INDUCTION OF PROTECTIVE IMMUNITY AGAINST CHLAMYDIA

描述（由申请人提供）：沙眼衣原体由15种不同的血清型（A - K和L1 - L3）组成，其中血清型D - K和性病淋巴肉芽肿株L1 - L3可引起性传播疾病，是引起性传播疾病最常见的细菌，如不及时治疗，通常会导致严重的并发症，包括盆腔炎、女性异位妊娠和不孕。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。一种有效的衣原体疫苗应能诱导针对不同衣原体血清型的广泛、持久的免疫。我们之前已经证明重组霍乱弧菌鬼（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到免疫系统。结果表明，实现长期的、交叉保护的衣原体免疫是可能的，这需要粘膜递送特异性的多种衣原体抗原和对宿主免疫反应的有效免疫调节。因此，本研究的目的是利用基于rVCG的多亚单位候选疫苗和分子粘膜佐剂来验证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细胞对衣原体的保护反应的特征和质量。我们建议测试直肠内（IR）递送选择的多种衣原体抗原和分子佐剂将增强生殖道免疫力，并提供广泛的，持久的保护，以抵抗阴道内的挑战的总体假设。在具体目标1中，我们将建立基于rvcg的疫苗与Flt3配体（FL）的IR递送将增强长期的交叉保护性衣原体免疫。特异性目的2将研究FL佐剂对衣原体疫苗经直肠粘膜递送后引起的免疫效应物的形态和质量的影响。最后，Specific aim 3的研究将阐明表达FL的rVCG疫苗诱导免疫应答的分子机制，并确定抗原提呈细胞在rVCG疫苗IR递送后的迁移途径。

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.