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（由适用提供）：呼吸道合胞病毒（RSV）是婴儿和幼儿下呼吸道感染的主要原因，但是目前尚无疫苗。这笔赠款的总体目的是开发最佳的活衰减RSV疫苗候选者。该P01的意义在于，它汇集了一个多学科研究人员，以利用一种新的观察结果，即患有严重RSV疾病的婴儿表现出一种不足（或抑制）免疫调查的模式。该赠款将通过开发具有增加免疫原性的疫苗，以一种新颖的“可调节”方式衰减病毒，从而提高其在细胞培养物中的产量以改善疫苗的产生，并使用基因表达和新的抗体检测工具来分析免疫剂量，以预测疫苗的有效性和安全性。这些候选者将首先在原发性分化的人类气道上皮培养物中进行测试。将选择具有所需特征的疫苗候选物以在棉花大鼠的体内进行测试 他们的衰减和诱导“安全”宿主反应（类似于婴儿的天然轻度RSV疾病）以及对RSV的潜在中和抗体的能力。组合突变体将通过该系统回收，从而选择了一种最佳疫苗候选者和优秀备份的等级顺序。通过将对RSV感染的宿主反应与改善这些反应的病毒的修饰整合在一起，该P01的四个项目将协同作用，以开发优化的活体减弱的RSV疫苗候选者，准备在人类初级和可能的临床试验中进行测试。