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

新一代 B 群脑膜炎球菌疫苗，对所有年龄段的人群均具有更高的有效性

• 批准号: 10402320
• 负责人: Gregory Robert Moe
• 金额: $ 100万
• 依托单位: OMVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402320
• 关键词: 10 year old; Address; Adolescent; Adult; Affect; Africa; Amino Acid Sequence; Antibodies; Antibody Response; Antigens; Attenuated; Autoantibodies; Binding; Binding Proteins; Biological Assay; Child; Childhood Acute Lymphocytic Leukemia; Communities; Complement; Complement Factor H; Conjugate Vaccines; Data; Development; Disease; Disease Outbreaks; Effectiveness; Endotoxins; Epidemic; Epidemiology; Europe; Family; Formulation; Goals; Human; Immunization; Infant; Integration Host Factors; Licensure; Macaca; Manufacturer Name; Measures; Mediating; Membrane; Meningitis; Meningococcal meningitis; Meningococcal vaccine; Methods; Mus; Mutation; Neisseria meningitidis; Oryctolagus cuniculus; Phase; Phase I Clinical Trials; Polysaccharides; Predisposition; Preparation; Process; Production; Proteins; Recombinants; Research; Risk; Safety; Sepsis; Septicemia; Serogroup B Neisseria meningitidis; Serum; Structure; Technology; Teenagers; Testing; Toxicology; Vaccination; Vaccine Research; Vaccines; Variant; Vesicle; age group; analytical method; bactericide; base; capsule; clinical lot; college; human tissue; immunogenicity; improved; in vitro testing; mutant; next generation; novel vaccines; overexpression; phase 1 testing; preservation; prevent; prototype; response; stability testing; vaccine access; vaccine efficacy; vaccine immunogenicity; vaccine safety; young adult

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.

摘要 脑膜炎奈瑟菌是脑膜炎和败血症的主要原因。B群(MenB)菌株占 对于婴儿和青少年中的大多数侵袭性疾病病例以及几乎所有美国大学疫情。The MenB 胶囊与宿主抗原发生交叉反应，这阻止了基于胶囊的MenB结合物的形成 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 脑膜炎双球菌H因子结合蛋白(FHBP)，在美国被许可用于青少年和年轻人，但 不适用于婴幼儿，这是风险最大的年龄段。OMVax，Inc.正在开发一种改进的 MANB疫苗适用于所有年龄段，包括婴儿和幼儿。我们已经证明了主机的绑定 FHBP疫苗的补体因子H(FH)可降低保护性抗体反应， 接种许可的MenB疫苗的健康年轻人可以诱导出FH自身抗体，这可能是安全的 问题。OMVax疫苗使用专有的天然外膜囊泡(NOMV)技术， 保留天然结构的基因减毒内毒素，与过表达突变体FHBP相结合 与FH结合较低的抗原。在婴儿猕猴中，NOMV-FHBP疫苗的原型诱导了更大的 与许可的MenB相比，更广泛和更高的血清杀菌活性(SBA)效价反映了保护 与获得许可的疫苗不同，该疫苗不会产生抗FH自身抗体。OMVax疫苗还可以保护 对抗在非洲引起疫情的非B型病毒株。我们的假设是OMVax疫苗比 比目前许可的MenB疫苗更有效和更好的耐受性，它将减少鼻咽 并因此提供社区保护，这是当前MenB疫苗的一个关键限制。在目标1中，我们 将开发符合GMP标准的生产菌株(A或B亚家族各有一株FHBP过表达) 适合一期疫苗释放的分析方法的制备和开发 产品。我们将为小鼠的免疫原性研究、兔子的毒理学研究和 体外稳定性试验和小鼠效力试验。这些数据将允许编制SOP和批次 创纪录的生产出了大量适合第一阶段人体试验的疫苗。在目标2中，我们将确立 证明疫苗效力的人类补体SBA方法。菌株对抗FHBP SBA的敏感性 可以受到FHBP氨基酸序列和表达水平变化的影响，我们将开发 使用4至8株具有不同FHBP序列变体和 表达级别。这些检测将用于评估NOMV-FHBP研究批次在小鼠身上的免疫原性， 随后，对1期人血清进行符合GLP标准的检测。拟议中的研究将有助于预测 覆盖相关的MenB毒株，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群体，包括婴儿，对于 OMVax期望为所有年龄段提供更有效和更安全的MenB疫苗的许可。