O-Specific Polysaccharide Responses and Cholera

描述（申请人提供）：霍乱是由霍乱弧菌引起的严重脱水性疾病。针对霍乱的保护是血清群特异性的，并且血清群特异性由霍乱弧菌脂多糖（LPS）的O-特异性多糖（OSP）组分定义。我们最近表明，记忆B细胞的反应，目标霍乱弧菌LPS与保护霍乱家庭接触的霍乱指数患者在孟加拉国，和以前相关的保护霍乱家庭接触的霍乱患者基线血浆和粪便抗LPS伊加反应，以及杀弧菌反应（后者主要是由抗LPS IgM反应）。我们最近还表明，野生型霍乱患者产生了针对霍乱弧菌LPS的强大记忆B细胞应答，但目前可用的口服灭活霍乱疫苗的接受者没有。后一种观察结果可能在很大程度上解释了为什么目前可用的霍乱疫苗不能诱导霍乱幸存者的高水平和长期保护。尽管有这些观察结果，但霍乱和霍乱疫苗接种后的抗OSP免疫应答从未被表征。因此，在该项目中，我们建议利用我们最近获得的纯化霍乱弧菌OSP的能力，无论是作为独立抗原还是以缀合物形式，继续与NIDDK碳水化合物部门负责人Paul Kovac建立合作，并与正在进行的NIAID赞助的达卡霍乱免疫研究协同作用，孟加拉国，涉及达卡国际腹泻病研究中心（ICDDR，B）和波士顿马萨诸塞州哈佛大学总医院的研究人员。在这个应用程序中，我们建议在孟加拉国的儿童和成人霍乱患者，以及在口服灭活霍乱疫苗的接受者，包括评估记忆和粘膜免疫反应（在霍乱患者的十二指肠活检标本）的特征OSP反应。我们还建议评估抗OSP免疫与达卡霍乱指数患者的家庭接触者中的霍乱保护之间的关联，以及评估OSP缀合物诱导小鼠抗OSP应答的能力，所述应答与保护人类免受霍乱相关。通过该计划获得的知识将大大提高我们对免疫反应的认识，这是预防霍乱的最可能决定因素，抗OSP反应，并将为开发改进的霍乱疫苗或免疫策略提供重要信息。

DESCRIPTION (provided by applicant): 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 an OSP-conjugate to induce in mice anti-OSP responses that correlate with protection from cholera in humans. 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.