O-Specific Polysaccharide Responses and Cholera

描述（申请人提供）：霍乱是一种由霍乱弧菌引起的严重脱水疾病。对霍乱的保护是血清群特异性的，血清群特异性是由霍乱弧菌脂多糖（LPS）的o特异性多糖（OSP）成分定义的。我们最近表明，针对霍乱弧菌LPS的记忆B细胞反应与孟加拉国霍乱指数患者家庭接触者的霍乱保护有关，并且先前已将霍乱患者家庭接触者的霍乱保护与基线血浆和粪便抗LPS IgA反应以及杀弧菌反应（后者主要由抗LPS IgM反应组成）相关。我们最近还表明，野生型霍乱患者产生针对霍乱弧菌LPS的强大记忆B细胞反应，但目前可用的口服灭活霍乱疫苗的接受者却没有。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在霍乱幸存者身上产生高水平和长期的保护作用。尽管有这些观察结果，霍乱和霍乱疫苗接种后的抗osp免疫反应从未被描述过。因此，在这个项目中，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结合形式，继续与NIDDK首席碳水化合物部门的Paul Kovac建立合作关系，并与正在进行的niaid资助的霍乱免疫研究协同在达卡进行。孟加拉国的研究人员参与了达卡国际腹泻病研究中心（ICDDR，B）和波士顿麻省总医院-哈佛大学的研究。在这项应用中，我们建议表征孟加拉国儿童和成人霍乱患者以及口服灭活霍乱疫苗接受者的ops反应，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中）。我们还建议评估抗osp免疫与达卡霍乱指数患者家庭接触者预防霍乱的关系，以及评估osp偶联物诱导小鼠抗osp反应的能力，这种反应与人类预防霍乱的能力相关。通过该项目获得的知识将大大提高我们对免疫反应的认识，免疫反应最有可能是预防霍乱的决定因素，抗osp反应，并将为开发改进的霍乱疫苗或免疫策略的努力提供重要信息。

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.