Discovery of Yellow Fever Virus-Specific Epitopes for Development of an Accurate Serodiagnostic Assay Abstract Antibodies to many pathogenic viruses can be detected in blood, serum and/or saliva. Among these are many arboviruses, that share endemic regions in the western hemisphere and in other parts of the world. These include the related flaviviruses yellow fever virus (YFV), dengue virus (DENV), Zika virus (ZIKV) and West Nile virus (WNV) as well as the alphavirus chikungunya virus (CHIKV). Antibodies to these viruses are often cross-reactive, making diagnostics for a particular virus challenging. The current outbreak of yellow fever in Brazil and the high mortality associated with this disease as well as the recent history of outbreaks in South America and Africa create an urgent need for YFV-specific serodiagnostics, to aid control of the spread of yellow fever. Moreover, such diagnostics would facilitate clinical and public health efforts against these and other, related arboviruses. We propose a novel strategy to develop methods for specific and sensitive detection of antibodies against YFV that do not cross react with other arboviruses. We will employ an innovative, comprehensive proteomic approach with a unique serum sample collection that will allow discovery and validation of specific biomarkers capable of distinguishing YFV from other arboviruses. This will allow us to develop a specific and sensitive test for YFV infection in Phase II of this project. A practical, sensitive and specific test for YFV infection is a high priority goal due to the recent outbreak of yellow fever in Brazil, possible future outbreaks and the likely spread of yellow fever to southern US states bordering the Gulf of Mexico and Puerto Rico where Aedes spp. mosquitos might rapidly spread the infection.