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<div><p>Understanding the epidemiology and ecology of yellow fever in endemic regions is critical for preventing future outbreaks. Ghana is a high-risk country for yellow fever. In this study we estimate the disease burden, ecological cycles, and areas at risk for yellow fever in Ghana based on historical outbreaks. We identify 2387 cases and 888 deaths (case fatality rate 37.7%) from yellow fever reported in Ghana from 1910 to 2022. During the approximately 30-year periods before and after implementation of routine childhood vaccination in 1992, the reported mean annual number of cases decreased by 80%. The geographic distribution of yellow fever cases has also changed over the past century. While there have been multiple large historical outbreaks of yellow fever in regions throughout Ghana, recent outbreaks have originated in northern regions. Comparing the locations where yellow fever outbreaks have emerged, we find patterns with seasons and different ecological transmission cycles. Using an ecological niche modeling framework, we predict areas in Ghana that are similar to where prior yellow fever outbreaks have originated based on temperature, precipitation, vegetation, and human population density. We find that these predictions differ depending on the ecological cycles of outbreaks. Ultimately, these findings and methods could be used to inform further subnational risk assessments for yellow fever in Ghana and other high-risk countries.</p></div>