A universal vaccine for the prevention of meningococcal meningitis in Africa

100多年来，撒哈拉以南非洲地区地方性脑膜炎双球菌疾病的发病率很高 以及周期性疫情，涉及10万多例病例。2010年，低成本的A组血清 在该地区引入了多糖-蛋白质结合疫苗(MenAfriVac)。疫苗可以提供 对A组(MENA)疾病和无症状鼻咽部MENA携带者的保护，但 对带有其他血清群的菌株没有影响，这些菌株也会导致该地区的流行病。多价血清群 A、C、Y和W结合疫苗在工业化国家可用，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由MenX引起的疾病 菌株，这也可能导致该地区的流行病。最近，两种基于NeisSeries因子的MenB疫苗 H结合蛋白(FHBP)已在美国和欧洲获得许可。FHBP专门结合人类或非人类 人类灵长类补体FH。我们正在开发一种新型的天然外膜囊泡(NOMV)疫苗 用基因减毒的内毒素和高表达的低FH结合突变体FHBP(NOMV-FHBP)。在……里面 一种非人类婴儿灵长类动物模型--具有两个氨基酸取代的突变型重组FHBP抗原 与与FH结合的对照FHBP疫苗相比，可引起更广泛的血清杀菌抗体反应。在……里面 人类FH转基因小鼠，我们的NOMV-FHBP疫苗比获得许可的多价疫苗提供了更广泛的保护 A、C、Y和W结合疫苗或诺华公司开发的含有结合FH的FHBP的MenB疫苗。 然而，FHBP随着属于A和B两个亚家族的蛋白质序列而变化。我们的原型NOMV- FHBP疫苗只含有B亚家族FHBP。我们的假设是，包括第二个子家族A FHBP 在NOMV-FHBP中，将产生一种针对FHBP亚家族A或B亚家族毒株的非洲“通用”疫苗，而 同时在全球范围内扩大对MenB菌株的覆盖范围。此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，用于预防脑膜炎双球菌疾病 总的来说，特别是在非洲。为了实现这一目标，在目标1中，我们将生产具有过量- FHBP在A、B亚家族中均有表达。免疫原性将在已建立的转基因中进行评估 表达人FH的(TG)小鼠模型及其在补体介导下诱导抗体的功能活性 血清杀菌分析(SBA)，这是一种已建立的与人类疾病预防相关的方法。在……里面 目的2，我们将在MenAfriVac成功的基础上，将其与新的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中东和北非病毒株，而 同时抑制来自其他血清群的新的致病菌株的出现。

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.