Universal T cell targeted influenza vaccine

描述（由申请人提供）：流感每年在世界范围内造成显著的发病率和死亡率，并且当出现以前未在人类中传播的新毒株时，会导致严重的大流行。由于病毒的高突变率，必须根据每年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作用——疾病预防控制中心估计流感疫苗的效力为70-90%，但只有当它与流行的病毒很好地匹配时才有效。

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.