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This proposal is for a five year K08 Mentored Clinical Scientist Research Development Award for Daniel T. Leung, M.D., M.Sc. This candidate completed a clinical fellowship in Infectious Diseases at Beth Israel Deaconess Medical Center, and has entered post-doctoral research training in the laboratory of Dr. Edward T. Ryan in the Division of Infectious Diseases at Massachusetts General Hospital (MGH). The proposed training plan, with Dr. Ryan as primary mentor, will include both didactic and practical training focused on immune responses of Vibrio cholera infection in children. This research builds upon a longstanding collaboration between MGH and the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B). Dr. Firdausi Qadri, Director of Center for Vaccine Sciences at ICDDR,B, will provide co-mentorship to the applicant. Dr. Stephen B. Calderwood, Professor and Chief of ID at MGH will chair the Training Advisory Group. Cholera is an acute dehydrating diarrheal disease caused by Vibrio cholera, endemic in over 50 countries, and affecting 2 to 3 million people each year, causing more than 100,000 deaths. In endemic areas, children under 5 years of age have a high burden of disease. Despite this, currently available cholera vaccines achieve a lower efficacy and a shorter duration of protection in young children compared to that achieved in adults. Even in adults, immunity after vaccination is short-lived. In comparison, protective immunity after natural infection lasts for several years, and duration of protection in young children is thought to be comparable to that of adults. The mediators and mechanism of protective immune response to cholera in children remain poorly understood. The candidate has spent the last 24 months beginning to address this deficiency, has moved to Bangladesh, and has begun to characterize the acute and convalescent immune- responses to cholera infection and vaccination in children in Dhaka, Bangladesh. In this application, the applicant now proposes a K08 career development program that extends these studies, and builds upon ongoing and fully approved NIAID and SIDA/SAREC supported projects.<P> This career development program would assist the candidate in his development into an independent biomedical investigator, would improve our understanding of host- pathogen events during a human restricted infection of global significance, and could lead to a long acting and protective improved cholera vaccine for children, the population that bears the largest global burden of cholera.
Project Narrative / Public Health Relevance Cholera is a diarrheal disease affecting millions of people worldwide each year. Compared to natural infection, current oral cholera vaccines provide relatively short-term protection, especially in young children who bear the largest global burden of cholera. We propose a career development program that focuses on advancing our understanding of immune responses to cholera infection and vaccination in children in Bangladesh; such knowledge could lead to an improved cholera vaccine.