Meningococcal and gonococcal vaccine to prevent invasive disease and carriage

项目概要/摘要 脑膜炎奈瑟氏菌（Nm）可引起危及生命的细菌性脑膜炎和败血症，淋病 (Ng)每年导致数百万的性传播感染。出现多重抗生素耐药性 Ng和最近发病率的增加导致其被CDC指定为紧急威胁。 在美国，还没有获得许可的用于<10奥尔兹的Nm疫苗，这是最有可能感染的人群。 疾病并且没有获得许可的Ng疫苗。我们已经开发了基于以下的Nm血清群B（Nm B）疫苗： 天然外膜囊泡（NOMV），具有遗传上减弱的内毒素活性和过度 表达的突变体H因子结合蛋白（FHbp），具有降低的FH结合。在小鼠和婴儿 在猕猴中，疫苗引起了更高的人补体介导的血清杀菌抗体 (SBA)比获得许可的NMB疫苗更有效。疫苗NOMV-FHbp也引起SBA， 在小鼠和幼年猕猴中。我们使用抗NOMV-FHbp抗体来鉴定Ng抗原， 在Nm和Ng之间高度保守。我们的假设是， 产生的来自亚家族A和B的突变FHbp和保守的Nm/Ng抗原将引发抗体 这两种病原体在所有年龄组中都能提供广泛的保护。在目标1中，我们将使用 过量产生来自亚家族A和B的突变FHbp的工程化启动子，以及两个或更多个 - 引发保护性抗体的高度保守的Ng抗原（NmNg-NOMV疫苗）。在目标2中，我们 测试NmNg-NOMV在永生化和原发性鼻粘膜中防止定殖和侵袭的能力 和宫颈细胞培养模型。在目标3中，我们将测试优化的NmNg-NOMV疫苗的能力， 预防脑膜炎球菌鼻脑膜炎转基因小鼠模型中的定植和疾病症状 定植和脑膜炎，并在雌性雌二醇治疗的Tg小鼠模型的淋球菌阴道 殖民化防止殖民化和入侵对于提供个人保护很重要 预防疾病和防止个人之间的传播（即“社区免疫”）。的 总体目标是开发用于表达保守的奈瑟氏球菌的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 世界范围内。

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.