Live Attenuated RSV Vaccine with Optimized Safety and Immunogenicity

 描述（由申请方提供）：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。该资助的总体目标是开发最佳的RSV减毒活疫苗候选物。该P01的重要性在于，它汇集了一个多学科的研究者小组，以利用一个新的观察结果，即患有严重RSV疾病的婴儿显示出免疫应答不足（或抑制）的模式。这笔赠款将同时在多个方面解决这一问题，开发一种免疫原性增强的疫苗，以一种新的、“可调”的方式减毒，提高其在细胞培养中的产量以改进疫苗生产，并利用基因表达和新的抗体检测工具分析免疫反应，以预测疫苗的有效性和安全性。这些候选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。将选择具有所需特征的候选疫苗用于棉鼠体内试验， 它们的减毒和诱导“安全”宿主反应的能力（类似于婴儿中的天然轻度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再循环，从而选择一种最佳候选疫苗和优秀备份的排序。通过整合宿主对RSV感染的反应与改善这些反应的病毒修饰，本P01的四个项目将协同开发一种优化的减毒活RSV候选疫苗，可用于人类灵长类动物的测试和可能的临床试验。

 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.