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

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 甲型流感病毒在5%-20%的人口中引起疾病， 我们流感病毒因快速进化而产生的抗原漂移和移位，对每年一度的流感构成了严峻挑战 疫苗接种计划，这是有效的，取决于准确预测流感血清型， 会在下一个流感季节传播最近流感疫苗的失败和潜在的爆发， 流感大流行突出表明，迫切需要一种能够提供广泛保护的疫苗。干扰素 (IFN)是先天免疫系统的重要组成部分，也是先天免疫和适应性免疫之间的桥梁。 免疫反应。最近，我们使用定量和定量的方法研究了流感病毒基因组的抗干扰素功能， 高通量基因组学系统。通过将八个IFN敏感突变整合到流感基因组中， 产生了一种超干扰素敏感（HIS）病毒作为候选疫苗。HIS病毒是高度减毒的， 野生型和免疫缺陷型SCID小鼠，但在IFNAR缺陷型小鼠中完全胜任。HIS提供 针对同源和异源病毒攻击的保护。我们的核心假设是， 在病毒基因组的多个区段上消除IFN逃避功能产生适当的诱导， 先天免疫应答，其对于建立长期记忆B细胞应答和T细胞应答是必需的。 减毒活流感疫苗的反应。我们的目标是确定最小复制 流感病毒减毒活疫苗所需产能，确定并产生单轮 感染HIS病毒，其可以在体外诱导强IFNR信号传导，但在体外没有复制能力。 体内由于先天免疫反应。这种疫苗病毒候选人将限制一轮 在免疫过程中的感染，而IFN诱导活性将是足够强，非法 广泛的保护豁免权。我们将产生超干扰素敏感的病毒，没有复制能力， 体内，并表征其复制动力学和肺上皮细胞对IFN的反应性。在我们获得 我们将用疫苗候选病毒感染小鼠，并表征诱导的免疫应答。 最后，我们将确定候选疫苗病毒对不同流感病毒株的保护效力 体内病毒本项目的成果将促进我们对流感疫苗的认识 开发和促进通用流感疫苗的开发。