Global spread of the Clade Ib/sh2023 monkeypox virus: Investigating mechanisms of sustained human-to-human transmission

Mpox, formerly known as monkeypox, is a viral infectious disease caused by the monkeypox virus (MPXV), a member of the Orthopoxvirus genus of the Poxviridae family. Phylogenetically, MPXV is classified into two main clades: Clade I and Clade II, each with further subclades (Ia). Due to a surge in the confirmed mpox cases and multiple outbreaks of the novel Clade Ib/sh2023 in the Democratic Republic of Congo (DRC) and neighboring African countries, mpox has been declared as a Public Health Emergency of International Concern (PHEIC) between 14 August 2024 and 05 September 2025. However, the African continental alert remains, as active cases of the mpox are still circulating through community transmission in multiple African countries. The Clade Ib mpox virus (MPXV) was first reported in September 2023 in eastern Democratic Republic of Congo. Importantly, travel-associated cases of Clade Ib have been documented in other African countries, as well as in Europe, Asia, North America, South America, and Oceania, highlighting its global spread. In this study, we analyzed a total of 546 Clade Ib MPXV sequences reported from 17 countries as of 12 June 2025. Our analysis reveals three important genes of MPXV, including A24R (OPG150), B4R (OPG188), and E8L (OPG120), bearing emerging variants. A total of 119 OPG genes were found to have APOBEC3 (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3) mutations. Phylogenetic analysis demonstrated that most sequences from Uganda and Burundi formed two distinct clusters. Moreover, travel-associated cases showed grouping with multiple sub-lineages but had a close association with Uganda sequences when compared to others. Our study suggests that Clade Ib/sh2023 viruses are circulating globally in the environment from different locations.