Novel rabies virus vaccines that exploit innate immune signals

项目摘要/摘要 世界上超过三分之二的人口生活在狂犬病流行的地区，导致超过1500万人 全球每年接受多剂量暴露后预防(PEP)的人和超过75,000人死亡。一个 狂犬病病毒(RV)研究的主要目标是开发一种单剂暴露后预防(PEP)， 将简化疫苗接种方案，降低与RV预防相关的成本，并拯救生命。活着 复制缺陷的轮状病毒载体正在成为实现这一目标的有希望的疫苗。多重 信号导致最佳的B细胞激活和功能。在这些信号中，BAFF和APRLE弥合了差距 通过影响B细胞和T细胞功能来实现先天免疫和获得性免疫之间的关系。我们假设生活在 表达BAFF或APRIL的复制缺陷轮状病毒疫苗将诱导快速而强大的轮状病毒特异性 对致病性轮状病毒挑战的免疫和保护比基于父母活体轮状病毒的更有效 疫苗。这项应用的主要目标是研究B细胞激活和RV特异性免疫以及 表达RV基因的活复制缺陷疫苗对致病性RV攻击的保护作用 BAFF或4月，并确认无免疫病理。第一个目标的目标是建造， 表达BAFF的活基质(M)基因缺失轮状病毒疫苗载体(RRV-M)的回收与鉴定 或者四月。第二个目标是完成对功能的全面评估 轮状病毒特异性活疫苗载体表达BAFF或APRIL的后果 B细胞活化、免疫、保护和安全。B细胞和抗体的定性和定量检测 属性(B细胞激活、病毒中和活性、抗体亲和力和亚类分布)和CD4T细胞 (通过细胞内细胞因子染色偏向Th1/Th2)，这是对RV PEP至关重要的主要抗病毒反应， 将用小鼠模型分析轮状病毒的免疫原性和保护性。缺乏自身免疫力，B 将监测细胞淋巴细胞性疾病和极端炎症反应，以帮助确认新的 疫苗仍然是安全的。这一探索性拨款将可能确定一种单剂疫苗策略，该策略利用 先天免疫促进适应性B细胞反应的速度，导致抗体能够 迅速中和和预防轮状病毒感染。未来的目标包括进行更多的测试，以确定 临床前环境中有效的疫苗接种策略、安全性和毒性，最终目标是减少 人类预防狂犬病和拯救生命的成本。

Project Summary/Abstract Over two-thirds of the world's population live in regions where rabies is endemic, resulting in over 15 million people receiving multi-dose post-exposure prophylaxis (PEP) and over 75,000 deaths per year globally. A major goal in rabies virus (RV) research is to develop a single-dose post-exposure prophylaxis (PEP) that would simplify vaccination protocols, reduce costs associated with RV prevention, and save lives. Live replication-deficient RV-based vectors are emerging as promising vaccines to achieve this goal. Multiple signals lead to optimal B cell activation and functions. Among these signals, BAFF and APRIL bridge the gap between innate and adaptive immunity by influencing B and T cell functions. We hypothesize that live replication-deficient RV-based vaccines expressing BAFF or APRIL will induce rapid and robust RV-specific immunity and protection against pathogenic RV challenge more effectively than a parental live RV-based vaccine. The major goal of this application is to investigate B cell activation and RV-specific immunity and protection against pathogenic RV challenge elicited by live replication-deficient RV-based vaccines expressing BAFF or APRIL and to confirm the absence of immune pathology. The goal for the first Aim is to construct, recover and characterize live matrix (M) gene-deleted RV-based vaccine vectors (rRV-M) expressing BAFF or APRIL. The goal of the second Aim is to complete a comprehensive evaluation of the functional consequences of expressing BAFF or APRIL from live RV-based vaccine vectors in the context of RV-specific B cell activation, immunity, protection and safety. Qualitative and quantitative measures of B cell and antibody attributes (B cell activation, virus neutralization activity, antibody avidity and subclass profile), and CD4 T cells (Th1/Th2 bias by intracellular cytokine staining), which are the primary anti-viral responses critical for RV PEP, will be analyzed using a mouse model of RV immunogenicity and protection. The absence of autoimmunity, B cell lymphocytic disorders and extreme inflammatory responses will be monitored to help confirm the new vaccines remain safe. This exploratory grant will potentially identify a single-dose vaccine strategy that exploits the speed by which innate immunity promotes adaptive B cell responses, resulting in antibodies capable of rapidly neutralizing and preventing RV infections. Future goals include additional testing to identify the most effective vaccination strategy, safety, and toxicity in pre-clinical settings with the ultimate goal of reducing the cost of rabies prevention in humans and saving lives.