IMMUNE RESPONSES TO V. CHOLERAE INFECTION IN BANGLADESH

孟加拉国对霍乱感染的免疫反应

基本信息

批准号：
6526397
负责人：
STEPHEN B. CALDERWOOD
金额：
$ 38.23万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-05 至 2003-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6526397
关键词：
Bangladesh Vibrio cholerae antibody titering bactericidal immunity cholera cholera vaccine clinical research cooperative study epidemiology human subject mucosal immunity

项目摘要

DESCRIPTION (adapted from application abstract): Vibrio cholerae causes a severe, dehydrating, and occasionally fatal diarrhea in humans. There are an estimated 5-7 million cases worldwide of cholera, with more than 100,000 deaths. Much of the impact of cholera occurs in developing areas of the world, particularly in South and Southeast Asia such as Bangladesh and India. Infection with V. cholerae induces long-lasting protective immunity to subsequent cholera, although the immune responses mediating protection are not fully understood. Many of the previous field studies of immune responses to V. cholerae infection were done in the 1970s, prior to the advent of more modern techniques for measuring mucosal immune responses, such as the use of antibody-secreting cell assays. More recent studies of V. cholerae infection in normal volunteers, many done in the United States, have provided important information on immune responses to infection with this pathogen, but these responses may differ substantially than those in patients in endemic areas, particularly as relates to the influence of age, morbidity, malnutrition and prior exposure to related antigens. Much work has been done recently on development of effective live, oral, attenuated V. cholerae vaccines, both for prevention of clinical cholera and as vectors for expressing heterologous antigens to protect against other infections at mucosal surfaces. This proposal would establish a long-term collaboration between scientists in the US and at the International Centre for Diarrhoeal Disease Research in Bangladesh to elucidate immune responses and protection from cholera infection in an endemic population. The Long-Term Goals of this project are to better understand mucosal immune responses after V. cholerae infection and vaccination, and to assess the effect of patient and microbial factors on these responses that may explain differences observed between patients from endemic areas and normal human volunteers. The Specific Aims of the proposal are: 1) determine the full range of immune responses, particularly mucosal antibody responses, in patients with cholera in Bangladesh, comparing vibriocidal and mucosal antibody responses and stratifying these responses by patient and microbial characteristics. We will test the hypothesis that the serum vibriocidal response represents a surrogate marker for a mucosal response to a relevant antigen or antigens that is actually protective: 2) correlate mucosal anti-V cholerae antibody levels on exposure to the organism with protection from subsequent clinical cholera. We will examine the hypothesis that pre-existing secretory immunity to LPS. CtxB, MSHA and/or TcpA at the time of colonization of V. cholerae protects against subsequent illness: 3) assess immune responses to CtxB at distant (non-intestinal) mucosal sites after clinical cholera, as a model for immune responses to heterologous antigens expressed by live, oral, attenuated V. cholerae vaccine vectors.

描述（根据应用程序摘要改编）：纤维状霍乱导致人类严重，脱水，偶尔腹泻。有一个估计全球霍乱的5-7万例病例，超过100,000 死亡人数。霍乱的大部分影响发生在世界发展地区，特别是在孟加拉国和印度等南亚和东南亚。 V.霍乱感染可诱导长期保护性免疫随后的霍乱，尽管介导保护的免疫反应不是完全理解。以前的许多对V的免疫反应的现场研究。霍乱感染是在1970年代进行的，在更现代的出现之前测量粘膜免疫反应的技术，例如使用分泌细胞分析。最近对霍乱谷感染的研究在普通志愿者中，许多在美国完成的志愿者提供了重要的有关这种病原体感染免疫反应的信息，但是这些反应可能与流行地区患者的反应明显不同，特别是与年龄，发病率，营养不良和事先暴露于相关抗原。最近已经完成了很多工作开发有效的现场直播，口服，衰减的V.霍乱疫苗，均用于预防临床霍乱和作为表达异源的向量抗原可预防粘膜表面的其他感染。这提案将建立科学家之间的长期合作美国和国际腹泻疾病研究中心孟加拉国以阐明免疫反应并防止霍乱感染在地方性人群中。该项目的长期目标是更好了解霍乱感染后的粘膜免疫反应和疫苗接种，并评估患者和微生物因素对这些反应可能解释了患者之间观察到的差异流行地区和正常的人类志愿者。提案的具体目的是：1）确定免疫反应的全部范围，尤其是粘膜孟加拉国霍乱患者的抗体反应比较颤动和粘膜抗体反应，并通过患者和微生物特征。我们将检验以下假设血清颤动反应代表粘膜的替代标记对实际保护性的相关抗原或抗原的反应：2）接触有机体的粘膜抗V霍乱抗体水平防止随后的临床霍乱。我们将检查假设对LPS的分泌免疫力。 CTXB，MSHA和/或TCPA 在殖民地殖民时，霍乱弧菌可防止随后疾病：3）评估远处（非智能）对CTXB的免疫反应临床霍乱后的粘膜部位，作为对免疫反应的模型通过现场，口服，减毒V.霍乱疫苗表达的异源抗原向量。