O-Specific Polysaccharide Responses and Cholera

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.<p/>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.<p/> 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 an OSP-conjugate to induce in mice anti-OSP responses that correlate with protection from cholera in humans. <p/>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.