Development of a vaccine for human chlamydia genital infection

项目摘要 该项目的长期目标是确定重组穹窿纳米颗粒， 工程化以包含免疫原性肽，产生先天性和适应性免疫应答。有 很少有许可的疫苗用于保护粘膜组织免受感染，即因为我们缺乏 设计诱导粘膜免疫的疫苗。我们假设这个空洞， 小微生物大小的重组穹窿可以被工程化以诱导粘膜免疫， 作为识别产生Th1细胞的关键免疫触发因子的工具，Th1细胞运输到生殖器粘膜组织（GT）。我们选择了病原体沙眼衣原体感染，它依赖于Th1粘膜免疫应答 对卫生保健来说是一个沉重的负担，而且没有有效的疫苗。C. 沙眼是性传播感染（STI）的主要原因，也是女性生殖系统疾病的煽动者。 功能障碍，在美国每年有超过100万例。小鼠适应的C. trachomatis、C. muridarum，诱导STI类似于人类衣原体STI，可以预防的 Th1在阴道组织中的存在。我们已经证明，拱顶疫苗与活性先天免疫系统相互作用， 免疫细胞，进一步重塑下游的适应性免疫反应。金库的独特之处在于 是具有自佐剂特性的天然纳米颗粒。在本提案中，我们将利用马赛克 疫苗设计和研究如何穹窿纳米粒子工程化含有衣原体蛋白诱导 小鼠对衣原体生殖器疾病的免疫应答和保护性免疫。在目标a中，我们利用 含有保守区域“嵌合体”MOMP序列和保守PMPG区域的穹窿疫苗 以确定最佳疫苗剂量。在目标B中。我们使用的保险库 相似的C.作为保护免受衣原体感染的“概念验证”试验的鼠源性（MoPn）序列 小鼠阴道激发试验。在Aim c.我们将使用含有嵌合MOMP序列和 在上述确定的最佳剂量下从人血清型中选择的PMPG保守区作为“证据 概念”，用于保护小鼠免受人沙眼衣原体攻击。该提案调查了 穹窿花叶疫苗是否以及如何提供广泛和深入的交叉血清型保护性免疫。我们 研究将揭示当前疫苗学领域需要回答的关键问题。这些 研究将与马赛克疫苗专家奥托·杨博士和伦纳德罗马博士合作进行， 他是拱顶纳米粒子技术的专家

Project Abstract The long term goal of this project is to identify the mechanisms whereby recombinant vault nanoparticles, engineered to contain immunogenic peptides, generate innate and adaptive immune responses. There are few licensed vaccines for protection against infections in mucosal tissues, namely because we lack an understanding for designing vaccines that induce mucosal immunity. We hypothesize that the hollow, recombinant vaults, the size of small microbes, could be engineered to induce mucosal immunity and be used as a tool to identify key immune triggers which produce Th1 cells that traffic to genital mucosal tissue (GT).We chose infection by the pathogen, Chlamydia trachomatis, which relies on Th1 mucosal immune responses for elimination, is a significant burden on health care, and for which there is no effective vaccine. C. trachomatis is a prominent cause of sexually transmitted infection (STI) and instigator of female reproductive dysfunction, with over 1 million cases in the U.S. annually. Vaginal delivery of the mouse-adapted strain of C. trachomatis, C. muridarum, induces an STI similar to human chlamydial STI and can be prevented by the presence of Th1 within vaginal tissues. We have shown that vault vaccines interact with and active innate immune cells, which further reshape adaptive immune responses downstream. Vaults are unique in that they are natural nanoparticles with self-adjuvant properties. In this proposal we will take advantage of mosaic vaccine design and investigate how vault nanoparticles engineered to contain chlamydial proteins induce immune responses and protective immunity against chlamydial genital disease in mice. In Aim a we utilize vault vaccines containing conserved region “mosaic” MOMP sequences and a conserved PMPG region covering all common human serovars to determine optimal vaccine doses. In Aim b. we use vaults containing the analogous C. muridarum (MoPn) sequences as a “proof of concept” test for protection against Chlamydia muridarum vaginal challenge. In Aim c. we will use vault vaccines containing mosaic MOMP sequences and a PMPG conserved region selected from human serovars at the optimal doses determined above as a “proof concept” for protection from human Chlamydia trachomatis challenge in mice. This proposal investigates whether and how vault mosaic vaccine will provide broad and depth crossing-serovar protective immunity. Our research will shed the light on the critical issues which need answers in the current vaccinology field. These studies will be done in collaboration with Dr. Otto Yang, an expert in mosaic vaccine and Dr. Leonard Rome, an expert in vault nanoparticle technology.