Host Immune Responses to Chlamydia trachomatis Candidate Vaccine Antigens and their Association with Clinical Correlates of Protective Immunity in Women

宿主对沙眼衣原体候选疫苗抗原的免疫反应及其与女性保护性免疫临床相关性的关系

• 批准号: 10392446
• 负责人: WILLIAM M GEISLER
• 金额: $ 64.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-11 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392446
• 关键词: Address; Adjuvant; Aftercare; Antibodies; Antibody Response; Antigens; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Clinical; Clinical Treatment; Clinical Trials; Coculture Techniques; Combined Vaccines; Data; Dendritic Cells; Detection; Development; Enzyme-Linked Immunosorbent Assay; Formulation; Foundations; GTP-Binding Protein alpha Subunits, Gs; Genital; Genitalia; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin G; In Vitro; Infection; Interferon Type II; Knowledge; Laboratories; Lead; Measures; Mediating; Membrane Proteins; Memory; Methods; Mononuclear; Mucosal Immune Responses; Mucous Membrane; Mus; Natural History; Organism; Outcome; Participant; Peripheral Blood Mononuclear Cell; Phagocytosis; Phenotype; Prevention; Sampling; Secretory Immunoglobulin A; Site; Specimen; Stains; Subunit Vaccines; System; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Test Result; Testing; Tissues; Tube; Vaccine Antigen; Vaccines; Vagina; Woman; chlamydia vaccine; cytokine; enzyme linked immunospot assay; immunogenicity; infection rate; major outer membrane protein; memory CD4 T lymphocyte; neutralizing antibody; novel strategies; phase 1 study; prevent; programs; public health priorities; reproductive; response; screening; vaccine candidate; vaccine development; vaccine formulation

Prevention of Chlamydia trachomatis (CT) infection is a public health priority because it causes reproductive sequelae. Since CT control programs have not reduced infection rates, a CT vaccine is needed. Our long-term goal is to generate knowledge that will advance CT vaccine development. One obstacle to CT vaccine development had been identifying immune and clinical correlates of protection in humans. We showed that CT- specific systemic CD4+ IFN-g is a correlate of immune protection in women and that spontaneous clearance of CT infection before treatment and absence of reinfection after treatment are clinical correlates of protection. With sparse data on CT-specific mucosal cellular immune responses in women, we developed a novel approach for studying these responses using mucosal mononuclear cells (MMCs) from menstrual blood (MB). Another obstacle in CT vaccine development has been identifying CT antigens that induce protective immunity. Using an immunoproteomic approach, Dr. Brunham’s laboratory identified five CT outer membrane proteins (OMPs) that elicited strong T helper type 1 (Th1) responses. They tested a CT and C. muridarum subunit vaccine that combined these OMPs with a Th1 polarizing adjuvant and found it accelerated infection clearance in mice. The potential immunogenicity of these CT OMPs and need for a CT vaccine provides strong rationale for extending immune studies of these promising CT antigens and others to humans. The major objective of our proposal (in response to FOA PA-19-096) is to study cellular and antibody responses to promising CT vaccine candidate antigens. Our hypothesis is that Th1 cytokine responses against candidate CT antigens will be associated with clinical correlates of protection and may correlate with functional antibody responses against CT organisms (EBs). Our study has 3 aims: Aim 1 - Investigate systemic cellular and humoral immune responses to candidate CT vaccine antigens and their association with clinical correlates of protection against CT in women. Peripheral blood mononuclear cells (PBMCs) from women with spontaneously cleared vs. persisting CT infection and women without vs. with CT reinfection will be stimulated ex vivo with promising CT vaccine candidate antigens and CD4+ and CD8+ T cell responses measured by intracellular cytokine staining (ICS). Sera will be tested for IgG to CT antigens and functional antibody responses to CT EBs. Aim 2 - Evaluate mucosal T cell and antibody responses induced by candidate CT vaccine antigens and their association with clinical correlates of protection against CT in women. From Aim 1 participants, MMCs from MB will be stimulated ex vivo with CT antigens and CD4+ and CD8+ T cell responses measured by ICS. Mucosal antibodies to CT antigens will be tested. Aim 3 - Use an in vitro human dendritic cell / CD4+ T cell co-culture method (MIMIC system) to confirm antigenicity and immunogenicity of promising candidate CT vaccine antigens in women. PBMCs from CT naïve women will be used in the MIMIC system to evaluate antigenicity and immunogenicity (when given with adjuvant) of the candidate CT antigens. Study findings may lead to a CT vaccine formulation for a phase I study.

预防沙眼衣原体（CT）感染是公共卫生的优先事项，因为它会导致生殖健康。 后遗症由于CT控制计划没有降低感染率，因此需要CT疫苗。我们的长期 我们的目标是产生知识，将促进CT疫苗的发展。CT疫苗的一个障碍 发展一直在确定人类保护的免疫和临床相关性。我们发现CT- 特异性系统性CD 4 + IFN-g是女性免疫保护和 治疗前CT感染和治疗后无再感染是保护的临床相关因素。与 关于女性CT特异性粘膜细胞免疫反应的稀疏数据，我们开发了一种新方法， 使用来自经血（MB）的粘膜单核细胞（MMCs）研究这些反应。另一 CT疫苗开发中的障碍是鉴定诱导保护性免疫的CT抗原。使用 通过免疫蛋白质组学方法，Brunham博士的实验室鉴定了五种CT外膜蛋白（OMP）， 引起强烈的辅助性T细胞1型（Th 1）反应。他们做了CT和C.小鼠亚单位疫苗， 将这些OMP与Th 1极化佐剂组合，发现其加速小鼠的感染清除。 这些CT OMP的潜在免疫原性和对CT疫苗的需求为以下方面提供了强有力的依据： 将这些有希望的CT抗原和其他抗原的免疫研究扩展到人类。我们的主要目标是 一项建议（响应FOA PA-19-096）是研究对有希望的CT疫苗的细胞和抗体应答 候选抗原我们的假设是，Th 1细胞因子对候选CT抗原的应答将是一种免疫应答。 与保护的临床相关性相关，并且可能与针对CT的功能性抗体应答相关 生物体（EBs）。我们的研究有3个目的：目的1 -研究全身细胞和体液免疫反应 候选CT疫苗抗原及其与女性CT保护临床相关性的相关性。 来自自发清除与持续CT感染女性的外周血单核细胞（PBMC） 没有CT再感染的妇女与有CT再感染的妇女将用有希望的CT候选疫苗离体刺激 抗原以及通过细胞内细胞因子染色（ICS）测量的CD 4+和CD 8 + T细胞应答。塞拉会 测试针对CT抗原的IgG和针对CT EB的功能性抗体应答。目的2 -评价粘膜T细胞 候选CT疫苗抗原诱导的抗体应答及其与临床相关性的关系 保护女性免受CT感染。从目标1参与者开始，将用CT离体刺激来自MB的MMC 抗原和通过ICS测量的CD 4+和CD 8 + T细胞应答。CT抗原的粘液抗体将是 测试.目的3 -使用体外人树突状细胞/CD 4 + T细胞共培养方法（MIMIC系统）来证实 在女性中有希望的候选CT疫苗抗原的抗原性和免疫原性。未经CT检查的PBMC 女性将用于MIMIC系统，以评价抗原性和免疫原性（与佐剂一起给药时） 候选CT抗原。研究结果可能会导致CT疫苗制剂的I期研究。