Epidemiology and Genetic Characterization of Distinct Ebola Sudan Outbreaks in Uganda

<b>Background</b>. Sudan virus (SUDV) has caused multiple outbreaks in Uganda over the past two decades, leading to significant morbidity and mortality. The recent outbreaks in 2022 and 2025 highlight the ongoing threat posed by SUDV and the challenges in its containment. This study aims to characterize the epidemiological patterns and phylogenomic evolution of SUDV outbreaks in Uganda, identifying key factors influencing transmission and disease severity. <b>Methods</b>. We conducted a retrospective observational study analyzing epidemiological and genomic data from SUDV outbreaks in Uganda between 2000 and 2025. Epidemiological data were collected from official sources, including the Ugandan Ministry of Health and the World Health Organization, supplemented with reports from public health organizations. Genomic sequences of SUDV were analyzed to investigate viral evolution and identify genetic variations associated with pathogenicity and transmissibility. <b>Results</b>. The 2022 outbreak involved 164 confirmed cases and a case fatality rate (CFR) of 33.5%, with significant geographic variation in case distribution. The 2025 outbreak, still ongoing, was first detected in Kampala, with evidence of both nosocomial and community transmission. Phylogenomic analysis revealed the presence of two main genetic groups, representing Sudan and Uganda, respectively. The genetic variability of the Ugandan cluster is higher than that observed in Sudan, suggesting a greater expansion potential, which aligns with the current outbreak. Epidemiological findings indicate that human mobility, weaknesses in the health system, and delays in detection contribute to the amplification of the outbreak. <b>Conclusions</b>. Our findings underscore the importance of integrated genomic and epidemiological surveillance in understanding SUDV transmission dynamics. The recurrent emergence of SUDV highlights the need for improved outbreak preparedness, rapid response mechanisms, and international collaboration. Strengthening real-time surveillance and enhancing healthcare system resilience are critical to mitigating the impact of future outbreaks.