The Evolving Landscape of Monkeypox: From Endemic Pathogen to Global Threat

Monkeypox (mpox) is a reemerging viral zoonosis caused by the mpox virus (MPXV) that has significant global public health implications following the 2022 and 2024 outbreaks. This review examines the evolving landscape of MPXV, focusing on its genomic organization, epidemiological shifts, phylogenetic relationship with variola virus, zoonotic transmission cycles, and the critical interventions for therapeutic targets and vaccine development.

A comprehensive narrative review of literature from 2020 to 2026 was conducted. Key thematic insights were synthesized using Bibliometrix, Scopus Analytics, and VOSviewer to analyze global trends in transmission dynamics, clinical manifestations, and therapeutic interventions.

The review highlights the divergence of MPXV into Clades I and II, noting that while Clade IIb drove the 2022 global outbreak, the more virulent Clade Ib has dominated the 2024 reemergence. Zoonotic spillover remains a primary risk through contact with reservoirs such as rope squirrels and Gambian pouch rats, although human-to-human transmission has evolved to include rapid community spread among specific high-risk populations. Genomic analyses identify key mutations in proteins like H3L that facilitate host-specific adaptability and immune evasion. Current clinical management relies on supportive care, with targeted use of the JYNNEOS vaccine and antivirals like tecovirimat for severe cases.

The continued reemergence of mpox underscores the necessity for an integrated "One Health" approach to surveillance and pandemic preparedness. Future research must prioritize environmental wildlife monitoring, genomic surveillance of emerging clades, and the development of multi-epitope vaccines to effectively mitigate both zoonotic spillover and human transmission.