A novel cholera subunit vaccine based on 4 colonization factors

描述（由申请人提供）：基于目前对霍乱弧菌（Vc）定植、发病机制和人类对霍乱的免疫应答的理解，提出了一种开发霍乱亚单位疫苗的新方法。目前，口服的灭活全细胞（W-C）Vc疫苗在世界上霍乱问题严重的大部分地区使用。它诱导的保护程度取决于接种者的年龄和以前对Vc的暴露。灭活的W-C霍乱疫苗不表达在感染期间表达的几种Vc保护性抗原的免疫原性水平。为了规避这一点，我们提出了一个战略的基础上，部分非常成功的H。流感病毒B型和B型。百日咳疫苗利用与载体蛋白结合的碳水化合物表位或多种毒力因子和类毒素来实现持久免疫。抗Vc、LPS和3种定植因子的抗体在动物模型中具有保护作用。这些VC毒力因子将用于配置霍乱亚单位疫苗，以诱导对VC发病机制中关键第一步的集中免疫反应。我们假设，亚单位霍乱疫苗，由4个保护性Vc定植/粘附因子将诱导1剂量的保护性免疫。脱乙酰化（det）稻叶LPS将与三种毒力因子之一缀合：毒素共调节菌毛A（TcpA）、TcpF或几丁质结合蛋白A（CBP-A）。载体特异性T细胞帮助将增强抗LPS应答并帮助诱导保护性载体特异性Ab。这些研究汇集了在霍乱研究方面具有丰富经验的韦德博士和格兰德让博士。W博士韦德在免疫发病机制方面受过训练。他率先开发了与载体蛋白结合的合成Vc LPS表位的疫苗接种方案。他是抗Vc LPS反应的专家。Grandjean博士是一位有成就的碳水化合物化学家，他已经产生了Vc LPS：蛋白质结合物。公共卫生相关性：霍乱仍然是一种每年使数百万人患病并导致数千人死亡的疾病。我们提出了一种新的亚单位霍乱疫苗的基础上确定的保护性表位在一个已知的霍乱弧菌毒力蛋白：TcpA。我们实验室以前的工作表明，LPS和TcpA可以形成霍乱疫苗的基础。我们将致力于开发一种霍乱亚单位疫苗，该疫苗基于与引起当前大流行的霍乱弧菌菌株定殖所需的3种蛋白组分结合的解毒LPS。

DESCRIPTION (provided by applicant): A novel approach is proposed to develop a cholera subunit vaccine based on the current understanding of Vibrio cholerae (Vc) colonization, pathogenesis, and the human immune response to cholera. Currently, a killed, whole-cell (W-C) Vc vaccine delivered orally is used in much of the world where cholera is problematic. The degree of protection it induces depends on the age and the previous exposure of the vaccinees to Vc. The killed W-C cholera vaccines do not express immunogenic levels of several Vc protective antigens that are expressed during infection. To circumvent this, we propose a strategy based in part on the highly successful H. influenzae type b and B. pertussis vaccines that utilize either carbohydrate epitopes bound to carrier proteins, or multiple virulence factors and a toxoid to achieve long-lasting immunity. Individual antibodies (Abs) to Vc LPS and 3 colonization factors are protective in animal models. These Vc virulence factors will be used to configure a cholera subunit vaccine to induce a concentrated immune response to the critical first step(s) in Vc pathogenesis. We hypothesize that a subunit cholera vaccine, composed of 4 protective Vc colonization/adhesion factors will induce protective immunity with 1 dose. Detoxified (det) Inaba LPS will be conjugated to one of three virulence factors: Toxin Co-Regulated pilus A (TcpA), TcpF or chitin-binding protein A (CBP-A). Carrier-specific T cell help will enhance the anti-LPS response and help for induction of protective carrier-specific Abs. The studies bring together Drs. Wade and Grandjean who have extensive experience in cholera research. Dr. W. Wade is trained in immunopathogenesis. He pioneered the development of the vaccination protocols for synthetic Vc LPS epitopes conjugated to carrier proteins. He is an expert in the anti-Vc LPS response. Dr. Grandjean is an accomplished carbohydrate chemist who has generated Vc LPS:protein conjugates. Public Health Relevance: Cholera is still a disease that sickens millions and kills thousands yearly. We propose to formulate a new subunit cholera vaccine based on identification of protective epitopes in a known virulence proteins of V. cholerae: TcpA. Previous work from our lab has shown that LPS and TcpA can form the basis for a cholera vaccine. We will pursue the development of a cholera subunit vaccine based on detoxified-LPS bound to 3 protein component required for colonization of the strain of V. cholera that is causing the current pandemic.