With the Mpox Biology, Outcome, Transmission, and Epidemiology in South Kivu (MBOTE-SK) project, we seek emergency funding to address one of the most alarming mpox outbreaks currently unfolding: the ongoing emergence of a new lineage of monkeypox virus (MPXV, clade Ib) in South Kivu, Democratic Republic of the Congo (DRC). This outbreak is particularly concerning due to its extensive human-to-human transmission through sexual contact in a densely populated region characterized by a large sex industry and significant cross-border movement. Without swift intervention, there is a high risk of the outbreak spreading internationally, penetrating sexual networks worldwide. In this project, we will leverage our extensive experience with mpox outbreaks in the DRC and our current presence in South Kivu to tackle this outbreak through a combined approach of research and response. To achieve this, we will build on local and national expertise and strengthen the DRC's research institutions, and align with the international response. This project has four foundational pillars, each designed to simultaneously strengthen the response and comprehensively describe clade Ib MPXV, including its clinical presentation, mode of transmission, at-risk populations, and virological evolution. Pillar 1 strengthens active case finding and epidemiological surveillance to map and monitor the spread of clade Ib MPXV. Pillar 2 supports real-time genomic surveillance to track the genetic evolution of the strain. Pillar 3 enhances clinical care through an in-depth clinical characterization study. Pillar 4 engages key populations (including sex workers) to study community spread, vaccine hesitancy and stigma. These four pillars eventually feed into Pillar 5, by informing on how to best target the Ministry of Healths planned vaccination campaign (with the Modified Vaccinia Ankara vaccine) and documenting its impact and real-world effectiveness (using the established platforms of Pillars 1-4).