Determine the minimal level of replication required for broad protective immunity of influenza vaccine

确定流感疫苗广泛保护性免疫力所需的最低复制水平

• 批准号: 10084270
• 负责人: Yuan Shi
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084270
• 关键词: Affect; Amino Acids; Antibody Formation; Antigens; Attenuated; B-Lymphocytes; Cell Culture Techniques; Cell Line; Cell Maturation; Cessation of life; Complement; Data; Death Rate; Dendritic Cells; Development; Disease; Engineering; Epidemic; Epithelial Cells; Epitopes; Evolution; Failure; Ferrets; Frequencies; Genome; Genomics; Histology; Hospitalization; IFNAR1 gene; Immune; Immune response; Immunity; Immunization; Immunization Programs; Immunologics; In Vitro; Individual; Infection; Inflammatory Response; Influenza; Influenza A virus; Influenza vaccination; Innate Immune Response; Innate Immune System; Interferon Type I; Interferons; Kinetics; Lead; Libraries; Lung; M2 protein; Measures; Membrane Proteins; Memory B-Lymphocyte; Mus; Mutagenesis; Mutate; Mutation; Nucleotides; Oseltamivir; Pathologic; Phenotype; Population; Production; Publishing; Research; SCID Mice; Safety; Science; Seasons; Signal Transduction; System; Systems Biology; T cell response; T-Cell Development; T-Lymphocyte; Testing; Update; Vaccinated; Vaccination; Vaccines; Viral; Viral Genome; Virus; Virus Diseases; Virus Replication; adaptive immune response; attenuation; combat; cytokine; dosage; flu; immunogenicity; in vivo; influenza infection; influenza outbreak; influenza virus strain; influenza virus vaccine; influenzavirus; inhibitor/antagonist; live attenuated influenza vaccine; long term memory; mutant; neutralizing antibody; next generation sequencing; novel; novel strategies; pandemic influenza; prevent; public health relevance; reconstitution; response; universal influenza vaccine; vaccine candidate; vaccine development; vaccine efficacy; Affect; Amino Acids; Antibody Formation; Antigens; Attenuated; B-Lymphocytes; Cell Culture Techniques; Cell Line; Cell Maturation; Cessation of life; Complement; Data; Death Rate; Dendritic Cells; Development; Disease; Engineering; Epidemic; Epithelial Cells; Epitopes; Evolution; Failure; Ferrets; Frequencies; Genome; Genomics; Histology; Hospitalization; IFNAR1 gene; Immune; Immune response; Immunity; Immunization; Immunization Programs; Immunologics; In Vitro; Individual; Infection; Inflammatory Response; Influenza; Influenza A virus; Influenza vaccination; Innate Immune Response; Innate Immune System; Interferon Type I; Interferons; Kinetics; Lead; Libraries; Lung; M2 protein; Measures; Membrane Proteins; Memory B-Lymphocyte; Mus; Mutagenesis; Mutate; Mutation; Nucleotides; Oseltamivir; Pathologic; Phenotype; Population; Production; Publishing; Research; SCID Mice; Safety; Science; Seasons; Signal Transduction; System; Systems Biology; T cell response; T-Cell Development; T-Lymphocyte; Testing; Update; Vaccinated; Vaccination; Vaccines; Viral; Viral Genome; Virus; Virus Diseases; Virus Replication; adaptive immune response; attenuation; combat; cytokine; dosage; flu; immunogenicity; in vivo; influenza infection; influenza outbreak; influenza virus strain; influenza virus vaccine; influenzavirus; inhibitor/antagonist; live attenuated influenza vaccine; long term memory; mutant; neutralizing antibody; next generation sequencing; novel; novel strategies; pandemic influenza; prevent; public health relevance; reconstitution; response; universal influenza vaccine; vaccine candidate; vaccine development; vaccine efficacy

Project Summary Influenza A virus causes disease in 5%-20% of the population with over 200,000 hospitalizations annually in US. The antigen drift and shift of influenza virus due to rapid evolution pose a serious challenge for annual flu vaccination program, which is effective depending on the accurate prediction of the influenza serotypes that will be circulating in the next flu season. The recent failure of influenza vaccine and potential outbreak of influenza pandemics highlights the urgent need for a vaccine that can provide broad protection. Interferon (IFN) is a critical component of the innate immune system and also the bridge between the innate and adaptive immune responses. We recently studied the anti-IFN function of influenza genome using a quantitative and high-throughput genomics system. By incorporating eight IFN-sensitive mutations into influenza genome, we generated a Hyper Interferon Sensitive (HIS) virus as a vaccine candidate. HIS virus is highly attenuated in wild type and immune-deficient SCID mice, but fully competent in IFNAR-deficient mice. HIS provides protection against homologous and heterologous viral challenges. Our central hypothesis is that systematical elimination of IFN-evasion functions on multiple segments of the virus genome generates proper induction of innate immune response, which is essential for establishing long term memory B cell response and T cell response by live attenuated influenza vaccine. Our objective is to determine the minimal replication capacity required for live attenuated influenza virus vaccine, identify and generate single-round infection HIS virus, which can induce strong IFNR signaling in vitro, but has no replication capacity in vivo due to innate immune response. Such vaccine virus candidate would have confined one-round infection during immunization whereas the IFN inducing activity would be strong enough to illicit broad protective immunity. We will generate hyper IFN sensitive virus that has no replication capacity in vivo, and characterize its replication kinetics and responsiveness to IFN in lung epithelial cells. After we obtain such virus, we will infect mice with vaccine candidate viruses and characterize the induced immune responses. Finally, we will determine protection efficacy of vaccine candidate viruses against different strains of influenza virus in vivo. The results achieved from this project will advance our understanding of influenza vaccine development and facilitate the development of universal influenza vaccine.

项目摘要 流感病毒导致5％-20％的人口中的疾病，每年超过200,000次住院 我们。由于快速进化而导致的抗原漂移和流感病毒的转移对年度流感构成严重挑战 疫苗接种计划，根据对流感血清型的准确预测有效的疫苗接种计划 将在下一个流感季节流通。流感疫苗的最近失败和潜在的爆发 流感大流星强调了对可以提供广泛保护的疫苗的迫切需求。干扰素 （IFN）是先天免疫系统的关键组成部分，也是先天和适应性之间的桥梁 免疫反应。我们最近使用定量和 高通量基因组学系统。通过将八个IFN敏感突变纳入流感基因组中，我们 产生了一种超级干扰素敏感（他的）病毒作为疫苗候选者。他的病毒高度减弱 野生型和免疫缺陷的SCID小鼠，但在IFNAR缺陷小鼠中完全胜任。他的提供 防止同源和异源病毒挑战。我们的中心假设是系统性的 消除IFN逃避功能在病毒基因组的多个段上产生适当的诱导 先天免疫反应，这对于建立长期记忆B细胞反应和T细胞至关重要 活体流感疫苗的反应。我们的目标是确定最少的复制 活衰减流感病毒疫苗所需的能力，识别和生成单一 感染他的病毒，可以在体外引起强烈的IFNR信号传导，但没有复制能力 由于先天免疫反应而导致的体内。这种疫苗病毒候选者将限制一轮 免疫过程中的感染，而IFN诱导活性将足够强将 广泛的保护性免疫。我们将生成无复制能力的超级IFN敏感病毒 体内并表征其复制动力学和对肺上皮细胞中IFN的反应性。获得后 这种病毒，我们将用疫苗候选病毒感染小鼠，并表征诱导的免疫反应。 最后，我们将确定疫苗候选病毒针对不同菌株的保护疗效 病毒在体内。从该项目获得的结果将提高我们对流感疫苗的理解 开发和促进普遍流感疫苗的开发。