PROJECT ABSTRACT Outbreaks of arthropod-borne viruses, such as dengue (DENV) and chikungunya (CHIKV) viruses, demonstrate the substantial cost and health burden of these emerging/re-emerging health threats to the developing and developed world. In sub-Saharan Africa, routine passive surveillance for these diseases detects only a fraction of their impact, given the high probability of misdiagnosis and unknown levels of transmission across different landscapes and within different susceptible populations. Known and unknown entomologic, environmental, and behavioral factors differentially drive transmission in different habitats. We hypothesize that a significant burden of human disease due to DENV and CHIKV is undetected in the clinical setting, leading to missed opportunities for prevention and heightened risk for large- scale outbreaks. Preliminary data demonstrate that Kenyan children and adults are frequently exposed to DENV and CHIKV, both between and during known outbreaks, although acute arboviral infections are rarely diagnosed in this setting. Our objectives are to assess the true burden of human disease related to DENV strains 1-4 and for CHIKV across Kenya, and then to determine the drivers of viral circulation, estimate the thresholds for outbreak initiation, and provide improved outbreak risk assessment. We will investigate transmission of CHIKV and DENV1-4 in two regions of Kenya that represent heterogeneous degrees of urbanization with varied landscape, climate, and populations. Using several novel approaches, we address the following aims: 1) Quantify the incidence of human infection and disease due to CHIKV and DENV1-4 and determine their relative contribution to acute febrile illness; 2) Measure the level of CHIKV and DENV1- 4 circulation in Aedes mosquito vectors and non-human primate reservoirs and estimate the amount of human-vector contact in Kenya; and 3) Detect and predict spatial and temporal patterns of CHIKV and DENV transmission in rural and urban settings by integrating data on circulation in humans (Aim 1) and vectors (Aim 2) with environmental and weather/climate data collected both in situ and using satellite imagery. This research involves cohorts in and near Msambweni (coastal) and Kisumu (western), Kenya, where there is year-round transmission of arboviruses, and is based on 10 years of collaborative longitudinal studies. Methodologies include analyses of the relationship between well-defined entomologic, clinical, epidemiologic, and climatologic findings and immune biomarkers of virus and mosquito exposure. These studies will fill knowledge gaps about the persistence of CHIKV and DENV in local habitats and the factors that contribute to persistence during inter-epidemic periods and to regional variation during epidemic periods. The data will also answer fundamental questions about arboviral etiologies in severe fever syndromes among at-risk populations while providing better estimates of related disease burden and long- term sequelae.