Monkeypox, an emerging Orthopoxvirus with a similar disease presentation to smallpox, is a zoonotic virus which can spread from person to person. Although to date, monkeypox events have erupted in West and Central African rainforests, their frequency, size, and geographic scope have expanded substantially in recent years. Imported cases have been detected in multiple locations, including Europe. Yet many aspects of this emerging infectious disease remain unclear, including its animal reservoir, its risk factors for zoonotic and interhuman transmission and ecological characteristics that may facilitate monkeypox emergence. As a result, the 2018 WHO Research & Development Blueprint designated monkeypox as an emerging disease requiring “accelerated research & development and public health action”. The AFRIPOX collaboration will mobilize an international, multidisciplinary One Health partnership spanning epidemiology, anthropology, zoology, environmental ecology, virology and mathematical modelling to tackle four research objectives investigating monkeypox at the human-animal-ecosystem interface: - Identify the animal reservoir and secondary hosts of monkeypox in areas of Central Africa where monkeypox is known to circulate - Identify risk factors for zoonotic and human-to-human monkeypox transmission during outbreaks using quantitative and qualitative methods; determine interhuman transmissibility of monkeypox and its epidemic potential - Understand differences in viral strains circulating in animals and human populations; strengthen diagnostic and response capacities, develop field diagnostic and next generation sequencing capacities for monkeypox in areas of Central Africa where the virus is known to circulate - Determine ecological factors associated with monkeypox emergence in Central Africa and its potential geographic scope in this region The partners’ extensive field experience and knowledge, their internationally recognised expertise, and their existing collaborations will ensure achievement of these objectives. Systematic outbreak investigation and response will improve outbreak control and identify risk factors for spillover and for human-to-human transmission. Studies of past and on-going outbreaks will yield deeper understanding of recent trends in the epidemic potential of the disease and strengthen infection prevention and control measures. An ethno-historical approach will excavate local knowledge about monkeypox and about the ecological and animal behavioural changes that precede or accompany outbreaks; such insights can point to new, unexplored investigations of ecological/zoological dynamics of monkeypox emergence. Investigation of local understandings of human transmission will permit the development of locally acceptable risk communications and prevention measures. The virology work package will conduct phylogenetic analysis to compare human and animal viral strains; it will also improve diagnostic capacities by developing a specific serological assay and field diagnostic test. With strengthened surveillance and field-adapted methods, our study will reduce the time to response, critical for controlling monkeypox and reducing the importation risk, as well as for containing other viral emergence. Understanding the animal species and environmental characteristics which contribute to the emergence of monkeypox will help to pinpoint zones at risk of zoonotic spillover and enhance outbreak preparedness activities there. Through its investigation of monkeypox, AFRIPOX will set the critical foundations for understanding and controlling a global infectious threat. Our multi-disciplinary collaboration will address research about monkeypox and preparedness to outbreaks: it will develop crucial scientific knowledge, identify appropriate response, and strengthen Central African Republic capacity to manage this and other emerging zoonotic diseases, beyond the duration of the project.