Meningococcal and gonococcal vaccine to prevent invasive disease and carriage

项目摘要/摘要 脑膜炎奈瑟菌(Nm)引起危及生命的细菌性脑膜炎、败血症和淋球菌 (Ng)每年导致数百万的性传播感染。新出现的多重抗生素耐药性 Ng和最近发病率的增加导致它被疾控中心指定为紧急威胁。 在美国，没有针对10岁儿童的获得许可的新城疫疫苗，这是患肺炎风险最高的人群 疾病，没有获得许可的Ng疫苗。我们已经开发出一种Nm血清B群(NMB)疫苗，其基础是 天然外膜囊泡(NOMV)具有遗传减弱的内毒素活性和过量的 表达突变的因子H结合蛋白(FHBP)，FH结合减少。对小鼠和婴儿都是如此 猕猴，该疫苗可诱导出更高的人类补体介导的血清杀菌抗体 (SBA)反应比获得许可的NMB疫苗更好。这种名为NOMV-FHBP的疫苗也引发了SBA对 在小鼠和幼年猕猴体内。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，一种超过 从A和B亚家族产生突变的FHBP和保守的Nm/Ng抗原会引起抗体 对所有年龄段的这两种病原体的疾病提供广泛的保护。在目标1中，我们将使用 一种工程启动子，可从A和B亚家族以及两个或更多个亚家族中过量生产突变的FHBP 高度保守的Ng抗原，可产生保护性抗体(NmNg-NOMV疫苗)。在目标2中，我们将 检测NmNg-NOMV在永生化鼻腔和原代鼻腔中的定植和侵袭能力 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 预防脑膜炎双球菌鼻腔感染转基因小鼠模型的定植和疾病症状 淋球菌阴道定植和脑膜炎及雌雄激素处理的转基因小鼠模型 殖民主义。防止殖民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”)。这个 总体目标是开发一个NOMV疫苗平台，用于表达保守的奈瑟菌 具有天然结构的抗原，可引起对这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.