Immune responses to Vibrio cholerae in children

简介(申请人提供)：本建议书为五年K08临床科学家导师研究发展奖，授予梁振英医学博士，M.Sc。这位候选人在贝丝以色列女执事医学中心完成了传染病临床研究奖学金，并在马萨诸塞州总医院(MGH)传染病科爱德华·T·瑞安博士的实验室接受了博士后研究培训。拟议的培训计划由瑞安博士担任主要导师，将包括讲授和实践培训，重点是儿童感染霍乱弧菌的免疫反应。这项研究建立在MGH和孟加拉国国际腹泻病研究中心(ICDDR，B)之间的长期合作基础上。ICDDR B疫苗科学中心主任Firdausi Qadri博士将为申请者提供共同指导。麻省理工学院教授兼内科主任斯蒂芬·B·卡尔德伍德博士将主持培训咨询小组。霍乱是一种由霍乱弧菌引起的急性脱水腹泻疾病，在50多个国家流行，每年影响200万至300万人，造成10万多人死亡。在流行地区，5岁以下儿童的疾病负担很重。尽管如此，与成人相比，目前可用的霍乱疫苗在幼儿中的效力较低，保护期较短。即使在成年人中，接种疫苗后的免疫力也是短暂的。相比之下，自然感染后的保护性免疫可持续数年，幼儿的保护期被认为与成人相当。儿童对霍乱的保护性免疫反应的介体和机制尚不清楚。在过去的24个月里，候选人开始着手解决这一缺陷，并已移居孟加拉国，并开始描述孟加拉国达卡儿童对霍乱感染和疫苗接种的急性和恢复期免疫反应。在这份申请中，申请人现在提出了一项K08职业发展计划，该计划延长了这些研究，并建立在正在进行的和完全批准的NIAID和SIDA/SAREC支持的项目的基础上。这一职业发展计划将帮助候选人发展成为一名独立的生物医学调查员，将提高我们对具有全球意义的人类限制性感染期间宿主病原体事件的了解，并可能导致为儿童--承担全球最大霍乱负担的人群--提供长效和保护性的改进霍乱疫苗。 与公共卫生相关：霍乱是一种腹泻疾病，每年影响全球数百万人。与自然感染相比，目前的口服霍乱疫苗提供了相对短期的保护，特别是对承担全球最大霍乱负担的幼儿。我们提出了一个职业发展计划，重点是提高我们对霍乱感染的免疫反应和孟加拉国儿童接种疫苗的理解；这些知识可能会导致改进霍乱疫苗。

DESCRIPTION (provided by applicant): This proposal is for a five year K08 Mentored Clinical Scientist Research Development Award for Daniel T. Leung, M.D., M.Sc. This candidate completed a clinical fellowship in Infectious Diseases at Beth Israel Deaconess Medical Center, and has entered post-doctoral research training in the laboratory of Dr. Edward T. Ryan in the Division of Infectious Diseases at Massachusetts General Hospital (MGH). The proposed training plan, with Dr. Ryan as primary mentor, will include both didactic and practical training focused on immune responses of Vibrio cholera infection in children. This research builds upon a longstanding collaboration between MGH and the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B). Dr. Firdausi Qadri, Director of Center for Vaccine Sciences at ICDDR,B, will provide co-mentorship to the applicant. Dr. Stephen B. Calderwood, Professor and Chief of ID at MGH will chair the Training Advisory Group. Cholera is an acute dehydrating diarrheal disease caused by Vibrio cholera, endemic in over 50 countries, and affecting 2 to 3 million people each year, causing more than 100,000 deaths. In endemic areas, children under 5 years of age have a high burden of disease. Despite this, currently available cholera vaccines achieve a lower efficacy and a shorter duration of protection in young children compared to that achieved in adults. Even in adults, immunity after vaccination is short-lived. In comparison, protective immunity after natural infection lasts for several years, and duration of protection in young children is thought to be comparable to that of adults. The mediators and mechanism of protective immune response to cholera in children remain poorly understood. The candidate has spent the last 24 months beginning to address this deficiency, has moved to Bangladesh, and has begun to characterize the acute and convalescent immune- responses to cholera infection and vaccination in children in Dhaka, Bangladesh. In this application, the applicant now proposes a K08 career development program that extends these studies, and builds upon ongoing and fully approved NIAID and SIDA/SAREC supported projects. This career development program would assist the candidate in his development into an independent biomedical investigator, would improve our understanding of host- pathogen events during a human restricted infection of global significance, and could lead to a long acting and protective improved cholera vaccine for children, the population that bears the largest global burden of cholera. Public Health Relevance: Cholera is a diarrheal disease affecting millions of people worldwide each year. Compared to natural infection, current oral cholera vaccines provide relatively short-term protection, especially in young children who bear the largest global burden of cholera. We propose a career development program that focuses on advancing our understanding of immune responses to cholera infection and vaccination in children in Bangladesh; such knowledge could lead to an improved cholera vaccine.