ABSTRACT Recent pandemics of human pathogens have revealed the limitations of current surveillance systems. The sequential arboviral epidemics in the Americas showed how outbreak detection can be delayed and opportunities missed to collect well-characterized specimens and data for surveillance, basic science, clinical research, and development of vaccines and new diagnostics. In response, we have assembled a consortium of world-renowned investigators in arbovirology, epidemiology, immunology, viral diagnostics, phylogenetics, and clinical research, while leveraging research infrastructure and expertise in long-term cohort and hospital-based studies. This has resulted from 3 decades of collaborative international research, with over 200 joint publications, and extensive experience in preparing for and responding to outbreaks working closely with local and international health authorities and NIAID. With key sites in Asia and the Americas, we will use innovative molecular and serological methods to identify emerging pathogens and to address fundamental questions in dengue and other arboviral epidemiology and test viral, host and environmental determinants of differences between sites along a gradient of urbanicity. Our overarching goal is to develop an interconnected, harmonized network of clinical and laboratory sites to strengthen research programs, compare disease epidemiology and severity in different regions, develop and implement cutting-edge diagnostic methods, and respond efficiently and effectively to outbreaks. Standardized hospital studies and community-based cohorts in Ecuador, Nicaragua and Sri Lanka will characterize and compare human arboviral illnesses across urban, peri-urban and rural sites and develop sustainable infrastructure to rapidly respond to epidemics together with Ministries of Health, comple- mented by outbreak investigation, surveillance of non-human primates, and vector incrimination. We will imple- ment standardized plans for study administration, data and clinical management, and statistical analysis across sites, supported by an extensive on-site training program. Aim 1 will establish standard and novel multiplex assays at each site for surveillance, diagnosis and research of arboviruses and other pathogens. Aim 2 com- pares dengue/arbovirus epidemiology and transmission in cohort studies located in ecologically distinct regions over a continuum of urbanicity. In Aim 3, we will characterize complete viral genome sequences for comparative studies of arboviral phylogenetics, phylogeography and molecular epidemiology. Aim 4 consists of surveillance, identification, and characterization of novel and unrecognized human pathogens from severe hospitalized cases, unexpected outbreaks, vectors and non-human primates. Molecular and serological assays will be developed for newly identified pathogens and quickly implemented across study sites to characterize the epidemiology and clinical manifestations and will be made availab...