O-Specific Polysaccharide Responses and Cholera

O 特异性多糖反应和霍乱

• 批准号: 8836484
• 负责人: Edward T. Ryan
• 金额: $ 77.94万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8836484
• 关键词: 5 year old; Acute; Adult; Affect; Animal Model; Antigens; Area; Bangladesh; Biopsy Specimen; Boston; Carbohydrates; Case Fatality Rates; Cells; Child; Cholera; Cholera Toxin; Cholera Toxin Protomer B; Cholera Vaccine; Collaborations; Complement; Conjugate Vaccines; Country; Development; Disease; Disease Outbreaks; Dose; Epidemic; Feces; Frequencies; General Hospitals; Genes; Health; Household; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin M; India; Infection; Knowledge; Lipids; Lipopolysaccharides; Massachusetts; Measures; Memory; Memory B-Lymphocyte; Modeling; Mono-S; Mucosal Immune Responses; Mus; National Institute of Allergy and Infectious Disease; National Institute of Diabetes and Digestive and Kidney Diseases; O Antigens; Oral; Organism; Oryctolagus cuniculus; Patients; Phase; Plasma; Proteins; Public Health; Recombinants; Research; Research Personnel; Specificity; Sweden; Testing; Universities; Ursidae Family; Vaccination; Vaccines; Vibrio cholerae; Vibrio cholerae O1; Vibrio cholerae O139; capsule; field study; improved; indexing; international center; killings; long term memory; pathogen; programs; protective efficacy; response; sugar; vaccine development

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 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.

描述（由申请人提供）：霍乱是由霍乱弧菌引起的严重脱水性疾病。预防霍乱具有血清群特异性，血清群特异性由霍乱弧菌脂多糖 (LPS) 的 O 特异性多糖 (OSP) 成分定义。我们最近发现，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的家庭接触者免受霍乱的保护有关，并且之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体相关联。 -LPS IgA 反应，以及杀弧菌反应（后者主要由抗 LPS IgM 反应组成）。我们最近还发现，野生型霍乱患者会针对霍乱弧菌 LPS 产生强大的记忆 B 细胞反应，但目前口服灭活霍乱疫苗的接种者却不会。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对霍乱幸存者产生高水平和长期的保护。尽管有这些观察结果，但霍乱和霍乱疫苗接种后的抗 OSP 免疫反应从未得到表征。因此，在该计划中，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 碳水化合物科主任 Paul Kovac 和与 NIAID 资助的、孟加拉国达卡正在进行的霍乱免疫研究相协同，该研究涉及达卡国际腹泻病研究中心 (ICDDR,B) 和马萨诸塞州总医院的研究人员波士顿哈佛大学医院。在此应用中，我们建议描述孟加拉国儿童和成人霍乱患者以及口服灭活霍乱疫苗接种者的 OSP 反应特征，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）。我们还建议评估达卡霍乱指数患者家庭接触者中抗 OSP 免疫力与预防霍乱的关系，以及评估抗 OSP 反应对小鼠和兔子提供针对霍乱弧菌的保护的能力。通过该计划获得的知识将显着增强我们对免疫反应的了解，免疫反应是预防霍乱的最有可能的决定因素，即抗 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。