INDUCTION OF PROTECTIVE IMMUNITY AGAINST CHLAMYDIA

描述(由申请人提供)：沙眼衣原体由15个血清型(A至K和L1至L3)组成，其血清型为D至K，以及引起性传播疾病(STD)的淋巴肉芽肿菌株L1至L3，是导致性传播疾病的最常见细菌，如果不治疗，往往会导致严重的并发症，包括盆腔炎、宫外孕和女性不孕。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。我们先前已经证明，重组乔氏弧菌幽灵(RVCG)平台是一种有效的递送系统，能够同时将多个衣原体抗原递送到免疫系统。结果表明，实现长期、交叉保护的衣原体免疫是可能的，这需要黏膜递送多种衣原体抗原和有效的宿主免疫反应的免疫调节。因此，这项建议的目标是利用基于rVCG的多亚单位疫苗候选者和分子粘膜佐剂来验证疫苗递送和增强衣原体免疫的粘膜途径。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细胞反应的概况和质量，以保护免受衣原体感染。我们建议验证这样的总体假设，即选择多种衣原体抗原(IR)与分子佐剂一起直肠内递送将增强生殖道免疫，并提供广泛、持久的保护，抵御阴道内挑战。在具体目标1中，我们将确定IR递送基于rVCG的疫苗和Flt3配体(FL)将增强长期的交叉保护性衣原体免疫。具体目标2将检测FL佐剂对衣原体疫苗在直肠粘膜分娩后所诱导的免疫效应器的特性和质量的影响。最后，特异靶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rVCG疫苗IR递送后抗原提呈细胞的迁移途径。 公共卫生意义：生殖器衣原体感染是全世界最常见的细菌性性病(STD)。妇女通常很少或根本没有与感染有关的症状，这往往会导致延误治疗和发展感染并发症，如盆腔炎和不孕不育，并增加感染艾滋病毒的可能性。这些研究将更好地了解针对衣原体的广泛、持久的保护性免疫的抗原性和免疫学相关性，并将指导合理制定疫苗策略，帮助减轻因感染并发症的高昂治疗成本而对公共医疗系统造成的经济负担。

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.