•The limited genetic diversity in clade Ib illustrates recent emergence in humans Molecular characterization of MPXV highlights two patterns of transmission contributing to the source of mpox cases in DRC: the traditional paradigm of zoonotic spillover, with interspecies transmission events (clade Ia), and the more recently observed sustained human-to-human transmission, with an enrichment of APOBEC3-type mutations (clade Ib).