Subunit Vaccine for Cryptosporidiosis

隐孢子虫病亚单位疫苗

• 批准号: 10312809
• 负责人: William A Petri
• 金额: $ 20.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-07 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312809
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Antigens; Categories; Cells; Child; Chronic diarrhea; Clinical; Collaborations; Cryptosporidiosis; Cryptosporidium; Cyclic GMP; DNA Resequencing; Development; Diarrhea; Enteral; Environment; Enzyme-Linked Immunosorbent Assay; Escherichia coli; Etiology; Formulation; Foundations; Foxes; Generations; Genetic; Genetic Variation; Genome; Goals; Immunization; Immunoglobulin A; Immunoglobulin G; Immunology; Infant; Infantile Diarrhea; Infection; Infection prevention; Interferon Type II; Intestines; Lead; Life; Life Cycle Stages; Liposomes; Measurement; Measures; Mucosal Immunity; Mucous Membrane; Mus; North America; Parasites; Particle Size; Pathogenesis; Pharmacologic Substance; Positioning Attribute; Prevention; Proteins; Research Personnel; Role; Route; Safety; Sporozoites; Staphylococcus hominis; Subunit Vaccines; TLR4 gene; TLR7 gene; Testing; Universities; Vaccine Design; Vaccines; Virginia; acquired immunity; anti-IgA; biodefense; child protection; enteric infection; global health; high risk; immunogenicity; innovation; light scattering; low and middle-income countries; microbial; mouse model; mucosal vaccine; novel; programs; prototype; response; waterborne; weight maintenance

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.

项目概要 简介：我们建议在基础上开发一种隐孢子虫病原型亚单位粘膜疫苗 我们发现针对 Cp23 和 Cp17 的粘膜 IgA 与保护儿童有关 以免再次感染 假设：粘膜疫苗将通过粘膜 IgA 和 IFNg 提供广泛的中和保护。 前提：针对隐孢子虫病的自然获得性免疫力的存在表明疫苗是有效的 尽管存在寄生虫遗传多样性，但仍可行。 意义：目前尚无疫苗，且针对婴儿的治疗效果欠佳。隐孢子虫病位居前十名 低收入和中等收入国家出生后第一年腹泻的原因。在北美它是领先的 水源性腹泻的病因学、B 类生物防御剂以及艾滋病慢性腹泻的原因。 研究者：弗吉尼亚大学的 William Petri 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 在儿童中的重要性 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。 由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 IgA 对抗隐孢子虫 Cp23 和 Cp17 抗原与防止再次感染有关，开创性地开发了粘膜佐剂 肠道感染，并证明 Cp23、CpGAPM2 以及较小程度的遗传保守性 来自基因组重测序的 Cp17。 方法： 具体目标 1. 开发粘膜疫苗原型。抗原（Cp23、Cp17 和 CpGAPM2）将 在大肠杆菌中表达，纯化并与我们领先的药学上可接受的粘膜佐剂混合。 具体目标2.优化免疫原性并测试粘膜疫苗的保护作用。粘膜 IgA 和 系统性 IFNg 将在隐孢子虫病小鼠模型中进行优化和保护测试。 环境：Petri 实验室是全球健康和微生物强有力计划的一部分 弗吉尼亚大学免疫学/发病机制。 这一高风险、高回报的探索项目的成功完成将为 开发隐孢子虫病粘膜疫苗。