INDUCTION OF PROTECTIVE IMMUNITY AGAINST CHLAMYDIA

描述（由申请人提供）：沙眼衣原体由15个奇数血清型（A至K和L1至L3）组成，血清型为D至K，性病淋巴肉芽肿菌株L1 - L3引起性传播疾病（STD），是STD最常见的细菌病因，如果不治疗，通常会导致严重的并发症，包括盆腔炎、异位妊娠和女性不孕症。由于大多数感染者因缺乏明显症状而不寻求治疗，预防性免疫接种将是预防感染和控制衣原体疾病的最佳选择。有效的衣原体疫苗应诱导针对不同衣原体血清型的基础广泛、持久的免疫。我们先前表明，重组霍乱弧菌鬼（rVCG）平台是一种有效的递送系统，能够同时将多种衣原体抗原递送至免疫系统。结果表明，实现一个长期的，交叉保护衣原体免疫是可能的，将需要粘膜提供特定的多重衣原体抗原和有效的免疫调节宿主的免疫反应。因此，该提议的目标是利用基于rVCG的多亚单位疫苗候选物与分子粘膜佐剂一起来验证用于疫苗递送和衣原体免疫增强的粘膜途径。我们将研究粘膜给药途径和粘膜佐剂的组合如何影响抗体和T细胞应答的概况和质量，以保护免受衣原体感染。我们建议测试的总体假设，即直肠内（IR）交付选择多种衣原体抗原与分子佐剂将增强生殖道免疫，并提供广泛的，持久的保护，对阴道内的挑战。在具体目标1中，我们将确定基于rVCG的疫苗与Flt 3配体（FL）一起的IR递送将增强长期的交叉保护性衣原体免疫。具体目标2将检查FL佐剂对直肠粘膜递送后衣原体疫苗引起的免疫效应物的概况和质量的影响。最后，具体目标3中的研究将阐明表达FL的rVCG疫苗诱导免疫应答的分子机制，并确定rVCG疫苗IR递送后抗原呈递细胞的迁移途径。 公共卫生相关性：生殖器衣原体感染是世界上最常见的细菌性传播疾病（STD）。妇女通常很少或没有与感染有关的症状，这往往导致治疗延误和感染并发症的发展，如盆腔炎和不孕症，并增加了感染艾滋病毒的可能性。这些研究将提供一个更好的了解广泛的，持久的保护性免疫衣原体的抗原和免疫学相关性，并将指导疫苗策略的合理开发，这将有助于减少公共卫生系统的经济负担，由于感染性并发症的高治疗成本。

DESCRIPTION (provided by applicant): Chlamydia trachomatis, composed of 15 odd serovars (A through K and L1 to L3) with serovars D through K and the lymphogranuloma venereum strains L1 - L3 causing sexually transmitted diseases (STDs), is the most common bacterial cause of STDs and if untreated often lead to severe complications, including pelvic inflammatory disease, ectopic pregnancy and infertility in women. Since most infected individuals do not seek treatment due to lack of obvious symptoms, prophylactic immunization will be the best option for preventing infection and controlling chlamydial diseases. An efficacious chlamydial vaccine should induce broad-based, long lasting immunity against the different chlamydial serovars. We previously showed that the recombinant Vibrio choerae ghost (rVCG) platform is an effective delivery system capable of simultaneously delivering multiple Chlamydia antigens to the immune system. The results suggested that achievement of a long-term, cross-protective chlamydial immunity is possible and would require the mucosal delivery of specific multiple chlamydial antigens and effective immunomodulation of host immune response. Thus, the goal of this proposal is to utilize an rVCG- based multisubunit vaccine candidate together with a molecular mucosal adjuvant to validate a mucosal route for vaccine delivery and enhancement of chlamydial immunity. We will examine how a combination of the mucosal route of administration and mucosal adjuvant affect the profile and quality of antibody and T cell response for protection against Chlamydia. We propose to test the overall hypothesis that intrarectal (IR) delivery of select multiple chlamydial antigens together with a molecular adjuvant will enhance genital tract immunity and provide broad-based, long-lasting protection against intravaginal challenge. In specific aim 1, we will establish that IR delivery of an rVCG-based vaccine together with Flt3 ligand (FL) will enhance long-term, cross- protective chlamydial immunity. Specific aim 2 will examine the effect of FL adjuvant on the profile and quality of immune effectors elicited by a chlamydial vaccine after rectal mucosal delivery. Finally, studies in Specific aim 3 will elucidate the molecular mechanisms involved in the induction of immune responses by an rVCG vaccine expressing FL and determine the migration pathway of antigen presenting cells after IR delivery of rVCG vaccine. PUBLIC HEALTH RELEVANCE: Genital Chlamydia infection is the most common bacterial sexually transmitted disease (STD) worldwide. Women usually have few or no symptoms associated with infection, which often leads to delays in treatment and the development of infectious complications such as pelvic inflammatory disease and infertility and increased likelihood of acquiring HIV infection. These studies will provide a better understanding of the antigenic and immunologic correlates of broad-based, long-lasting protective immunity against Chlamydia and will guide the rational development of vaccine strategies that will aid in reducing the economic burden on the public healthcare system due to high treatment costs of infectious complications.