Subunit Vaccine for Cryptosporidiosis

项目摘要 前言：我们建议开发一种隐孢子虫病的亚单位粘膜疫苗原型，以此为基础 我们发现针对Cp23和Cp17的粘膜免疫球蛋白A与儿童保护有关 避免再次感染 假设：黏膜疫苗将通过粘膜IgA和IFNG提供广泛的中和保护。 前提：针对隐孢子虫病的天然获得性免疫力的存在表明，疫苗是 尽管存在寄生虫遗传多样性，但这是可行的。 意义：目前还没有疫苗，对婴儿的治疗也不是最理想的。隐孢子虫病是排名前十的 低收入和中等收入国家出生第一年腹泻的原因。在北美，它是领先的 水传播腹泻的病原学，一种B类生物防御剂，以及艾滋病慢性腹泻的原因。 研究人员：弗吉尼亚大学的威廉·佩里博士率先将隐孢子虫鉴定为 婴儿腹泻的主要原因，发现粘膜抗隐孢子虫IgA对儿童的重要性 用于获得性免疫，并引领了粘膜靶向佐剂在亚单位疫苗设计中的应用。 因此，为隐孢子虫病疫苗的快速发展奠定了基础。 创新：创新包括发现粪便中的IgA对抗隐孢子虫Cp23和Cp17 抗原与防止再次感染有关，开创了黏膜佐剂的发展 肠道感染，并在较小程度上证明了Cp23、CpGAPM2和 Cp17来自基因组重测序。 方法： 具体目的1.研制一种黏膜疫苗原型。抗原(Cp23、Cp17和CpGAPM2)将 在大肠杆菌中表达，纯化，并与我们的先导药物可接受的粘膜佐剂混合。 具体目的2.优化黏膜疫苗的免疫原性和试验保护性。粘膜免疫球蛋白A和 系统免疫球蛋白将在隐孢子虫病小鼠模型中进行优化和保护测试。 环境：佩里实验室是一项关于全球健康和微生物的强有力计划的一部分 弗吉尼亚大学的免疫学/发病机制。 这一高风险、高回报的勘探项目的顺利完成将为 隐孢子虫病粘膜疫苗的研制。

Project Summary Introduction: We propose to develop a prototype subunit mucosal vaccine for cryptosporidiosis, building on our discovery that mucosal IgA directed against Cp23 and Cp17 is associated with protection of children from re-infection Hypothesis: A mucosal vaccine will provide broadly neutralizing protection via mucosal IgA and IFNg. Premise: The presence of naturally acquired immunity against cryptosporidiosis indicates that a vaccine is feasible despite the presence of parasite genetic diversity. Significance: Currently no vaccine exists and therapy for infants is suboptimal. Cryptosporidiosis is a top ten cause of diarrhea in the 1st year of life in low and middle-income countries. In North America it is the leading etiology of water-borne diarrhea, a biodefense category B agent, and cause of chronic diarrhea in AIDS. Investigator: Dr. William Petri at the University of Virginia pioneered the identification of cryptosporidium as a major cause of infant diarrhea, discovered the importance in children of mucosal anti-cryptosporidium IgA for acquired immunity and has led the application of mucosal-targeted adjuvants for subunit vaccine design. The stage is thus set for rapid advancement of a cryptosporidiosis vaccine. Innovation: Innovation includes the discovery that fecal IgA against the cryptosporidium Cp23 and Cp17 antigens are associated with protection from re-infection, pioneering development of mucosal adjuvants for enteric infections, and demonstrating the genetic conservation of Cp23, CpGAPM2 and to a lesser extent Cp17 from genome resequencing. Approach: Specific Aim 1. Develop a prototype mucosal vaccine. Antigens (Cp23, Cp17 and CpGAPM2) will be expressed in E. coli, purified and mixed with our lead pharmaceutically acceptable mucosal adjuvant. Specific Aim 2. Optimize immunogenicity and test protection of the mucosal vaccine. Mucosal IgA and systemic IFNg will be optimized and protection tested in the mouse model of cryptosporidiosis. Environment: The Petri lab is part of a robust program on global health and microbial immunology/pathogenesis at the University of Virginia. Successful Completion of this high-risk and high-payoff exploratory project will provide a foundation for development of a mucosal vaccine for cryptosporidiosis.