Multivalent Tick-Microbe targeted Lyme disease vaccines

标题 针对莱姆病的多价壁虱-微生物疫苗 项目摘要/摘要 莱姆病在世界许多地区仍然是一种流行的扁虱传播感染。仅在美国， 每年有超过30万例新病例发生。感染是由伯氏疏螺旋体引起的 LATO是一组非典型的胞外细菌病原体，通过复合体在自然界中生存 地方性感染循环，涉及扁虱(属于肩部硬蜱复合体)和一系列脊椎动物 宿主，最常见的是野生啮齿动物。尽管在过去的几年里为控制感染做出了认真的努力 几十年来，这种疾病仍在全球范围内出现，主要是由于缺乏有效的控制 防治扁虱感染、缺乏人类疫苗、诊断困难和临床并发症的措施 与使用目前可用的抗菌剂的治疗有关。具体地说，几个月后 标准护理抗生素治疗的一部分患者可能会经历一系列持续或复发 症状，称为慢性莱姆病或治疗后莱姆病综合征，对其进一步 治疗方案仍然不可用。因此，疫苗的开发是非常有必要的 与莱姆病作斗争。这个项目追求我们的目标，开发一种新的疫苗接种活动， 包括来自莱姆病病原体和壁虱媒介的精选抗原，表达自井- 建立了病毒载体系统。该方法结合了一组新的疫苗靶点，这些靶点表达了 在微生物表面上或朝向扁虱肠道的管腔表面。正如最近出版的和 初步数据显示，用这些靶标免疫哺乳动物可产生保护性免疫。我们会 利用基于狂犬病病毒的高效疫苗系统(RABV)，该系统具有广泛的应用，如 许多传染病的合格疫苗平台，并显示出显著的安全性特征，如 它们目前用于人类疫苗接种证明了这一点。总体目标具体体现在三个方面 目的：1)构建具有复制能力、复制缺陷的重组RABV 和表达伯氏杆菌和壁虱抗原的病毒粒子，2)疫苗构建物的特征 小鼠模型的长期免疫原性，以及3)最有效疫苗的鉴定 候选人(S)，调节伯氏杆菌感染并产生保护性免疫。我们还将 进行研究以了解与体液和细胞免疫反应相关的机制 具有主机保护功能。总体而言，这些研究将促进更安全的下一代疫苗的设计 预防莱姆型疏螺旋体病的发生。此外，同样的方法可以作为一种范例 抗击其他由壁虱传播的感染。 好了！ 好了！ 好了！

TITLE MULTIVALENT TICK-MICROBE TARGETED LYME DISEASE VACCINES PROJECT SUMMARY/ABSTRACT Lyme disease remains a prevalent tick-borne infection in many parts of the world. In the United States alone, there are over 300,000 new cases occurring each year. The infection is caused by Borrelia burgdorferi sensu lato, which is a group of atypical extracellular bacterial pathogens that survive in nature through a complex enzootic infection cycle involving ticks (belonging to the Ixodes scapularis complex) and an array of vertebrate hosts, most commonly wild rodents. Despite serious efforts to control the infection over the past several decades, the disease is still emerging around the globe, largely due to the absence of effective control measures against tick infestation, lack of human vaccines, difficulties in diagnosis, and clinical complications associated with treatments which use currently available antimicrobials. Specifically, several months after standard-care antibiotic therapy, a subset of patients can experience a series of persistent or relapsing symptoms, known as chronic Lyme disease or post-treatment Lyme disease syndrome, for which further treatment options remain unavailable. Therefore, the development of vaccines is highly warranted to combat Lyme disease. This project pursues our goals to develop a novel vaccination campaign that comprises selected antigens from both the Lyme disease pathogen and the tick vector, expressed from a well- established viral vector system. The approach incorporates a set of novel vaccine targets that are expressed on the microbial surface or towards the luminal surface of the tick gut. As highlighted in recently-published and preliminary data, immunization with these targets generates protective immunity in mammals. We will utilize highly efficient Rabies virus-based vaccine systems (RABV), which have broad applications as competent vaccine platforms for many infectious diseases and display remarkable safety profiles, as evidenced from their current use for human vaccination. The overall objective is embodied in three specific aims: 1) construction of a battery of recombinant replication-competent, replication-deficient RABVs and virions expressing B. burgdorferi and tick antigens, 2) characterization of vaccine constructs for long-term immunogenicity in murine models, and 3) identification of the most effective vaccine candidate(s) that modulate B. burgdorferi infection and generate protective immunity. We will also perform studies for understanding the mechanisms of the humoral and cellular immune responses associated with host protection. Overall, these studies will facilitate the design of safer, next generation vaccines to prevent the incidence of Lyme borreliosis. Moreover, the same approach may serve as a paradigm for combating other tick-borne infections. ! ! !