Regulation of humoral immunity to a virus-like particle vaccine candidate

项目摘要和相关性 人类呼吸道合胞病毒(RSV)是引起严重下呼吸道感染的主要原因。 以及婴儿、老年人和免疫功能低下者的住院。自然感染不会 诱导对病毒的持久保护性免疫，即使在同一年内也可能发生多次再感染。 到目前为止，还没有有效的疫苗或治疗方法。我们研制了一种新型的RSV病毒样颗粒 由新城疫病毒核蛋白和膜蛋白组成的(VLP)候选疫苗 表达RSV F和G糖蛋白胞外结构域与新城疫病毒糖蛋白胞浆结构域融合。这位贵宾 一次给药诱导小鼠保护性中和抗体反应和记忆B细胞 没有佐剂。免疫后感染RSV的小鼠清除病毒，不显示 加重的肺部疾病。因为这种保护性免疫反应不需要佐剂，所以我们 建议VLP直接刺激先天免疫系统，如TLRs或MAV。我们会调查的 这种可能性是通过使用先天免疫系统单一成分缺陷的突变小鼠模型和 对发展持久保护性免疫的影响。这些研究将为以下工作提供必要的信息 我们候选疫苗的未来发展，并确定最有效的TLR激动剂用于临床 测试

Project Summary and Relevance Human respiratory syncytial virus (RSV) is a major cause of serious lower respiratory tract infections and hospitalization in infants, the elderly and immunocompromised individuals. Natural infection does not induce durable protective immunity to the virus and multiple reinfections can occur even within the same year. To date, there is as yet no effective vaccine or treatment. We have developed novel RSV-virus-like particle (VLP) vaccine candidates composed of Newcastle Disease Virus nucleoprotein and membrane proteins that express RSV F and G glycoproteins ectodomains fused with NDV glycoprotein cytoplasmic domains. This VLP induces long-lived protective neutralizing antibody responses and memory B cells in mice when given once in the absence of adjuvant. Mice challenged with RSV post immunization clear the virus and do not display enhanced pulmonary disease. Because adjuvant is not required for this protective immune response, we propose that the VLP directly stimulates the innate immune system, such as TLRs or MAV. We will investigate this possibility by using mutant mouse models deficient in single components of the innate immune system and the impact on development of durable protective immunity. These studies will provide essential information for the future development of our vaccine candidate and define the most efficacious TLR agonists for clinical testing