Novel Influenza nano vaccines for broad cross protection

摘要 流感是一项重大的公共卫生风险。目前的季节性流感疫苗对密切相关的人有效 与健康成年人的病毒相匹配，但它不能防止流行病或大流行的爆发，因为 流感病毒频繁变异，人畜共患病病毒株可以跨越物种障碍进入人类体内。其他 季节性流感疫苗的缺点包括每个季节都需要生产新的疫苗， 在选择疫苗毒株方面的不确定性，以及不匹配病毒的效力受损。一本小说 被称为通用流感疫苗的流感疫苗的产生将克服这些挑战。在 在之前的资助期间，我们已经从保存下来的HA茎中生产出了层状蛋白质纳米颗粒(纳米簇 甲型流感的抗原和M2蛋白的胞外结构域纳米簇免疫诱导的交叉保护 针对来自两个甲型流感系统发生组的病毒，包括可能发生大流行的禽类毒株。 甲型流感和乙型流感都会在人类中引起流感流行。在这项建议中，我们建议 构建由新设计的抗原蛋白组成的多价层状纳米簇制剂 甲型流感和乙型流感都是一种通用流感疫苗。新疫苗将导致广泛的交叉- 对两种流感类型的保护。我们有三个具体目标： 目的1.设计和构建甲型和乙型流感的保守抗原，制备纳米簇 从这些和以前设计的抗原蛋白，并表征这些新的纳米簇。我们 将优化这些纳米簇的编排、组成和稳定性，用于生理激活 树突状细胞摄取后游离抗原蛋白的释放、抗原的处理和递呈， 这些纳米簇分布到引流淋巴结，并诱导强烈的抗原特异性免疫 小鼠的反应。 目标2.测试这些层状纳米簇或最佳组合是否会导致广泛的 反应性免疫反应以及这种免疫是否会对病毒产生交叉保护 在小鼠身上同时感染甲型流感和乙型流感。 目的3.测试领先的多价纳米簇组合是否会诱导强大的免疫 赋予雪貂广泛交叉保护的反应。 总体而言，我们的研究将开发一种广泛交叉保护的通用流感疫苗。

SUMMARY Influenza is a major public health risk. The current seasonal influenza vaccine is effective against closely matched viruses in healthy adults, but it cannot prevent the outbreaks of epidemics or pandemics because influenza viruses mutate frequently and zoonotic strains can jump the species barrier into humans. Other disadvantages of the seasonal influenza vaccine include the need to produce new vaccines every season, the uncertainty in selecting vaccine strains, and the compromised efficacy for mismatched viruses. A novel generation of influenza vaccines, termed universal influenza vaccines, will overcome these challenges. In the previous grant period, we have produced layered protein nanoparticles (nanoclusters) from conserved HA stalk antigens and the M2 protein ectodomain of influenza A. Nanocluster immunizations induced cross protection against viruses from both phylogenic groups of influenza A, including pandemic-potential avian strains. Both influenza A and influenza B cause influenza epidemics in humans. In this proposal, we propose to construct a multivalent layered nanocluster formulation composed of newly designed antigenic proteins from both influenza A and influenza B as a universal influenza vaccine. The new vaccine will induce broad cross- protection against both influenza types. We have three specific aims: Aim 1. To design and construct conserved antigens from influenza A and B, fabricate nanoclusters from these and previously designed antigenic proteins, and characterize these new nanoclusters. We will optimize the orchestration, composition, and stability of these nanoclusters for the physiologically-activated release of free antigenic proteins, antigen-processing and presentation after the uptake by dendritic cells, distribution of these nanoclusters to draining lymph nodes, and induction of strong antigen-specific immune responses in mice. Aim 2. To test whether these layered nanoclusters or an optimal combination will induce broadly reactive immune responses and whether the immunity will grant cross-protection against viruses spanning both influenza A and influenza B in mice. Aim 3. To test whether the leading multivalent nanocluster combinations will induce robust immune responses which confer broad cross-protection in ferrets. Overall, our research will develop a broadly cross-protective universal influenza vaccine.