Live Attenuated RSV Vaccine with Optimized Safety and Immunogenicity

具有优化安全性和免疫原性的 RSV 减毒活疫苗

• 批准号: 9133254
• 负责人: Mark E. Peeples
• 金额: $ 148.92万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-27 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9133254
• 关键词: 5 year old; A549; Address; Adopted; Affect; Animal Model; Antibodies; Attenuated; Attenuated Vaccines; Biological Assay; Cause of Death; Cell Culture Techniques; Cell Line; Cell model; Cells; Cessation of life; Characteristics; Child; Cleaved cell; Clinical; Clinical Trials; Cotton Rats; Data; Data Analyses; Detection; Development; Doctor of Medicine; Doctor of Philosophy; Environment; Epithelial; Experimental Designs; Future; GTP-Binding Proteins; Gene Expression; Genes; Genetic; Goals; Grant; Hospitalization; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Infant; Infection; Influenza; Interferon Type I; Interferons; Life; Lower Respiratory Tract Infection; Malaria; Measles; Measures; Methods; Methyltransferase; Modeling; Modification; Molecular Virology; Morbidity - disease rate; Mumps; Mutagenesis; Mutation; Pathogenicity; Pattern; Primates; Process; Production; Proteins; Recombinants; Recycling; Research Personnel; Resources; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Safety; Sampling; Structure of respiratory epithelium; Symptoms; System; Testing; Time; Vaccine Production; Vaccines; Vero Cells; Viral; Viral Nonstructural Proteins; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; adaptive immunity; attenuation; clinical application; design; glycoprotein G; immune activation; immunogenicity; improved; in vivo; mortality; multidisciplinary; mutant; neutralizing antibody; nonhuman primate; novel; novel vaccines; pathogen; prevent; public health relevance; repaired; respiratory; response; success; tool; vaccine candidate; vaccine development; vaccine effectiveness; vaccine evaluation; vaccine safety; vaccine trial

 DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in infants and young children, however no vaccine is currently available. The overall objective of this grant is to develop optimal live attenuated RSV vaccine candidate(s). The significance of this P01 is that it brings together a multidisciplinary group of investigators to leverage a novel observation that infants with severe RSV disease display a pattern of inadequate (or suppressed) immune responses. The grant will simultaneously attack this problem on multiple fronts by developing a vaccine with increased immunogenicity, attenuating the virus in a novel, `tunable' way, improving its yield in cell culture to improve vaccine production, and using gene expression and new antibody detection tools for analysis of the immune response in order to predict vaccine effectiveness and safety. These candidates will be tested first in vitro in primary well differentiated human airway epithelial cultures. Vaccine candidates with the desired characteristics will be selected for testing in vivo in cotton rats for their attenuation and their ability to induce a `safe' host response (similar to natural mild RSV disease in infants), and potent neutralizing antibodies to RSV. Combination mutants will be recycled through this system, resulting in the selection of one optimal vaccine candidate and rank order of excellent backups. By integrating the host response to RSV infection with modifications of the virus that improve these responses, the four projects of this P01 will synergize to develop an optimized live attenuated RSV vaccine candidate ready for testing in human primates and possibly clinical trials.

 描述（申请人提供）：呼吸道合胞病毒（RSV）是婴幼儿下呼吸道感染的主要原因，但目前尚无疫苗可用。这笔赠款的总体目标是开发最佳的减毒活 RSV 候选疫苗。该 P01 的重要性在于，它汇集了多学科研究人员小组，利用一项新的观察结果，即患有严重 RSV 疾病的婴儿表现出免疫反应不足（或受到抑制）的模式。这笔赠款将同时从多个方面解决这个问题，包括开发一种具有更高免疫原性的疫苗，以一种新颖的“可调节”方式减弱病毒，提高细胞培养物的产量以提高疫苗生产，并使用基因表达和新的抗体检测工具来分析免疫反应，以预测疫苗的有效性和安全性。这些候选药物将首先在原代分化良好的人气道上皮培养物中进行体外测试。将选择具有所需特性的候选疫苗进行棉鼠体内测试 它们的减毒作用和诱导“安全”宿主反应的能力（类似于婴儿中自然的轻度 RSV 疾病），以及针对 RSV 的有效中和抗体。组合突变体将通过该系统循环利用，从而选择一种最佳候选疫苗并对优秀备用疫苗进行排序。通过将宿主对 RSV 感染的反应与改善这些反应的病毒修饰相结合，该 P01 的四个项目将协同开发一种优化的减毒活 RSV 候选疫苗，准备在人类灵长类动物中进行测试，并可能进行临床试验。