In August 2024, the Africa CDC and WHO declared Mpox a Public Health Emergency of Continental Security and a Public Health Emergency of International Concern, respectively, following a devastating global outbreak driven by newly emerged virulent clades I (Ia, IIb) and II (IIa, IIb) of the Mpox virus. These new clades are genetically and phylogenetically distinct from previously known strains, with the re-emerging variants originating from the Democratic Republic of the Congo (DRC) and rapidly spreading to neighbouring regions and across the globe. The ongoing epidemic is characterized by alarming morbidity and mortality, and the newly identified clades are linked to significant changes in the epidemiology of the disease, resulting in worse clinical outcomes. Sexual transmission has emerged as a key factor in sustaining the spread of the virus, particularly among sexually active young adults, facilitating the virus's spread beyond Africa. To combat the growing threat, there is an urgent need for the development of a polyvalent vaccine that incorporates the diverse circulating clades as part of other mitigation measures.. Widespread vaccination with such a vaccine could help achieve herd immunity and complement other infection prevention and control strategies to effectively mitigate the impact of this global health crisis.