Universal T cell targeted influenza vaccine

通用 T 细胞靶向流感疫苗

• 批准号: 9887681
• 负责人: Daniel F. Hoft
• 金额: $ 79.64万
• 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/9887681
• 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, 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; 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 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 流感每年在全世界造成重大发病率和死亡率，并导致严重的 当新的病毒株出现且以前未曾在人类中传播过时，就会出现流行病。病毒突变率高 需要根据每年流行毒株的流行情况来生产新疫苗。这些 重新配制的流感疫苗并不总是具有保护作用；疫苗有效性（VE）各不相同 根据疫苗毒株与流行毒株的匹配程度，过去 10 年从 10% 增加到 60%。 对诱导更强的交叉保护性免疫力的流感疫苗的迫切需求尚未得到满足。我们 提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产生 具有普遍意义的疫苗。我们之前 R21 资助的工作已经提供了原理证明： 先进的免疫信息学工具可用于有效识别高度保守的甲型流感表位， 包括混杂的 CD4+ T 细胞表位和 HLA-A2 限制性 CD8+ T 细胞表位，即 具有免疫原性，可诱导保护性免疫。此外，我们已经令人信服地证明了 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。我们现在建议扩展我们的 R21 研究，以更全面地评估混杂的 CD4+ T 细胞 表位以确认这些表位可以在 >95% 的人类中引发有效的 CD4+ T 细胞反应 表达不同的 HLA II 类等位基因。我们还将鉴定受限制的相关 CD8+ T 细胞表位 额外的非 HLA-A2 I 类超型，以获得足够的表位以覆盖广泛的人群（>95% 人类）。然后我们将开发并比较多表位疫苗的免疫原性和保护功效 使用多种最先进的疫苗递送平台，包括：重组“裸”DNA、纯化蛋白质 与新型佐剂混合的新型腺病毒（Ad）疫苗旨在逃避预先存在的人类腺病毒 免疫和病毒样颗粒 (VLP) 衣壳 RNA 疫苗。疫苗将在体外进行测试 人 PBMC 和体内使用表达转基因 HLA 的人源化小鼠。异型功效将是 针对 3 种不同的甲型流感毒株（H1N1、H3N2 和 H5N1）的攻击进行了评估。拟议的工作 可以为流感疫苗开发提供变革性新产品和方向，重点关注 诱导广泛保护性 T 细胞反应的范式转变概念。