Acute infectious diarrhea remains the world's second leading cause of death in children under 5 years old, and in Africa is responsible for one quarter of all deaths in this age group. The introduction of rotavirus vaccination represents an important step in reducing diarrhea mortality in developing countries; however estimates of vaccine performance are significantly lower than from developed countries. Accurate estimation of pathogen-specific disease burdens as well assessment of pathogen-specific interventions requires uniformly sensitive detection methods for a wide range of pathogens. However, traditional diagnostics, including culture, microscopy, and antigen-based testing, suffer from heterogeneity in test performance. In this K23 Mentored Career Development Award application, Dr. James Platts-Mills, a fellow in Infectious Diseases at the University of Virginia, proposes to 1) use next-generation quantitative molecular diagnostics to improve estimates of the pathogen-specific etiology and burden of diarrhea in children in developing countries, 2) develop speciation and typing assays for epidemiologically important pathogens that can be performed directly on stool and can be used to prioritize pathogen-specific interventions, and 3) apply these tools to understand the impact of infections with non-rotavirus enteropathogens on rotavirus vaccine performance. This work will be carried out in the context of 1) an ongoing multisite birth cohort study of enteropathogen infection, diarrhea, and childhood development in the developing world (MAL-ED); 2) an ongoing clinical trial on the impact of enteropathogen infections and tropical enteropathy on rotavirus vaccine immunogenicity and efficacy in children in Bangladesh (PROVIDE); and 3) a new case-control study of rotavirus vaccine effectiveness in rural Tanzania. Dr. Platts-Mills proposes a career development plan which includes mentorship, fieldwork, coursework, publications, and clinical time that will situate him as an independent investigator with expertise in the application of next-generation molecular diagnostic tools to field studies of enteric infections in children in developing countries.
This work will help a) establish priorities for subsequent pathogen-specific interventions, in particular by providing revised estimates of pathogen-specific burdens of disease in diverse settings both before and after introduction of the rotavirus vaccine, b) validate diagnostics for epidemiologically important pathogens that can be employed in subsequent studies including clinical trials of pathogen-specific interventions, and c) identify strategies for improving rotavirus vaccine performance in developing countries. Successful completion of this work will facilitate a wide range of additional studies in the epidemiology of enteric infections, vaccine development, and therapeutics.
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