Mucosal Vaccines against Gonorrhea

淋病粘膜疫苗

• 批准号: 7764312
• 负责人: Ann E. Jerse
• 金额: $ 37.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7764312
• 关键词: Active Immunization; Adherence; Adjuvant; Affect; Agglutination; Amino Acid Sequence; Antibiotic Resistance; Antibodies; Antibody-mediated protection; Antigenic Variation; Antigens; Attenuated; Binding; Binding Proteins; Biological Assay; Biological Response Modifiers; Cells; Cervical; Cholera Toxin; Collaborations; Complement; Complement Factor H; Cyclic Peptides; Development; Dose; Effectiveness; Epithelial Cells; Female; Genital system; Gonorrhea; HIV; Human; Human Factor H; Immune; Immune response; Immunization; Immunoglobulin A; Immunoglobulin G; Immunoglobulin Variable Region; Immunology; In Vitro; Infection; Infection prevention; Intestines; Ion Channel; Laboratories; Lead; Length; Lipoproteins; Measures; Mediating; Membrane; Membrane Proteins; Modeling; Multi-Drug Resistance; Mus; Neisseria gonorrhoeae; Outer Limiting Membrane; Passive Immunization; Pelvic Inflammatory Disease; Peptides; Play; PorB porin; Predisposition; Protein Binding; Proteins; Recombinants; Relative (related person); Research; Resistance; Role; Secretory Immunoglobulin A; Serum; Sexually Transmitted Diseases; Surface; System; Testing; Vaccination; Vaccine Antigen; Vaccines; Vagina; antimicrobial peptide; bactericide; base; complement 4b-binding protein; design; efflux pump; gonorrhea vaccine; granulocyte; in vivo; interest; mouse model; mucosal vaccine; mutant; novel; porin; prophylactic; protective efficacy; resistant strain; response; tool; transmission process; vaccine candidate

The development of an effective gonorrhea yaccine is challenged by the antigenic variability of the Neisseria gonorrhoeae (Gc) surface and a lack of information on the correlates of protection against infection. Gc porin is a good vaccine candidate based on its abundance in the outer membrane (OM), limited variability, and its roles in epithelial cell invasion and serum resistance via binding to C4bp-binding protein (C4BP) and factor H (fH). Other promising vaccine targets are MtrE, the OM channel of the MtrCMtrD- MtrE active efflux pump, and OmpA, a conserved OM protein that confers adherence to and invasion of human genital tract cells. Our primary objective is to target surface-exposed loops of GC porin in active and passive immunization strategies against gonorrhea. We will also test the protective efficacy of MtrE and OmpA. Specifically, we will 1) characterize Abs against selected porin loops for in vitro and in vivo correlates of protection and the capacity to block C4BP- and fH-binding to serum resistant strains. The bactericidal and opsonophagocytic activity of Abs against cyclic porin peptides will be measured against Gc strains of different porin types. The capacity of Abs to inhibit porin-mediated invasion of human cervical cells and to block the binding of human fH and C4BP to serum resistant Gc will be tested. We will perform passive protection studies with normal, complement- and granulocyte-deficient mice to identify mechanisms of antibody-mediated protection. We will also ii) develop an active immunization strategy based on cyclic porin loop peptides to protect mice from Gc infection. The optimum dose of peptide and type of adjuvant needed to induce high titer serum and mucosal antibodies with anti-Gc activity will be determined. Mice will be immunized with the most promising peptides, and immunized and unimmunized mice will be challenged intravaginally with the homologous Gc strain to determine if immunization affects susceptibility to infection or colonization load. The local and systemic immune response to two peptides that show protection and an analogous peptide that does not will be thoroughly characterized to define correlates of protection, ill.) Finally, we will investigate the protective potential of MtrE and OmpA as vaccine candidates based on their demonstrated importance in experimental murine infection. We will utilize MtrE- and OmpA-specific antibodies to investigate in vitro correlates of protection and perform immunization/challenge studies with purified MtrE, OmpA and surface-exposed regions of these molecules to measure their potential as vaccine antigens against N. gonorrhoeae in vivo.

有效的淋病Yaccine的发展受到抗原变异性的挑战 淋病的奈瑟氏菌（GC）表面，缺乏有关保护的相关性的信息 感染。 GC Porin是基于外膜（OM）的丰度的良好疫苗候选者 有限的可变性及其在上皮细胞侵袭和通过与C4BP结合结合的作用 蛋白质（C4bp）和因子H（FH）。其他有希望的疫苗靶标是MTRE，MTRCMTRD-的OM通道 MTRE主动排出泵和OMPA，一种保守的OM蛋白 人类生殖道细胞。我们的主要目的是靶向活跃的GC孔蛋白的表面暴露环 和针对淋病的被动免疫策略。我们还将测试MTRE的保护功效 和Ompa。具体而言，我们将对体外和体内的选定旋转环的ABS表征1） 保护和阻断C4BP和FH结合到血清耐血清菌株的能力。这 ABS对环状孔蛋白肽的杀菌性和肠孢细胞活性将测量 不同类型的GC菌株。 ABS抑制孔蛋白介导的人宫颈的侵袭的能力 将测试细胞并阻止人FH和C4BP与血清抗性GC的结合。我们将表演 用正常，补体和粒细胞缺陷的小鼠进行的被动保护研究，以识别 抗体介导的保护机理。我们还将ii）制定主动免疫策略 基于环状孔磷酸环肽，以保护小鼠免受GC感染。肽的最佳剂量和 诱导具有抗GC活性的高滴度血清和粘膜抗体所需的佐剂类型将是 决定。小鼠将用最有前途的肽进行免疫，并免疫和无免疫 小鼠将通过同源GC菌株在静脉内受到挑战，以确定免疫是否影响 对感染或定植负荷的敏感性。对两种肽的局部和全身免疫反应 该显示的保护和类似的肽不会被彻底表征以定义 生病的保护。）最后，我们将研究MTRE和OMPA的保护潜力 疫苗候选物基于其在实验鼠感染中的重要性。我们将 利用MTRE和OMPA特异性抗体来研究保护和执行的体外相关性 这些分子的纯化MTRE，OMPA和表面暴露区域的免疫/挑战研究 在体内测量其作为疫苗抗原的疫苗抗原的潜力。