Development of a Universal Influenza Vaccine Against Influenza A and B Viruses

开发针对甲型和乙型流感病毒的通用流感疫苗 流感病毒每年都会导致广泛的死亡和发病。此外，流感的威胁 疫情持续持续。为了使当前季节性许可的疫苗对流感毒株有效 配方应与人群中流通的配方相匹配。不幸的是，做出了预测 未来可能在人群中传播的流感毒株的预测并不十分可靠。作为一个 结果，预测错误可能导致疫苗失效。疫苗存在这种不可靠性 因为该疫苗基于一种最丰富的膜蛋白，称为血凝素， 流感病毒表面。由于血凝素从一种菌株到另一种菌株都会发生变化，因此适当的匹配 流行的流感毒株与疫苗中的流感毒株之间的差异很重要。此外，由于身份 未来的大流行毒株无法预测，因此很难根据其开发针对大流行流感的疫苗 血凝素的头部区域作为抗原。 为了克服当前疫苗设计的局限性，我们建议使用高度保守的抗原 研制流感疫苗。这些保守抗原之一来自离子通道膜蛋白 称为矩阵 2 (M2)。暴露在病毒表面的M2结构域称为M2e，保留了下来 在人类甲型流感病毒株中高度保守。通过将共有的人类 M2e 附着在金纳米颗粒上 从表面上看，我们已经显示出针对 H1N1 和 H3N2 甲型流感病毒株的广泛保护作用，甚至是高度 致病性禽流感病毒株 H5N1。然而，该疫苗只能部分预防高度感染 致病性甲型禽流感 H7N9 株。原因是禽流感和猪流感病毒株上的 M2e 显示 与人类流感病毒株的 M2e 有一些不同之处。因此，我们建议将 M2e 纳入 人、禽和猪流感毒株作为疫苗抗原将增加保护的广度。的 第二个保守抗原是来自流感病毒神经氨酸酶膜蛋白的表位。这个 表位在甲型和乙型流感病毒株中是保守的。 我们假设同时包含 M2e 和保守的神经氨酸酶表位将有助于 设计一种针对多种毒株的通用流感疫苗。我们的具体目标是： AIM 1： 开发多抗原疫苗配方，并在 Balb/c 中确定其保护的广度和寿命 老鼠。目标 2：表征体液和细胞免疫在保护机制中的作用，以及 评估疫苗的生物分布和安全性。目标 3：确定雪貂疫苗的功效，以及 评估疫苗的热稳定性。通过这项研究设计的流感疫苗预计将具有 对公共卫生产生广泛而重大的影响。如果成功，该疫苗将针对这两种疾病提供广泛的保护 甲型和乙型流感病毒株，消除了对季节性疫苗的需求，并显着减少了流感的威胁 流感病毒引起的大流行。

Development of a Universal Influenza Vaccine Against Influenza A and B Viruses Influenza virus causes widespread mortality and morbidity every year. In addition, the threat of an influenza pandemic continues to persist. For current seasonal licensed vaccines to be effective the influenza strain in the formulation should match that which is circulating in the human population. Unfortunately, making a prediction of the influenza strains that are likely to circulate in the human population in the future is not very reliable. As a result, an error in this prediction can make the vaccine ineffective. This unreliability of the vaccine exists because the vaccine is based on one of the most abundant membrane proteins called hemagglutinin found on the influenza virus surface. Because hemagglutinin changes from one strain to the next, a proper match between circulating influenza strains and that in the vaccine is important. Furthermore, because the identity of a future pandemic strain cannot be predicted, it is hard to develop a vaccine for pandemic influenza based on hemagglutinin's head region as an antigen. To overcome the limitation of the current vaccine design we propose to use highly conserved antigens to formulate an influenza vaccine. One of these conserved antigens is from the ion channel membrane protein called matrix 2 (M2). The domain of M2 exposed on the surface of the virus is called M2e, and it has remained highly conserved in human influenza A strains. By attaching consensus human M2e on the gold nanoparticle surface we have shown breadth of protection against H1N1 and H3N2 influenza A strains, and even the highly pathogenic avian influenza strain H5N1. The vaccine was however only partially protective against the highly pathogenic avian influenza A H7N9 strain. The reason is that M2e on avian and swine influenza strains shows some dissimilarity from M2e of human influenza strains. Therefore, we propose that inclusion of M2e of human, avian and swine influenza strains as the vaccine antigen will increase the breadth of protection. The second conserved antigen is an epitope from the neuraminidase membrane protein of the influenza virus. This epitope is conserved across influenza A and B strains. We hypothesize that inclusion of both M2e and the conserved neuraminidase epitope will help to design a universal influenza vaccine protective against a broad range of strains. Our specific aims are: AIM 1: Develop the multi-antigen vaccine formulation, and establish its breadth and longevity of protection in Balb/c mice. AIM 2: Characterize the role of humoral and cellular immunity in the mechanism of protection, and assess biodistribution and safety profile of the vaccine. AIM 3: Establish vaccine efficacy in ferrets, and evaluate vaccine thermal stability. The influenza vaccine designed through this research is expected to have a broad and significant impact on public health. If successful, the vaccine will offer broad protection against both influenza A and B strains, eliminating the need for seasonal vaccines, and significantly reducing the threat of pandemic outbreaks due to influenza virus.