A universal vaccine for the prevention of meningococcal meningitis in Africa

用于预防非洲流行性脑膜炎球菌性脑膜炎的通用疫苗

• 批准号: 9198719
• 负责人: Gregory Robert Moe
• 金额: $ 30万
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198719
• 关键词: Africa; Africa South of the Sahara; African; Aluminum; Amino Acid Sequence; Amino Acid Substitution; Antibodies; Antibody Response; Antigens; Attenuated; Binding; Binding Proteins; Biological Assay; Businesses; Carrier Proteins; Cessation of life; Clinical Trials; Combined Vaccines; Complement; Complement Factor H; Conjugate Vaccines; Country; Developed Countries; Disease; Dose; Endemic Diseases; Endotoxins; Engineering; Ensure; Epidemic; Epitopes; Europe; Familial Mediterranean Fever; Family; Future; Goals; Human; India; Infant; Institutes; Lead; Length; Licensing; Licensure; Measures; Mediating; Membrane; Meningococcal meningitis; Meningococcal vaccine; Modeling; Mus; Nigeria; Peptide Sequence Determination; Phase; Polysaccharides; Prevention; Primates; Production; Proteins; Recombinants; Sahara; Salts; Serum; Small Business Technology Transfer Research; Source; Testing; Time; Transgenic Mice; Vaccine Antigen; Vaccines; Variant; Vesicle; bactericide; base; commercialization; cost; falls; global health; immunogenicity; mouse model; mutant; nonhuman primate; novel; prevent; prototype; reconstitution; success; vaccine evaluation

For more than 100 years, sub-Saharan Africa has suffered with high rates of endemic meningococcal disease and periodic epidemic epidemics involving over 100,000 cases. In 2010, a low cost serogroup A polysaccharide-protein conjugate vaccine (MenAfriVac) was introduced in the region. The vaccine confers protection against serogroup A (MenA) disease as well as asymptomatic nasopharyngeal MenA carriage, but has no effect on strains with other serogroups that also cause epidemics in the region. Multivalent serogroup A,C,Y and W conjugate vaccines are available in industrialized countries but are not affordable in Sub-Sahara, which is one of the poorest regions of the world. These vaccines also do not prevent disease from MenX strains, which also can cause epidemics in the region. Recently, two MenB vaccines based on Neisserial factor H binding protein (FHbp) have been licensed in the US and Europe. FHbp specifically binds human or non- human primate complement FH. We are developing a novel native outer membrane vesicle (NOMV) vaccine with genetically attenuated endotoxin and over-expressed mutant FHbp with low FH binding (NOMV-FHbp). In a non-human infant primate model, a mutant recombinant FHbp antigen with two amino acid substitutions elicited broader serum bactericidal antibody responses than the control FHbp vaccine that bound FH. In human FH transgenic mice, our NOMV-FHbp vaccine provided broader protection than a licensed multivalent A,C,Y and W conjugate vaccine or the MenB vaccine developed by Novartis that contains FHbp that binds FH. However, FHbp is variable with protein sequences falling into two sub-families, A and B. Our prototype NOMV- FHbp vaccine only contained sub-family B FHbp. Our hypothesis is that including a second sub-family A FHbp in NOMV-FHbp will result in a “universal” vaccine for Africa against strains with FHbp sub-family A or B, while at the same time expanding coverage against MenB strains worldwide. The goal of this Phase I proposal is to produce a safe, broadly protective, affordable vaccine for use in preventing meningococcal disease generally and in Africa specifically. To accomplish this goal, in Aim 1, we will produce NOMV with over- expressed FHbp from both A and B sub-families. Immunogenicity will be evaluated in established transgenic (Tg) mouse models expressing human FH and functional activity of elicited antibodies in complement-mediated serum bactericidal assays (SBA), which is an established correlate of protection against disease in humans. In Aim 2, we will build upon the success of MenAfriVac by combining it with the new NOMV-FHbp A+B vaccine. The combined vaccine has the potential to ensure coverage against all of the predominant MenA strains while at the same time suppressing the emergence of new pathogenic strains from other serogroups.

100 多年来，撒哈拉以南非洲地区流行性脑膜炎球菌病的发病率很高 周期性流行病病例数超过10万例。 2010年，低成本血清群A 该地区推出了多糖蛋白结合疫苗（MenAfriVac）。该疫苗赋予 预防血清群 A (MenA) 疾病以及无症状鼻咽部 MenA 携带，但是 对在该地区也引起流行的其他血清群的菌株没有影响。多价血清群 A、C、Y 和 W 结合疫苗在工业化国家有售，但在撒哈拉以南地区却买不起。 这是世界上最贫穷的地区之一。这些疫苗也不能预防 MenX 疾病 菌株，这也可能在该地区引起流行病。最近，两种基于奈瑟氏球菌因子的 MenB 疫苗 H 结合蛋白 (FHbp) 已在美国和欧洲获得许可。 FHbp 特异性结合人类或非 人灵长类补体 FH。我们正在开发一种新型天然外膜囊泡 (NOMV) 疫苗 具有基因减毒内毒素和过表达具有低 FH 结合的突变体 FHbp (NOMV-FHbp)。在 非人类婴儿灵长类动物模型，具有两个氨基酸取代的突变重组 FHbp 抗原 比结合 FH 的对照 FHbp 疫苗引起更广泛的血清杀菌抗体反应。在 人类 FH 转基因小鼠，我们的 NOMV-FHbp 疫苗比许可的多价疫苗提供更广泛的保护 A、C、Y 和 W 结合疫苗或诺华公司开发的 MenB 疫苗含有结合 FH 的 FHbp。 然而，FHbp 是可变的，蛋白质序列分为两个亚家族，A 和 B。我们的原型 NOMV- FHbp 疫苗仅包含 B 亚科 FHbp。我们的假设是，包括第二个亚科 A FHbp NOMV-FHbp 将为非洲带来针对 FHbp 亚家族 A 或 B 菌株的“通用”疫苗，同时 同时扩大全球范围内针对 MenB 菌株的覆盖范围。第一阶段提案的目标是 生产安全、具有广泛保护性、负担得起的疫苗，用于预防脑膜炎球菌病 一般而言，特别是在非洲。为了实现这一目标，在目标 1 中，我们将生产具有超 A 和 B 亚家族均表达 FHbp。将在已建立的转基因中评估免疫原性 (Tg) 表达人 FH 的小鼠模型以及补体介导的引发抗体的功能活性 血清杀菌测定（SBA），这是人类预防疾病的既定相关性。在 目标 2，我们将在 MenAfriVac 成功的基础上，将其与新型 NOMV-FHbp A+B 疫苗相结合。 联合疫苗有可能确保覆盖所有主要的 MenA 毒株，同时 同时抑制其他血清群新致病菌株的出现。