Universal T cell targeted influenza vaccine

通用 T 细胞靶向流感疫苗

基本信息

批准号：
10469008
负责人：
Daniel F. Hoft
金额：
$ 74.13万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469008
关键词：
Adenoviruses Adjuvant Alleles Alphavirus Antigens B-Lymphocytes Baculoviruses Biological Assay CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Codon Nucleotides Collaborations Consensus Sequence DNA DR1 gene Effector Cell Encapsulated Epidemic Epitopes Funding Generations Genome Goals HLA-A2 Antigen HLA-DR Antigens HLA-DR1 Antigen Hemagglutinin Human Immune Immunity Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H3N2 Subtype Influenza A Virus, H5N1 Subtype Influenza A virus Mediating Morbidity - disease rate Mus Mutation Peripheral Blood Mononuclear Cell Persons Plasmids Population Population Heterogeneity Prevalence Proteins RNA RNA vaccine Recombinants Replicon T cell response T-Cell Development T-Lymphocyte T-Lymphocyte Epitopes Testing Transgenic Mice Transgenic Organisms Universities Vaccine Design Vaccine Production Vaccines Viral Viral Proteins Virus Virus-like particle Washington Work base cell type enzyme linked immunospot assay expression vector humanized mouse immunogenic immunogenicity in vitro testing in vivo influenza infection influenza virus strain influenza virus vaccine mortality neutralizing antibody novel novel vaccines pandemic disease protective effect protective efficacy response stem cells success tool translational potential vaccine delivery vaccine development vaccine effectiveness vaccine evaluation vector vaccine

项目摘要

Abstract 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 that new vaccines be generated based on the prevalence of circulating strains every year. These reformulated versions of influenza vaccines are not always protective; vaccine effectiveness (VE) has varied from 10 to 60% over the past 10 years based on how well vaccine strains are matched with circulating strains. There is an urgent unmet need for influenza vaccines that induce greater cross-protective immunity. We propose to harness the immunogenic potential of broadly reactive influenza-specific T cell epitopes to produce vaccines with universal significance. Our previous R21 funded work has provided proof-of-principle that advanced immunoinformatic tools can be used to efficiently identify highly conserved influenza A epitopes, including promiscuous CD4+ T cell epitopes and HLA-A2-restricted CD8+ T cell epitopes, that are immunogenic and can induce protective immunity. Furthermore, we have convincingly demonstrated that T cell-based vaccines designed to stimulate human T cell responses can induce heterotypic protective immunity. We now propose to extend our R21 studies to more fully evaluate promiscuous CD4+ T cell epitopes to confirm that these epitopes can elicit potent CD4+ T cell responses in >95% of all humans expressing diverse HLA class II alleles. We also will identify relevant CD8+ T cell epitopes restricted by additional non-HLA-A2 class I supertypes, to obtain sufficient epitopes for broad population coverage (>95% of humans). We then will develop and compare immunogenicity and protective efficacy of multi-epitope vaccines using several state-of-the art vaccine delivery platforms including: recombinant ‘naked’ DNA, purified proteins mixed with novel adjuvants, novel adenovirus (Ad) vaccines designed to evade preexisting human Ad immunity, and virus-like particle (VLP) encapsidated RNA vaccines. Vaccines will be tested in vitro using human PBMC and in vivo using humanized mice expressing transgenic HLA. Heterotypic efficacy will be evaluated upon challenge with 3 distinct influenza A strains (H1N1, H3N2, and H5N1). The proposed work can provide transformational new products and direction for influenza vaccine development, focusing on a paradigm-shifting concept of inducing broadly protective T cell responses.

抽象的流感对全世界的病态和死亡率有重要的影响，并导致严重当菌株会进化以前没有在人类中循环的帽子时。需要根据循环菌株的流行而生成新的疫苗。流感疫苗的重新制定版本并非总是有效的疫苗（VE）在过去的10年中，根据疫苗菌株与循环菌株匹配的程度，从10％到60％。迫切需要诱导更大的交叉保护免疫的流感疫苗提议利用广泛反应性的流感特异性T细胞表位的免疫原性潜力产生普遍意义的疫苗。先进的免疫信息工具可用于有效识别肠道consenza Apitopes，包含烟草CD4+ T细胞表位和HLA-A2限制CD8+ T细胞表位，即免疫原性，可以诱导保护性免疫。旨在刺激人类T细胞反应的基于T细胞的疫苗可以诱导异型保护者免疫力。我们现在建议将R21研究扩展表位确认表位可以在> 95％的所有人类中引起有效的CD4+ T细胞反应表达不同的HLA Classe II无所不能。额外的非HLA-A2 I类超级型，以获得广泛人口覆盖范围的足够表位（> 95％人类）。使用几个最先进的疫苗输送平台，包括：重组“裸” DNA，纯化蛋白与新颖的佐剂混合，新型腺病毒（AD）疫苗旨在逃避人类AD 免疫力和病毒样颗粒（VLP）封装的RNA疫苗将在体外测试人类PBMC和体内使用人源化小鼠表达转基因HLA。通过3种不同的流感A菌株进行挑战（H1N1，H3N2和H5N1）可以为流感疫苗开发提供转型的新产品和指导，重点在诱导广泛保护性T细胞反应的范式转变中。