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. 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.

Public Health Relevance

/ 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.

National Institute of Health (NIH)
Clinical Investigator Award (CIA) (K08)
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Microbiology and Infectious Diseases Research Committee (MID)
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Hall, Robert H
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University of Utah
Salt Lake City
United States
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Uddin, Taher; Aktar, Amena; Xu, Peng et al. (2014) Immune responses to O-specific polysaccharide and lipopolysaccharide of Vibrio cholerae O1 Ogawa in adult Bangladeshi recipients of an oral killed cholera vaccine and comparison to responses in patients with cholera. Am J Trop Med Hyg 90:873-81
Weil, Ana A; Begum, Yasmin; Chowdhury, Fahima et al. (2014) Bacterial shedding in household contacts of cholera patients in Dhaka, Bangladesh. Am J Trop Med Hyg 91:738-42
Leung, Daniel T; Bhuiyan, Taufiqur R; Nishat, Naoshin S et al. (2014) Circulating mucosal associated invariant T cells are activated in Vibrio cholerae O1 infection and associated with lipopolysaccharide antibody responses. PLoS Negl Trop Dis 8:e3076
Alam, Mohammad Murshid; Bufano, Megan Kelly; Xu, Peng et al. (2014) Evaluation in mice of a conjugate vaccine for cholera made from Vibrio cholerae O1 (Ogawa) O-specific polysaccharide. PLoS Negl Trop Dis 8:e2683
Leung, Daniel T; Das, Sumon K; Malek, M A et al. (2014) Impact of Ramadan on clinical and microbiologic parameters of patients seen at a diarrheal hospital in urban Dhaka, Bangladesh, 1996-2012. Am J Trop Med Hyg 90:294-8
Bhuiyan, Saruar; Sayeed, Abu; Khanam, Farhana et al. (2014) Cellular and cytokine responses to Salmonella enterica serotype Typhi proteins in patients with typhoid fever in Bangladesh. Am J Trop Med Hyg 90:1024-30
Charles, Richelle C; Liang, Li; Khanam, Farhana et al. (2014) Immunoproteomic analysis of antibody in lymphocyte supernatant in patients with typhoid fever in Bangladesh. Clin Vaccine Immunol 21:280-5
Charles, Richelle C; Sultana, Tania; Alam, Mohammad Murshid et al. (2013) Identification of immunogenic Salmonella enterica serotype Typhi antigens expressed in chronic biliary carriers of S. Typhi in Kathmandu, Nepal. PLoS Negl Trop Dis 7:e2335
Alam, Mohammad Murshid; Tsai, Lillian L; Rollins, Sean M et al. (2013) Identification of in vivo-induced bacterial proteins during human infection with Salmonella enterica serotype Paratyphi A. Clin Vaccine Immunol 20:712-9
Das, Sumon Kumar; Ahmed, Shahnawaz; Ferdous, Farzana et al. (2013) Changing emergence of Shigella sero-groups in Bangladesh: observation from four different diarrheal disease hospitals. PLoS One 8:e62029

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