Meningococcal serogroup B vaccine to prevent invasive disease and carriage

描述（由申请人提供）：脑膜炎奈瑟菌（Nm）是脑膜炎和败血症的主要原因。血清B组（NmB）菌株在不同人群中占侵袭性疾病的30%至80%。荚膜多糖蛋白结合疫苗可用于除NmB外的所有主要血清群，NmB与宿主抗原发生交叉反应。一种针对NmB菌株的蛋白抗原疫苗（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的NmB携带，这有助于政策制定者在英国初步决定不推荐常规疫苗接种。虽然大量数据表明糖结合疫苗既能预防侵袭性疾病，又能减少鼻咽定植，但在其潜在机制以及如何改进基于蛋白质的疫苗以更有效地减少携带方面，还存在重要的知识空白。我们的假设是，提高血清抗体的数量和质量（即亲和力、表位反应性的广度和功能活性）和/或靶向其他抗原，将增加NmB疫苗减少携带的能力。阻碍研究这些问题的主要挑战是，1)纳米对人类宿主的特异性，以及2)缺乏适当的体外和体内模型。例如，人CEACAM1特异性介导Nm对气道上皮细胞的粘附，人补体因子H （fH）特异性下调补体激活，允许脑膜炎球菌逃避人体内的细菌溶解。我们的实验室从具有遗传减毒内毒素和过表达因子H结合蛋白（fHbp）的突变体中开发了一种具有广泛保护作用的脑膜炎球菌天然外膜囊泡疫苗（NOMV）。数据表明，当在NOMV疫苗中过表达fHbp时，抗体对fHbp的反应质量高于重组fHbp疫苗。为了确定NOMV-fHbp免疫对携带的影响，并确定可能添加到疫苗中以减少携带的其他抗原，我们建议：1)建立体外呼吸道脑膜炎球菌定植模型，2)生成表达人CEACAM1和人fH的转基因小鼠定植模型，3)使用这些模型系统评估我们的NOMV-fHbp疫苗和新抗原阻止定植的能力。该结果将增加我们对疫苗接种减少脑膜炎球菌携带机制的理解，并将进一步开发具有广泛保护性的血清B群脑膜炎球菌疫苗，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.