Novel rabies virus vaccines that exploit innate immune signals

利用先天免疫信号的新型狂犬病病毒疫苗

• 批准号: 8752938
• 负责人: JAMES P MCGETTIGAN
• 金额: $ 19.38万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8752938
• 关键词: Antibodies; Antibody Avidity; Antibody Formation; Antiviral Response; Autoimmunity; B-Cell Activation; B-Lymphocytes; CD4 Positive T Lymphocytes; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cessation of life; Cloning; Communicable Diseases; Data; Disease; Dose; Evaluation; Event; Future; Genes; Goals; Grant; HIV; Human; Immune; Immunity; Immunoglobulin G; Immunoglobulin M; Immunoglobulin-Secreting Cells; In Vitro; Inflammatory Response; Laboratories; Lead; Life; Link; Lymphocyte; Malaria; Measures; Mediating; Methods; Modeling; Monitor; Mus; Natural Immunity; Pathology; Pathway interactions; Peripheral; Population; Prevention; Prophylactic treatment; Protocols documentation; Rabies; Rabies Vaccines; Rabies virus; Regimen; Research; Role; Safety; Signal Transduction; Site; Speed; Staining method; Stains; T-Lymphocyte; TALL-1 protein; Techniques; Testing; Time; Toxic effect; Up-Regulation; Vaccination; Vaccines; Viral Vaccines; Virus; Virus Diseases; adaptive immunity; base; combat; cost; cytokine; global health; human ANP32B protein; immunogenicity; improved; in vivo; influenzavirus; mouse model; neutralizing antibody; nonhuman primate; novel; novel vaccines; pre-clinical; prevent; public health relevance; response; transgene expression; vaccination strategy; vaccine-induced immunity; vector; vector-based vaccine

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.

项目总结/摘要 超过三分之二的世界人口生活在狂犬病流行的地区， 接受多剂量暴露后预防（PEP）的人和全球每年超过75，000人死亡。一 狂犬病病毒（RV）研究的主要目标是开发一种单剂量暴露后预防（PEP）， 将简化疫苗接种方案，降低与RV预防相关的成本，并挽救生命。生活 基于复制缺陷型RV的载体正在成为实现这一目标的有希望的疫苗。多 信号导致最佳的B细胞活化和功能。在这些信号中，BAFF和APRIL弥合了差距 通过影响B和T细胞功能，在先天免疫和适应性免疫之间起作用。我们假设 表达BAFF或APRIL的基于复制缺陷型RV的疫苗将诱导快速和稳健的RV特异性免疫应答。 免疫力和针对致病性RV攻击保护比基于亲本活RV的更有效 疫苗本申请的主要目的是研究B细胞活化和RV特异性免疫， 针对由活的复制缺陷型RV疫苗引起的致病性RV攻击的保护，所述活的复制缺陷型RV疫苗表达 BAFF或APRIL，并确认不存在免疫病理学。第一个目标的目标是建造， 回收和表征活基质（M）基因缺失的基于RV的疫苗载体（rRV-M）表达BAFF 或四月。第二个目标的目标是完成功能的综合评价 在RV特异性免疫的情况下，从基于活RV的疫苗载体表达BAFF或APRIL的结果 B细胞活化、免疫、保护和安全。B细胞和抗体的定性和定量测量 属性（B细胞活化、病毒中和活性、抗体亲合力和亚类谱）和CD 4 T细胞 (Th1/Th 2偏倚（通过细胞内细胞因子染色），这是对RV PEP至关重要的主要抗病毒应答， 将使用RV免疫原性和保护的小鼠模型进行分析。无自身免疫，B 细胞淋巴细胞疾病和极端炎症反应将被监测，以帮助确认新的 疫苗是安全的。这项探索性拨款将有可能确定一种单剂量疫苗战略， 先天免疫促进适应性B细胞反应的速度，导致抗体能够 快速中和和预防RV感染。未来的目标包括额外的测试，以确定最 有效的疫苗接种策略，安全性和毒性，在临床前的设置，最终目标是减少 预防人类狂犬病和拯救生命的成本。