Meningococcal and gonococcal vaccine to prevent invasive disease and carriage

脑膜炎球菌和淋球菌疫苗可预防侵袭性疾病和携带

基本信息

批准号：
10551230
负责人：
Gregory Robert Moe
金额：
$ 37.37万
依托单位：
OMVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-05 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551230
关键词：
10 year old Address Adolescent and Young Adult Affect Age Agreement Animals Antibiotic Resistance Antibodies Antibody Response Antibody titer measurement Antigen Presentation Antigenic Variation Antigens Attenuated Bacteremia Bacterial Meningitis Binding Binding Proteins Bulla CEACAM1 Cell Culture Techniques Cells Cervical Characteristics Child Communities Complement Complement Factor H Conjugate Vaccines Data Detergents Development Disease Disease Outbreaks Effectiveness Endotoxins Engineering Epithelial Cells Epitopes Estradiol Event Female Flow Cytometry Fluorescence Microscopy Goals Grant Human Immunity Immunize Immunoglobulin G Immunoglobulin M Immunoprecipitation Incidence Individual Infant Invaded Knock-out Licensing Life Macaca Macaca mulatta Measures Mediating Membrane Membrane Proteins Meningitis Microbial Biofilms Modeling Mus Nasal Epithelium Neisseria Neisseria gonorrhoeae Neisseria meningitidis Nose Nucleic Acids Pathogenesis Polysaccharides Population Proteins Public Health Publishing Recombinant Proteins Research Research Personnel Serogroup B Neisseria meningitidis Serum Sexually Transmitted Diseases Structure Surface Symptoms Testing Toxic effect Transgenic Mice Vaccines Vagina Variant Vesicle age group bactericide disorder prevention disorder risk experience gonorrhea vaccine human pathogen immunogenicity mortality mouse model mutant novel overexpression pathogen preservation prevent promoter resistant strain transmission process vaccine platform

项目摘要

Project Summary/Abstract Neisseria meningitidis (Nm) cause life-threatening bacterial meningitis and sepsis and N. gonorrhoeae (Ng) cause millions of sexually transmitted infections annually. Emerging multiple antibiotic resistance by Ng and recent increases in incidence have led to its designation as an urgent threat by the CDC. There are no licensed Nm vaccines in the US for <10 year olds, the population at greatest risk of disease and no licensed Ng vaccine. We have developed an Nm serogroup B (NmB) vaccine based on native outer membrane vesicles (NOMV) with genetically attenuated endotoxin activity and over- expressed mutant Factor H binding protein (FHbp) with reduced FH binding. In both mice and infant macaques, the vaccine elicited much higher human complement-mediated serum bactericidal antibody (SBA) responses than a licensed NmB vaccine. The vaccine, NOMV-FHbp, also elicited SBA against Ng in mice and in infant macaques. We used anti-NOMV-FHbp antibodies to identify Ng antigens that are highly conserved between Nm and Ng. Our hypothesis is that an NOMV vaccine with over produced mutant FHbps from subfamilies A and B and conserved Nm/Ng antigens will elicit antibodies that provide broad protection against disease by both pathogens in all age groups. In Aim 1, we will use an engineered promoter to over produce mutant FHbps from subfamilies A and B and two or more highly conserved Ng antigens that elicit protective antibodies (NmNg-NOMV vaccine). In Aim 2, we will test the ability of NmNg-NOMV to prevent colonization and invasion in immortalized and primary nasal and cervical cell culture models. In Aim 3, we will test the ability of optimized NmNg-NOMV vaccines to prevent colonization and symptoms of disease in transgenic mouse models of meningococcal nasal colonization and meningitis and in a female estradiol-treated Tg mouse model of gonococcal vaginal colonization. Preventing colonization and invasion is important for providing individual protection against disease and preventing transmission between individuals (i.e. “community immunity”). The overall goal is development of an NOMV vaccine platform for expression of conserved Neisseria antigens with native structures that can elicit broadly protective antibodies against both pathogens. Successful development of an NmNg-NOMV vaccine would have a significant public health impact world-wide.

项目概要/摘要脑膜炎奈瑟菌 (Nm) 和淋病奈瑟菌会导致危及生命的细菌性脑膜炎和败血症 (Ng) 每年导致数百万例新出现的多重抗生素耐药性。吴氏病毒和最近发病率的增加已导致其被疾病预防控制中心指定为紧急威胁。美国没有获得许可的针对 10 岁以下儿童的 Nm 疫苗，该人群是感染风险最大的人群我们开发了一种基于 Nm 血清群 B (NmB) 的疫苗。天然外膜囊泡 (NOMV) 具有基因减弱的内毒素活性和过度在小鼠和婴儿中表达突变的 H 因子结合蛋白 (FHbp)，且 FH 结合减少。在猕猴中，该疫苗引发了更高的人补体介导的血清杀菌抗体 (SBA) 反应优于获得许可的 NmB 疫苗。该疫苗 NOMV-FHbp 也能引发针对 SBA 的反应。我们使用抗 NOMV-FHbp 抗体来鉴定小鼠和幼年猕猴中的 Ng 抗原。 Nm 和 Ng 之间高度保守。我们的假设是 NOMV 疫苗具有超过。从亚科 A 和 B 产生突变型 FHbp 以及保守的 Nm/Ng 抗原将引发抗体在目标 1 中，我们将使用针对所有年龄组的两种病原体疾病提供广泛的保护。一个工程启动子，用于从亚科 A 和 B 以及两个或多个亚科中过量产生突变型 FHbp 高度保守的 Ng 抗原可引发保护性抗体（NmNg-NOMV 疫苗）。在目标 2 中，我们将。测试 NmNg-NOMV 预防永生化和原发性鼻腔定植和侵袭的能力在目标 3 中，我们将测试优化的 NmNg-NOMV 疫苗的能力。预防鼻膜炎球菌转基因小鼠模型的定植和疾病症状定植和脑膜炎以及雌性雌二醇处理的淋球菌阴道 Tg 小鼠模型防止殖民化和入侵对于提供个体保护很重要。预防疾病并防止人与人之间的传播（即“社区免疫”）。总体目标是开发用于表达保守奈瑟菌的 NOMV 疫苗平台具有天然结构的抗原可以引发针对两种病原体的广泛保护性抗体。 NmNg-NOMV 疫苗的成功开发将对公共卫生产生重大影响全世界。