A next-generation meningococcal serogroup B vaccine with improved effectiveness for all age groups

摘要 脑膜炎奈瑟菌是脑膜炎和败血症的主要原因。血清群B（MenB）菌株占 大多数婴儿和青少年的侵袭性疾病病例以及几乎所有美国大学爆发的病例。则MenB 胶囊与宿主抗原交叉反应，这妨碍了基于胶囊的MenB缀合物的开发 疫苗两家制造商开发了针对蛋白质抗原的MenB疫苗。两者都含有重组 脑膜炎球菌H因子结合蛋白（FHbp），并在美国被许可用于青少年和年轻人， 不适用于婴儿和幼儿，这是风险最大的年龄组。OMVax公司正在开发一种改进的 MenB疫苗适用于所有年龄组，包括婴儿和幼儿。我们已经证明， FHbp疫苗的补体因子H（FH）降低了保护性抗体应答， 健康的年轻人接种许可的MenB疫苗可以引发FH的自身抗体，这可能会带来安全性 问题. OMVax疫苗使用专有的天然外膜囊泡（NOMV）技术， 基因减毒的内毒素，保留天然结构，与过表达的突变型FHbp结合 与FH结合低的抗原。在幼年猕猴中，原型NOMV-FHbp疫苗引起了更大的 通过比许可的MenB更广泛和更高的血清杀菌活性（SBA）滴度反映的保护 与许可的疫苗不同，它不会引发抗FH自身抗体。OMVax疫苗还可以保护 对抗在非洲引起流行病的非乙型病毒株。我们的假设是OMVax疫苗 比目前许可的MenB疫苗更有效，耐受性更好， 定殖，从而提供社区保护，这是当前MenB疫苗的关键限制。在目标1中， 将开发符合GMP要求的生产菌株（分别具有来自亚家族A或B的过表达FHbp） 适用于1期疫苗放行的工艺和处方以及分析方法的开发 产品我们将表征研究疫苗批次，用于小鼠免疫原性研究、兔毒理学研究和 体外稳定性测试和小鼠效力测定。这些数据将允许编写SOP和批次 记录生产，以生产大量适用于1期人体试验的疫苗。在目标2中，我们将建立 用于证明疫苗效力的人补体SBA方法。菌株对抗FHbp SBA的敏感性 FHbp的氨基酸序列和表达水平的变化可能会影响，我们将开发 使用4至8种具有不同FHbp序列变体的流行病学相关MenB菌株的测定， 表达水平。该试验将用于评估NOMV-FHbp研究批次在小鼠中的免疫原性， 随后，用于1期人血清的GLP合规性检测。这项研究将有助于预测 相关MenB毒株的覆盖率，并使NOMV-FHbp能够在 健康的成年人，以及随后的青少年和更年轻的年龄组，包括婴儿， OMVax预计将为所有年龄组提供更有效，更安全的MenB疫苗。

Abstract Neisseria meningitidis is a major cause of meningitis and septicemia. Serogroup B (MenB) strains account for most cases of invasive disease in infants and teenagers and nearly all U.S. college outbreaks. The MenB capsule cross-reacts with host antigens, which precluded development of a capsular-based MenB conjugate vaccine. Two manufacturers developed MenB vaccines that target protein antigens. Both contain recombinant meningococcal Factor H binding protein (FHbp) and are licensed in the U.S. for teenagers and young adults but not for infants and young children, the age groups at greatest risk. OMVax, Inc. is developing an improved MenB vaccine for all age groups, including infants and young children. We have shown that binding of host complement Factor H (FH) to FHbp vaccines decreases protective antibody responses and that immunization of healthy young adults with a licensed MenB vaccine can elicit autoantibodies to FH, which may pose safety issues. The OMVax vaccine uses proprietary native outer membrane vesicle (NOMV) technology with genetically attenuated endotoxin that preserves native structures, combined with over-expressed mutant FHbp antigens with low binding to FH. In infant macaques, a prototype NOMV-FHbp vaccine elicited greater protection as reflected by broader and higher serum bactericidal activity (SBA) titers than a licensed MenB vaccine and, unlike the licensed vaccine, did not elicit anti-FH autoantibodies. The OMVax vaccine also protects against non-B strains causing epidemics in Africa. Our hypotheses are that the OMVax vaccine is more effective and better tolerated than currently licensed MenB vaccines and that it will decrease nasopharyngeal colonization and thereby provide community protection, a key limitation of current MenB vaccines. In Aim 1 we will develop production strains (one each with over-expressed FHbp from sub-family A or B) for GMP-compliant process and formulation and development of analytical methods suitable for release of Phase 1 vaccine product. We will characterize research vaccine lots for immunogenicity studies in mice, toxicology in rabbits and stability testing in vitro and with mouse potency assays. The data will allow preparation of SOPs and batch record production to produce a lot of vaccine suitable for Phase 1 human testing. In Aim 2, we will establish human complement SBA methods for demonstrating vaccine efficacy. Strain susceptibility to anti-FHbp SBA can be affected by variations in both FHbp amino acid sequence and level of expression, and we will develop assays using 4 to 8 epidemiologically relevant MenB strains with different FHbp sequence variants and expression levels. The assays will be used to assess immunogenicity of NOMV-FHbp research lots in mice and, subsequently, for GLP-compliant testing of Phase 1 human sera. The proposed studies will help predict coverage of relevant MenB strains and enable NOMV-FHbp to undergo safety and immunogenicity testing in healthy adults and, subsequently, in adolescents and younger age groups, including infants, necessary for licensure of what OMVax anticipates to be a more effective and safer MenB vaccine for all age groups.