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

甲型和乙型流感通用疫苗的研制 流感病毒每年造成广泛的死亡和发病。此外，流感的威胁 大流行仍在持续。目前获得季节性许可的疫苗要有效，流感病毒株在 配方应该与人类人口中流通的物质相匹配。不幸的是，做一个预测 未来可能在人类人群中传播的流感毒株中的一种并不是很可靠。作为一名 结果，这一预测中的错误可能会使疫苗无效。疫苗的这种不可靠是存在的 因为疫苗是基于一种最丰富的膜蛋白，称为血凝素，在 流感病毒浮出水面。因为血凝素从一种菌株变化到另一种菌株，合适的匹配 流行的流感病毒株和疫苗中的流感病毒株之间的关系很重要。此外，因为身份是 无法预测未来的大流行毒株，很难根据以下情况开发大流行流感疫苗 血凝素的头部区域作为抗原。 为了克服目前疫苗设计的局限性，我们建议使用高度保守的抗原。 研制一种流感疫苗。这些保守的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结构域被称为M2e，它一直存在 在人类甲型流感病毒株中高度保守。通过将共识人类M2e附着在金纳米颗粒上 表面上，我们对甲型H1N1和H3N2型流感病毒株有广泛的保护作用，甚至高度 致病性禽流感H5N1株。然而，疫苗只能部分保护人们免受高度 致病性甲型禽流感H7N9株。原因是M2E对禽流感和猪流感病毒株的影响 与人类流感病毒株M2e有一些不同。因此，我们建议将M2e纳入 人、禽流感和猪流感病毒株作为疫苗抗原将增加保护的广度。这个 第二个保守抗原是流感病毒神经氨酸酶膜蛋白的表位。这 A型和B型流感病毒株之间的表位是保守的。 我们假设，包括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：目标1： 开发多抗原疫苗配方，并建立其在Balb/c中的广泛性和长效性 老鼠。目的2：描述体液免疫和细胞免疫在保护机制中的作用 评估疫苗的生物分布和安全性。目标3：确定疫苗在雪貂身上的效力，以及 评价疫苗的热稳定性。通过这项研究设计的流感疫苗预计将具有 对公众健康产生广泛而重大的影响。如果成功，疫苗将对这两种疾病提供广泛的保护。 甲型和乙型流感病毒株，消除了季节性疫苗的需要，并显著减少了 由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.