Unraveling the Transmission Dynamics and Evolutionary Trajectory of Mpox in South Korea: 2022–2025 Outbreak

The 2022 monkeypox (mpox) outbreak, driven by clade IIb monkeypox virus (MPXV), was facilitated by human-to-human transmission, particularly within heavy-tailed sexual networks. APOBEC3-associated mutations have been a prominent feature of MPXV genomic evolution during the global outbreak. National genomic data were collected from clinical samples by the Korea Disease Control and Prevention Agency to examine the transmission dynamics and molecular evolution of MPXV. Target enrichment-based next-generation sequencing was used to generate high-quality genomes. Mutation profiling was used to identify key genetic changes; clustering based on common variants provided insights into national transmission dynamics and molecular evolution. Analysis of mpox-positive samples revealed the linkage of most cases to sub-lineage C.1 and a few cases to C.1.1. Genomic clustering revealed an uneven distribution of cases, with a dominant cluster accounting for a substantial proportion of domestic transmission while most other cluster remained relatively limited in size, consistent with heterogeneous transmission patterns. APOBEC3-associated mutations progressively accumulated during the outbreak and were frequently observed in genomic regions associated with viral structural integrity and cell-to-cell transmission and host-modulation, indicating continued genomic diversification during human-to-human transmission. Together with the dominance of localized clusters, these findings suggest heterogeneous transmission patterns and the possible contribution of epidemiologically unrecognized transmission to the spread of MPXV in South Korea. These results underscore value of integrating genomic surveillance and targeted interventions to characterize transmission patterns and monitor viral genomic changes of potential biological or public health relevance.