Meningococcal serogroup B vaccine to prevent invasive disease and carriage

描述（由申请方提供）：脑膜炎奈瑟菌（Nm）是脑膜炎和败血症的主要原因。血清群B（Nm B）菌株占不同人群中侵袭性疾病的30%至80%。除了与宿主抗原交叉反应的NmB外，可获得针对所有主要血清群的荚膜多糖-蛋白质缀合物疫苗。一种靶向NmB毒株的基于蛋白抗原的疫苗（称为4CMenB）最近在欧洲获得许可。然而，4CMenB疫苗接种未能减少无症状NmB携带，这有助于政策制定者初步决定不建议在英国进行常规疫苗接种。虽然相当多的数据表明，糖缀合物疫苗预防侵袭性疾病和减少鼻咽定植，有重要的知识差距的基本机制，以及如何蛋白质为基础的疫苗可以改进，以减少更有效地携带。我们的假设是，提高血清抗体的数量和质量（即亲合力、表位反应性的宽度和功能活性）和/或靶向其他抗原，将提高NmB疫苗减少携带的能力。阻碍这些问题研究的主要挑战是，1）Nm对人类宿主的特异性，和2）缺乏适当的体外和体内模型。例如，人CEACAM 1特异性地介导Nm与气道上皮细胞的粘附，而人补体因子H（fH）特异性地下调补体激活并允许脑膜炎球菌逃避人体内的细菌溶解。我们的实验室已经开发了一种广泛的保护脑膜炎球菌天然外膜囊泡疫苗（NOMV）的突变体与遗传减毒内毒素和过表达的因子H结合蛋白（fHbp）。数据表明，当在NOMV疫苗中过表达时，对fHbp的抗体应答的质量大于对重组fHbp疫苗的抗体应答的质量。为了确定NOMV-fHbp免疫接种对携带的影响，并鉴定可能添加到疫苗中以减少携带的其他抗原，我们建议：1）开发脑膜炎球菌定殖的体外气道模型，2）产生表达人CEACAM 1和人fH两者的人定殖的转基因小鼠模型，和3）使用这些模型系统来评估我们的NOMV-fHbp疫苗和新抗原防止定殖的能力。这些结果将增加我们对接种疫苗减少脑膜炎球菌携带的机制的理解，并将进一步开发一种广泛保护的血清群B脑膜炎球菌疫苗，以预防侵袭性疾病和无症状携带。

DESCRIPTION (provided by applicant): Neisseria meningitidis (Nm) is a major cause of meningitis and septicemia. Serogroup B (NmB) strains account for 30 to 80 percent of invasive disease in different populations. Capsular polysaccharide-protein conjugate vaccines are available against all of the major serogroups except for NmB, which cross-reacts with host antigens. A protein antigen-based vaccine (referred to as 4CMenB) that targets NmB strains recently was licensed in Europe. However, failure of 4CMenB vaccination to decrease asymptomatic NmB carriage was instrumental in a preliminary decision by policy makers not to recommend routine vaccination in the UK. While considerable data indicate that glycoconjugate vaccines prevent both invasive disease and decrease nasopharyngeal colonization, there are important gaps in knowledge about the underlying mechanisms, and how protein-based vaccines can be improved to decrease carriage more effectively. Our hypotheses are that improving serum antibody quantity and quality (i.e, avidity, breadth of epitope reactivity, and functional activity) and/or targeting additional antigens, will increase the ability of NmB vaccine to decrease carriage. The major challenges that impede investigation of these questions are, 1) the specificity of Nm for the human host, and 2) the lack of appropriate in vitro and in vivo models. For example, human CEACAM1 specifically mediates adhesion of Nm to airway epithelial cells, and human complement factor H (fH) specifically down-regulates complement activation and permits meningococci to evade bacteriolysis in humans. Our laboratory has developed a broadly protective meningococcal native outer membrane vesicle vaccine (NOMV) from mutants with genetically attenuated endotoxin and over-expressed factor H binding protein (fHbp). Data indicate that the quality of the antibody responses to fHbp when over-expressed in an NOMV vaccine is greater than to recombinant fHbp vaccines. To determine the effect of NOMV-fHbp immunization on carriage, and to identify additional antigens that might be added to the vaccine to decrease carriage, we propose to: 1) develop in vitro airway models of meningococcal colonization, 2) generate a transgenic mouse model of human colonization that expresses both human CEACAM1 and human fH, and 3) use these model systems to evaluate the ability our NOMV-fHbp vaccine and new antigens to prevent colonization. The results will increase our understanding of the mechanisms by which vaccination decreases meningococcal carriage, and will further development of a broadly protective serogroup B meningococcal vaccine that prevents both invasive disease and asymptomatic carriage.