Universal T cell targeted influenza vaccine

描述(申请人提供)：流感每年在世界范围内造成严重的发病率和死亡率，当新的毒株演变成以前没有在人类中传播的病毒时，它会导致严重的大流行。病毒的高变异率要求每年根据流行毒株的流行情况生产新的疫苗。这些重新配制的流感疫苗并不总是具有保护性的--疾控中心估计流感疫苗的效力为70%-90%，但前提是它必须与正在传播的病毒很好地匹配。 目前迫切需要能够诱导更大毒株交叉保护免疫的流感疫苗，但尚未得到满足。我们推测，能够诱导针对保守的内部病毒蛋白的T细胞反应的疫苗可以提供更广泛的保护性流感免疫。因此，我们建议利用广泛反应的流感特异性T细胞表位的免疫原性潜力来生产具有普遍意义的疫苗。完成本申请中的以下特定目标将提供概念证明，即旨在刺激人类T细胞反应的基于T细胞的疫苗可以诱导广泛的异型保护性免疫，并为开发以T细胞为重点的疫苗以补充现有的B细胞疫苗奠定了坚实的基础。目的1：免疫信息学鉴定流感病毒核蛋白和基质蛋白中高度保守的、具有免疫原性共识的CD4和CD8表位。目的2：构建包含“普遍”相关的CD4和CD8T细胞表位的新型DNA和蛋白质流感疫苗。目的：评价新型“普遍相关”T细胞靶向流感疫苗对HLADR1/A2小鼠的免疫原性和免疫保护作用。这项拟议的工作可以为流感疫苗的开发提供重要的新产品和方向，重点是诱导广泛保护性T细胞反应的范式转换概念。

DESCRIPTION (provided by applicant): Influenza is responsible for significant morbidity and mortality worldwide every year and causes severe pandemics when new strains evolve that have not previously circulated in humans. The high viral mutation rate necessitates new vaccines be generated based on the prevalence of circulating strains every year. These reformulated versions of influenza vaccine are not always protective--the CDC estimates the influenza vaccine efficacy to be 70-90%, but only when it is well matched to the circulating virus. There is an urgent unmet need for influenza vaccines that induce greater strain cross-protective immunity. We hypothesize that vaccines capable of inducing T cell responses directed against conserved internal viral proteins could provide more broadly protective influenza immunity. Thus, we propose to harness the immunogenic potential of broadly reactive influenza-specific T cell epitopes to produce vaccines with universal significance. Completion of the following specific aims in this application will provide proof-of-concept that T cell-based vaccines designed to stimulate human T cell responses can induce broadly heterotypic protective immunity, as well as a strong basis for development of a T cell focused vaccine to complement existing B-cell focused vaccines. Aim 1: Immunoinformatic identification of highly conserved, HLA immunogenic consensus CD4 and CD8 epitopes in influenza NP and matrix proteins. Aim 2: Construction of new DNA and protein influenza vaccines containing "universally" relevant CD4 and CD8 T cell epitopes. Aim 3: Evaluation of immunogenicity and protection induced by new "universally" relevant T cell targeting influenza vaccines in HLA-DR1/A2 mice. The proposed work can provide important new products and direction for influenza vaccine development, focusing on a paradigm-shifting concept of inducing broadly protective T cell responses.