PROJECT SUMMARY Enteric fever, an invasive bacterial infection caused by Salmonella enterica serotypes Typhi and Paratyphi A, B, and C, remains a major cause of illness and death globally. Timely diagnosis and treatment are critical to reducing morbidity and risk of serious complications from enteric fever. However, there are currently no diagnostics with sufficient accuracy and speed for guiding treatment decisions. Rapid serologic diagnostics have low predictive value, particularly in typhoid-endemic settings. Blood culture has high specificity, but sensitivity is estimated at 60%, and results take 2-4 days to become available. Through high-throughput immunoscreens, we found that IgA antibodies to hemolysin E (HlyE) and S. Typhi lipopolysaccharide (LPS) are robust markers of acute enteric fever, reliably distinguishing patients with enteric fever from those with other acute infections in Nepal and Bangladesh (AUC 0.95). We have further developed a point-of-care immunochromatographic assay, using Chembio's dual path platform (DPP®) technology, to quantify anti-HlyE and anti-LPS IgA responses. Our preliminary data demonstrated excellent concordance with ELISA and high accuracy in distinguishing enteric fever cases from controls. We now propose to: 1) evaluate the accuracy of the DPP Typhoid assay using biobanked plasma from patients with enteric fever and a diverse array of other febrile illnesses collected from multi-country surveillance studies in South Asia and sub-Saharan Africa; and 2) prospectively evaluate the DPP Typhoid assay with fingerstick capillary blood among individuals with acute febrile illness in a typhoid-endemic setting. These studies will leverage diverse, globally representative enteric fever surveillance platforms, investigate alternative etiologies of febrile illness, and rigorously test the novel assay performance in direct comparison with existing enteric fever diagnostics. Successful completion of this project would fill a major gap in diagnostics for enteric fever which could improve clinical management, reduce overdiagnosis and unnecessary antibiotic use, and facilitate enteric fever control initiatives.