A universal vaccine for the prevention of meningococcal meningitis in Africa

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一直很高 以及10万例以上的周期性流行病。2010年，一种低成本血清型A 在该地区引进了多糖-蛋白质结合疫苗（MenAfriVac）。该疫苗使 预防血清组A（MenA）疾病以及无症状的鼻咽MenA携带，但 对在该地区引起流行病的其他血清群菌株没有影响。多价血清群 A、C、Y和W结合疫苗可在工业化国家获得，但在撒哈拉以南地区负担不起， 这是世界上最贫穷的地区之一。这些疫苗也不能预防MenX的疾病 菌株，这也可能导致该地区的流行病。最近，两种基于奈瑟菌因子的MenB疫苗， H结合蛋白（FHbp）已在美国和欧洲获得许可。FHbp特异性结合人或非人 人灵长类补体FH。我们正在开发一种新的天然外膜囊泡（NOMV）疫苗 用遗传减毒的内毒素和具有低FH结合的过表达突变体FHbp（NOMV-FHbp）。在 非人幼年灵长类动物模型，具有两个氨基酸取代的突变型重组FHbp抗原 引起比结合FH的对照FHbp疫苗更广泛的血清杀菌抗体应答。在 在人FH转基因小鼠中，我们的NOMV-FHbp疫苗提供了比许可的多价疫苗更广泛的保护。 A、C、Y和W结合疫苗或诺华开发的MenB疫苗，含有与FH结合的FHbp。 然而，FHbp是可变的，其蛋白质序列落入两个亚家族A和B。我们的原型NOMV- FHbp疫苗仅含有B亚家族FHbp。我们的假设是，包括第二个亚家族A FHbp 在NOMV-FHbp中，将产生针对具有FHbp亚家族A或B的菌株的非洲“通用”疫苗，而 与此同时，在全球范围内扩大对MenB菌株的覆盖范围。第一阶段提案的目标是 生产一种安全、广泛保护、负担得起的疫苗，用于预防脑膜炎球菌病， 特别是在非洲。为了实现这一目标，在目标1中，我们将生产NOMV， 表达来自A和B亚家族的FHbp。将在已建立的转基因动物中评价免疫原性。 (Tg)表达人FH的小鼠模型和在补体介导的免疫应答中引发的抗体的功能活性 血清杀菌测定（SBA），其是针对人类疾病的保护的确定相关物。在 目标2，我们将通过将MenAfriVac与新的NOMV-FHbp A+B疫苗组合来建立MenAfriVac的成功。 联合疫苗有可能确保覆盖所有主要的MenA毒株， 同时抑制来自其它血清群的新致病菌株的出现。

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.