Abstract
The declaration of a second Public Health Emergency of International Concern (PHEIC) for mpox in August 2024 underscores the urgent need for a comprehensive understanding of the evolving epidemiology [1] clinical manifestations, and zoonotic potential of this emerging threat [2]. This work delves into the intricate interplay between human and animal mpox infections, with a specific focus on the unique characteristics of various viral clades and their implications for individual and public health. There is a critical need to elucidate the factors driving multiple spillover events and the subsequent emergence of new clades better adapted to human-to-human transmission. We hypothesize that anthropogenic changes, including deforestation, urbanization, and climate change are facilitating increased human-to-animal contact, leading to more frequent zoonotic transmissions and viral adaptations. Our conceptual framework integrates One Health principles, evolutionary virology, and epidemiological modeling to investigate the demographic, clinical, and treatment differences among mpox clades in both humans and animals. We employ a mixed-methods approach, combining genomic analysis, clinical data review, and ecological surveys to construct a comprehensive picture of mpox's changing dynamics. The research questions explore the differences in epidemiological and clinical profiles among mpox clades and the factors that likely contribute to successful cross-species transmission and human adaptation. This manuscript introduces an updated Identify, Isolate, Inform (3I) Tool meticulously redesigned to significantly improve the early detection, containment, and reporting of mpox cases across diverse settings. By integrating clinical, virological, and ecological data, this work aims to lay the groundwork for enhanced risk assessment, targeted interventions, and global preparedness strategies in the face of this evolving zoonotic threat.