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

甲型和B型流感通用疫苗的研制 流感病毒每年都会引起广泛的死亡和发病。此外，流感的威胁 大流行病继续存在。为了使目前获得许可的季节性疫苗有效， 制剂应与在人群中循环的制剂相匹配。不幸的是，预测 对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 结果，这种预测中的错误可能使疫苗无效。这种疫苗的不可靠性存在 因为疫苗是基于一种最丰富的膜蛋白，称为血凝素， 流感病毒表面。因为血凝素在不同菌株间会发生变化， 流感病毒株和疫苗中的流感病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 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 来配制流感疫苗。这些保守的抗原之一是来自离子通道膜蛋白 矩阵2（M2）暴露在病毒表面的M2结构域被称为M2 e，它仍然保留在病毒表面。 在人类甲型流感病毒株中高度保守。通过将共有人M2 e附着在金纳米颗粒上， 表面上，我们已经显示出对H1N1和H3 N2甲型流感病毒株的广泛保护，甚至高度 H5 N1型禽流感病毒。然而，该疫苗仅部分保护了高度免疫的人。 致病性禽流感A H7N9毒株。原因是禽流感和猪流感病毒株上的M2 e显示， 与人流感病毒株M2 e的一些不同。因此，我们建议， 以人类，禽流感及猪流感病毒株作为疫苗抗原，可增加保护范围。的 第二种保守抗原是来自流感病毒神经氨酸酶膜蛋白的表位。这 表位在甲型和B型流感病毒株中是保守的。 我们假设，包含M2 e和保守的神经氨酸酶表位将有助于 设计一种通用的流感疫苗，对各种毒株都有保护作用。我们的具体目标是：目标1： 开发多抗原疫苗制剂，并确定其在Balb/c中的保护广度和寿命 小鼠目的2：描述体液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。目的3：确定疫苗在雪貂中的效力， 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，疫苗将提供广泛的保护， 甲型和B型流感毒株，消除了对季节性疫苗的需求，并大大减少了 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.