Universal T cell targeted influenza vaccine

通用 T 细胞靶向流感疫苗

• 批准号: 10246793
• 负责人: Daniel F. Hoft
• 金额: $ 75.32万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 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/10246793
• 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; 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; vaccine delivery; vaccine development; vaccine effectiveness; vaccine evaluation; vector vaccine

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 流感每年在全球范围内造成大量发病率和死亡率，并导致严重 当新菌株进化以前没有在人类中流传时，大流行。高病毒突变率 必须根据每年循环菌株的流行率生成新的疫苗。这些 重新制定的影响疫苗的版本并不总是受到保护；疫苗有效性（VE）有所不同 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％。 紧急未满足的对影响疫苗会引起更大的交叉保护免疫学。我们 利用广泛反应性影响特异性T细胞表位的免疫原性的提议产生 具有普遍意义的疫苗。我们以前的R21资助工作提供了原理证明 先进的免疫信息工具可用于有效识别高度组成的影响力， 包括混杂的CD4+ T细胞表位和HLA-A2限制的CD8+ T细胞表位，即 免疫原性，可以诱导受保护的免疫学。此外，我们令人信服地证明了这一点 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 免疫。现在，我们建议将R21研究扩展到更全面评估混杂的CD4+ T细胞 表位确认这些表位可以在所有人类中> 95％引起有效的CD4+ T细胞反应 表达潜水员HLA II类等位基因。我们还将确定受限制的相关CD8+ T细胞表位 其他非HLA-A2 I类超级型 人类）。然后，我们将开发和比较多诊断疫苗的免疫原性和保护效率 使用几个最先进的疫苗输送平台，包括：重组“裸” DNA，纯化蛋白 与新颖的调节器混合在一起，新型腺病毒（AD）疫苗旨在逃避已经存在的人类广告 免疫和病毒样颗粒（VLP）封装的RNA疫苗。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。异型效率将是 通过3种不同的影响力A菌株（H1N1，H3N2和H5N1）评估。拟议的工作 可以为影响力疫苗开发提供转型的新产品和指导 在诱导广泛保护的T细胞反应的范式转移概念上。