Toward a universal influenza virus vaccine based on live attenuated NS1-deleted influenza viruses

流感病毒继续对全球公共卫生构成重大威胁。因此，有一个至关重要的 需要产生新的流感病毒疫苗和创新的疫苗接种战略。这个 开发一种长效、广谱保护的流感病毒疫苗将对 世界范围内控制流感病毒的努力。此应用程序的目的是加速开发 通过临床前开发以下两种主要候选成分来开发通用流感病毒疫苗 这样的疫苗。自从我们最初发现流感疫苗的序贯免疫是基于 嵌合体在动物模型中对不同的流感病毒株具有广泛的保护作用，我们有 进入第一阶段临床试验，调查灭活疫苗的安全性和免疫原性 含嵌合组1的佐剂和冷适应甲型流感减毒活疫苗 流感病毒已经。这种疫苗在小鼠、雪貂和猪中诱导针对所有第1组的保护性免疫。 甲型流感病毒，包括H1、H2和H5病毒。保护与诱导高水平的 针对保守的第1组HA茎产生交叉反应的Fc受体结合抗体。如果这些中的任何一个 疫苗接种策略在人类中是成功的，加上2组甲型流感和乙型流感嵌合体 会对任何类型、亚型和毒株的流感病毒产生保护作用。这种“万能流感疫苗” 将消除每年接种流感病毒疫苗的需要，并防止未来的流感大流行。在 目前的应用我们建议生成GMP临床批次和IND使能信息，以便随后 使用表达嵌合Has的高免疫原性疫苗平台进行人体临床试验 减毒活的delNS1流感病毒。与冷适应流感疫苗不同，delNS1流感 由于去除了免疫拮抗基因NS1，疫苗具有高度的免疫刺激作用。对于 这笔赠款的目的是，我们西奈山伊坎医学院的团队率先使用了 CHIMERIC致力于普及流感病毒疫苗，并与生物技术公司Vivaldi合作 这使得基于delNS1的流感病毒疫苗正在临床开发中。在我们的提案结束时，我们 将产生两批基于delNS1的GMP第一组嵌合甲型流感病毒疫苗准备就绪 用于临床研究。这些批次将在#年完成序贯免疫拨款后使用。 人类获得其安全性和免疫原性概况。此外，我们预计人类流感病毒 接种灭活、冷适应和基于delNS1的嵌合HA疫苗后的挑战研究将 将疫苗平台在这三种平台之间进行区分，从而产生最佳保护水平。最好的平台是 作为进一步临床开发和纳入1组、2组和B型流感的基础 嵌合体必须预防所有可能的流感病毒。

Influenza viruses continue to pose a significant threat to global public health. Consequently, there is a vitally important need to generate new influenza virus vaccines and innovative vaccination strategies. The development of a long-lived broadly-protective influenza virus vaccine would have a tremendous impact on worldwide efforts to control influenza viruses. The purpose of this application is to accelerate the development of a universal influenza virus vaccine through the preclinical development of two lead candidate components of such a vaccine. Since our initial discovery that sequential immunization with influenza vaccines based on chimeric HAs induce broad protection against diverse influenza virus strains in animal models, we have moved into Phase 1 clinical trials that investigate the safety and immunogenicity of inactivated adjuvanted and cold-adapted live attenuated influenza A virus vaccines containing chimeric group 1 influenza virus HAs. Such vaccines induce protective immunity in mice, ferrets and pigs against all group 1 influenza A virus, including H1, H2 and H5 viruses. Protection correlates with the induction of high levels of cross-reactive Fc-receptor engaging antibodies against the conserved group 1 HA stalk. If any of these vaccination strategies are successful in humans, addition of group 2 influenza A and influenza B chimeric HAs would result in protection against any type, subtype and strain of influenza virus. This “universal flu vaccine” would eliminate the need for annual influenza virus vaccination and prevent future influenza pandemics. In the current application we propose to generate GMP clinical lots and IND-enabling information to subsequently perform human clinical trials with a highly immunogenic vaccine platform expressing chimeric HAs based on live attenuated delNS1 influenza viruses. In contrast to the cold-adapted influenza vaccines, delNS1 influenza vaccines are highly immunostimulatory due to the removal of the immune antagonist gene NS1. For the purpose of this grant, our group at Icahn School of Medicine at Mount Sinai, which pioneered the use of chimeric HAs for universal influenza virus vaccination, has partnered with Vivaldi, a biotechnology company that has delNS1-based influenza virus vaccines under clinical development. At the end of our proposal, we will have generated two GMP lots of delNS1-based group 1 chimeric HA influenza virus vaccines ready for clinical investigation. These lots will be used after completion of our grant for sequential immunizations in humans to obtain their safety and immunogenicity profiles. Moreover, we anticipate that human influenza virus challenge studies after vaccination with inactivated, cold-adapted and delNS1-based chimeric HA vaccines will differentiate the vaccine platform among these three resulting in best levels of protection. The best platform will be used as the basis for further clinical development and incorporation of group 1, group 2 and influenza B chimeric HAs to protect against all possible influenza viruses.