A novel cholera subunit vaccine based on 4 colonization factors

基于 4 个定植因子的新型霍乱亚单位疫苗

• 批准号: 7896772
• 负责人: WILLIAM Franklin WADE
• 金额: $ 23.41万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-21 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7896772
• 关键词: Address; Adhesions; Age; Animal Model; Antibodies; Antigens; B-Lymphocyte Epitopes; Bacterial Infections; Binding; Binding Proteins; Carbohydrates; Carrier Proteins; Categories; Cells; Child; Childhood; Chitin; Cholera; Cholera Toxin; Cholera Vaccine; Combined Vaccines; Communicable Diseases; Conjugate Vaccines; Development; Disease; Dose; Educational workshop; Enteral; Epitopes; Evaluation Research; Funding Mechanisms; Goals; Haemophilus influenzae; Human; Immune response; Immunity; Immunization; Individual; Infection; Institutes; Link; Microbiology; National Institute of Allergy and Infectious Disease; Pathogenesis; Pertussis Vaccine; Pilum; Proteins; Protocols documentation; Publishing; Research; Subunit Vaccines; T-Lymphocyte; Testing; Toxin; Toxoids; Training; United States National Institutes of Health; Vaccination; Vaccines; Vibrio cholerae; Virulence; Virulence Factors; Water; Work; base; cohort; experience; high risk; immunogenic; improved; killings; meetings; novel; novel strategies; pandemic disease; programs; protein B; public health relevance; research study; response; sound; vaccine efficacy

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.

描述（由申请人提供）：提出了一种新的方法，以基于当前对弧菌霍乱（VC）定植，发病机理和人类对霍乱的免疫反应的理解开发霍乱亚基疫苗。目前，在霍乱有问题的世界上，世界上大部分地区使用了口服的杀死的全细胞（W-C）VC疫苗。它引起的保护程度取决于疫苗对VC的年龄和先前暴露。杀死的W-C霍乱疫苗未表达在感染过程中表达的几种VC保护抗原的免疫原性。为了避免这种情况，我们提出了一种基于非常成功的B和B. b。百日咳疫苗的策略，该疫苗利用与载体蛋白结合的碳水化合物表位，或多种毒力因子和毒素来实现长期的免疫力。在动物模型中，对VC LP的单个抗体（ABS）和3个定植因子具有保护性。这些VC毒力因子将用于配置霍乱亚基疫苗，以诱导VC发病机理中关键第一步的浓缩免疫反应。我们假设由4种保护性VC定植/粘附因子组成的亚基霍乱疫苗将通过1剂诱导保护性免疫。解毒（DET）Inaba LPS将与三个毒力因素之一共轭：毒素共调节的菌毛A（TCPA），TCPF或几丁质结合蛋白A（CBP-A）。载体特异性T细胞的帮助将增强抗LPS反应，并有助于诱导保护性载体特异性ABS。研究汇集了Drs。韦德（Wade）和祖父母（Grandjean）在霍乱研究方面拥有丰富的经验。 W. Wade博士接受了免疫病变的训练。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的开发。他是抗VC LPS响应的专家。 Grandjean博士是一位出色的碳水化合物化学家，他生成了VC LPS：蛋白质结合物。公共卫生相关性：霍乱仍然是一种疾病，每年都会使数百万人患病并杀死数千人。我们建议根据V.霍乱：TCPA的已知毒力蛋白中保护性表位的鉴定来制定一种新的亚基霍乱疫苗。我们实验室的先前工作表明，LPS和TCPA可以构成霍乱疫苗的基础。我们将基于与3种蛋白质成分结合的霍乱亚基疫苗的开发，该疫苗与3个蛋白质成分结合了霍乱弧菌菌株所需的3蛋白质成分，该菌株正在引起当前的大流行。