Cholera is a severe dehydrating disease caused by Vibrio cholerae. Protection against cholera is serogroup specific, and serogroup specificity is defined by the O-specific polysaccharide (OSP) component of V. cholerae lipopolysaccharide (LPS). We have recently shown that memory B cell responses that target V. cholerae LPS are associated with protection from cholera among household contacts of cholera index patients in Bangladesh, and have previously correlated protection from cholera in household contacts of cholera patients with baseline plasma and stool anti-LPS IgA responses, as well as vibriocidal responses (the latter largely being comprised of anti-LPS IgM responses). We have also recently shown that patients with wild type cholera develop robust memory B cell responses targeting V. cholerae LPS, but that recipients of currently available oral killed cholera vaccines do not. The latter observation may in large measure explain why currently available cholera vaccines do not induce the high-level and long-term protection seen in patients who survive cholera. Despite these observations, the anti-OSP immune responses following cholera and cholera vaccination have never been characterized. In this program, we therefore propose to take advantage of our recently acquired ability to purify V. cholerae OSP, both as an independent antigen as well as in conjugate form, continuing an established collaboration with Paul Kovac, Chief-Carbohydrate Section, NIDDK, and to synergize with an ongoing NIAID-sponsored cholera immune study in Dhaka, Bangladesh that involves researchers at the International Centre for Diarrhoeal Disease Research in Dhaka (ICDDR,B) and the Massachusetts General Hospital-Harvard University in Boston. In this application, we propose to characterize OSP- responses in child and adult cholera patients in Bangladesh, as well as in recipients of oral killed cholera vaccines, including assessing memory and mucosal immune responses (in duodenal biopsy specimens of cholera patients). We also propose to assess the association of anti-OSP immunity with protection from cholera among household contacts of cholera index patients in Dhaka, as well as to assess the ability of anti-OSP responses to confer protection against V. cholerae in mice and rabbits. The knowledge gained through this program would significantly enhance our knowledge of the immune response that is the most likely determinant of protection against cholera, the anti-OSP response, and would critically inform efforts to develop an improved cholera vaccine or immunization strategy.

Public Health Relevance

to public health: Despite the fact that protective immunity against cholera is serogroup specific, and that serogroup specificity is defined by the O-specific polysaccharide (OSP) of Vibrio cholerae, OSP immune responses associated with cholera and cholera vaccination have never been studied. In this project, we propose to take advantage of our recently acquired ability to purify V. cholerae OSP, as well as our ongoing field studies in Bangladesh, to characterize anti-OSP responses in adult and child cholera patients and vaccinees in Dhaka, including assessing memory and mucosal immune responses, and evaluating whether anti-OSP responses are associated with protection against cholera among household contacts of cholera index patients;we also propose to complement these studies with supporting assessment of the ability of OSP responses to protect against cholera in established animal models. The information gained from this study could contribute significantly to the development of an improved cholera vaccine or immunization strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI106878-01A1
Application #
8689224
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Hall, Robert H
Project Start
2014-04-10
Project End
2019-03-31
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$552,123
Indirect Cost
$195,726
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Alam, Mohammad Murshid; Aktar, Amena; Afrin, Sadia et al. (2014) Antigen-specific memory B-cell responses to enterotoxigenic Escherichia coli infection in Bangladeshi adults. PLoS Negl Trop Dis 8:e2822
Sugimoto, Jonathan D; Koepke, Amanda A; Kenah, Eben E et al. (2014) Household Transmission of Vibrio cholerae in Bangladesh. PLoS Negl Trop Dis 8:e3314
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