Universal T cell targeted influenza vaccine

描述（由申请方提供）：流感每年在全球范围内造成显著的发病率和死亡率，当出现以前未在人类中传播的新菌株时，会导致严重的大流行。高病毒突变率需要根据每年流行的病毒株来生产新疫苗。这些重新配制的流感疫苗并不总是具有保护作用-CDC估计流感疫苗的有效性为70- 90%，但只有当它与流行病毒很好地匹配时。 对于诱导更强毒株交叉保护性免疫的流感疫苗存在迫切的未满足的需求。我们假设，能够诱导针对保守的内部病毒蛋白的T细胞应答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性流感特异性T细胞表位的免疫原性潜力来生产具有普遍意义的疫苗。本申请中以下具体目标的完成将提供设计用于刺激人T细胞应答的基于T细胞的疫苗可诱导广泛异型保护性免疫的概念验证，以及开发T细胞聚焦疫苗以补充现有B细胞聚焦疫苗的强有力基础。目的1：流感病毒NP和基质蛋白中高度保守的HLA免疫原性共有CD 4和CD 8表位的免疫信息学鉴定。目的2：构建含有“普遍”相关的CD 4和CD 8 T细胞表位的新型流感DNA和蛋白疫苗。目的3：评价新的“普遍”相关的T细胞靶向流感疫苗在HLA-DR 1/A2小鼠中诱导的免疫原性和保护性。拟议的工作可以为流感疫苗开发提供重要的新产品和方向，重点是诱导广泛保护性T细胞反应的范式转变概念。

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.