Mpox in the Post-2022 Era: A Comprehensive Review of Viral Evolution, Host Adaptation, and Clinical Management

The global 2022-2024 mpox outbreak is the largest notifiable case of human monkeypox ever reported and has altered our perception of this zoonotic orthopoxvirus forever: with far-reaching implications for the evolution, adaptation to host and emergence of pandemics. Here, this broad review combines data from 42 studies across 19 countries to investigate the evolutionary history of MPXV as it transformed from a geographically-localized pathogen to a global zoonotic threat. We find APOBEC3-mediated hypermutation to be a major evolutionary force, with Clade IIb displaying 6- to12-fold higher mutation rates relative to pre-2022 strains. The review describes the intricate immunopathogenesis of severe mpox, including NK cell malfunction, complement cascade blockage and cytokine-deregulation with a focus on immunosuppressed individuals. Clinical management has changed with 88% clinical improvement rates of tecovirimat and an 85% efficacy of the MVA-BN vaccine. Yet, there remain substantial inequities in allocation of resources, with high-income countries capturing 78% of the vaccines available while some African-endemic regions faced extreme shortages. This analysis frames mpox as a model system and the strategic priorities for global health security.