Mpox as Two Global Health Emergencies: Altered Transmission, Genomics, Clinical Manifestation and Public Health Impact

Mpox virus (MPXV) is the only pathogen that triggered two Public Health Emergency of International Concern (PHEIC) declarations, first in July 2022 and then again in August 2024. The 2022 outbreak was attributed primarily to clade IIb MPXV, specifically lineage B.1. However, the 2024 global outbreak was largely due to the emergence of clade Ib MPXV, which was first identified in the Sud Kivu region of the Democratic Republic of the Congo in 2023. During this period, the transmission route of MPXV transitioned from primarily zoonotic spillovers to sustained human-to-human transmission, disproportionately affecting vulnerable groups such as men-who-have-sex-with-men, immunocompromised individuals and marginalized populations with limited access to healthcare. This shift has been driven by critical mutations in genes associated with viral fitness, immune evasion and transmission dynamics. Moreover, these changes correspond with atypical and often milder yet more transmissible clinical presentations, complicating the detection and management of cases. Despite these challenges, health system preparedness has remained uneven. High-income countries leverage existing infrastructure to facilitate rapid responses through proactive policies and financial commitments. However, many low- and middle-income countries struggle with delayed case detection, limited surge capacity, community unawareness and fragmented outbreak governance. Although diagnostics, vaccines and antivirals have advanced, issues such as accessibility, affordability and distribution have persisted, hindering global solidarity efforts. This narrative review integrates evidence on the evolution of MPXV clades, clinical heterogeneity, and public health responses. Furthermore, by learning from past outbreaks, this review proposes actionable, time-sensitive recommendations to strengthen surveillance, ensure equitable deployment of countermeasures, secure supply chains and embed One Health approaches for increased resilience.