INDUCTION OF PROTECTIVE IMMUNITY AGAINST CHLAMYDIA

诱导针对衣原体的保护性免疫力

• 批准号: 8051700
• 负责人: Francis O. Eko
• 金额: $ 34.65万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8051700
• 关键词: Achievement; Adjuvant; Affect; Antibiotic Therapy; Antibodies; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bacterial Sexually Transmitted Diseases; CD8B1 gene; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Coupled; Detection; Development; Economic Burden; Ectopic Pregnancy; Elements; FLT3 ligand; Frequencies; Genital system; Goals; HIV; HIV Infections; HIV-1; Healthcare Systems; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Immunologics; Individual; Infection; Infection Control; Infection prevention; Infertility; Lead; Ligands; Luciferases; Lymphogranuloma Venereum; Maintenance; Mediating; Membrane Proteins; Memory B-Lymphocyte; Molecular; Motivation; Mus; NF-kappa B; Pathology; Pathway interactions; Pelvic Inflammatory Disease; Play; Public Health; Recombinants; Relative (related person); Reporter; Risk; Role; Route; Severities; Sexually Transmitted Diseases; Signal Transduction; Symptoms; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Treatment Cost; Vaccination; Vaccine Design; Vaccines; Vibrio; Woman; base; cross reactivity; immune activation; immunoregulation; migration; p65; porin; prevent; prophylactic; protective efficacy; protein B; public health relevance; rectal; response; therapy development; transmission process; vaccine candidate; vaccine delivery; vaccine development; vaccine efficacy

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.

描述（由申请人提供）：沙眼衣原体由 15 种奇怪的血清型（A 至 K 和 L1 至 L3）组成，其中血清型为 D 至 K 以及导致性传播疾病 (STD) 的性病淋巴肉芽肿菌株 L1 - L3，是 STD 最常见的细菌原因，如果不治疗，通常会导致严重的并发症，包括盆腔炎、宫外孕 以及女性不孕症。由于大多数感染者由于缺乏明显症状而不会寻求治疗，因此预防性免疫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广泛、持久的免疫力。我们之前表明，重组霍乱弧菌菌影（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，实现长期、交叉保护性衣原体免疫是可能的，并且需要粘膜递送特定的多种衣原体抗原和对宿主免疫反应进行有效的免疫调节。因此，该提案的目标是利用基于 rVCG 的多亚单位候选疫苗与分子粘膜佐剂一起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 细胞反应的特征和质量，以预防衣原体。我们建议测试以下总体假设：直肠内（IR）递送选定的多种衣原体抗原与分子佐剂将增强生殖道免疫力，并提供针对阴道内挑战的广泛、持久的保护。在具体目标 1 中，我们将确定基于 rVCG 的疫苗与 Flt3 配体 (FL) 一起进行 IR 递送将增强长期、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发的免疫效应物的特征和质量的影响。最后，具体目标 3 中的研究将阐明表达 FL 的 rVCG 疫苗诱导免疫反应的分子机制，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全世界最常见的细菌性传播疾病 (STD)。女性通常很少或没有与感染相关的症状，这往往会导致治疗延误和感染性并发症的发生，例如盆腔炎和不孕症，以及感染艾滋病毒的可能性增加。这些研究将更好地了解针对衣原体的广泛、持久的保护性免疫力的抗原和免疫学相关性，并将指导疫苗策略的合理开发，这将有助于减轻由于感染并发症的高昂治疗成本而给公共医疗系统带来的经济负担。