Multivalent Tick-Microbe targeted Lyme disease vaccines

多价蜱微生物靶向莱姆病疫苗

• 批准号: 10219933
• 负责人: UTPAL PAL
• 金额: $ 71.29万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-20 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219933
• 关键词: Aftercare; Animal Model; Antibiotic Therapy; Antibiotics; Antibody Response; Antigens; Attenuated; Biology; Black-legged Tick; Borrelia; Borrelia burgdorferi; Borrelia burgdorferi Group; Chronic; Clinical; Communicable Diseases; Complementary DNA; Complex; Cultured Cells; Data; Development; Diagnosis; Disease; FDA approved; Goals; Human; Immune response; Immunity; Immunization; Immunize; Inactivated Vaccines; Incidence; Infection; Infection Control; Intervention; Laboratories; Lyme Disease; Lyme Disease Vaccines; Mammals; Measures; Mediating; Membrane; Membrane Proteins; Methods; Microbe; Nature; Order Spirochaetales; OspA protein; Oxidases; Pathogenesis; Patients; Prevention; Prevention strategy; Preventive measure; Proteins; Publishing; Rabies; Rabies virus; Recombinant Proteins; Recombinants; Relapse; Research; Rodent; Role; Safety; Sales; Series; Set protein; Spirochaetales Infections; Surface; Symptoms; Syndrome; System; Tick Infestations; Tick-Borne Diseases; Tick-Borne Infections; Ticks; United States; Vaccination; Vaccines; Viral Vector; Virion; Virus Diseases; Virus-like particle; antimicrobial; base; cohort; combat; design; enzootic; experience; extracellular; immunogenicity; microbial; microorganism antigen; mouse model; neutralizing antibody; next generation; novel; novel strategies; novel vaccines; pathogen; pathogenic bacteria; patient subsets; persistent symptom; preclinical study; prevent; response; reverse genetics; standard care; tick transmission; transmission process; vaccination strategy; vaccine candidate; vaccine development; vector; vector tick; vector vaccine

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. ! ! !

标题 多价蜱-微生物靶向莱姆病疫苗 项目总结/摘要 莱姆病在世界许多地方仍然是一种流行的蜱传感染。仅在美国， 每年有30多万新病例。感染是由伯氏疏螺旋体引起的 Lato是一组非典型的细胞外细菌病原体，它们通过一种复杂的 涉及蜱（属于肩突硬蜱复合体）和一系列脊椎动物的地方性感染循环 宿主通常是野生啮齿动物尽管在过去几年中为控制感染做出了认真的努力， 几十年来，这种疾病仍在地球仪各地出现，主要是由于缺乏有效的控制 针对蜱虫感染的措施、缺乏人用疫苗、诊断困难和临床并发症 与使用目前可用的抗菌剂的治疗有关。具体来说，几个月后， 在标准抗生素治疗的情况下，一部分患者可能会经历一系列持续性或复发性 症状，称为慢性莱姆病或治疗后莱姆病综合征，对于其进一步 治疗方案仍然不可用。因此，疫苗的开发非常必要， 对抗莱姆病该项目追求我们的目标，开发一种新的疫苗接种运动， 包括选自莱姆病病原体和蜱载体的抗原，所述抗原从孔- 建立了病毒载体系统。该方法结合了一组新的疫苗靶点， 在微生物表面上或朝向蜱肠道的腔表面。正如最近出版的和 根据初步数据，用这些靶点免疫在哺乳动物中产生保护性免疫。我们将 利用高效的狂犬病病毒疫苗系统（RABV），该系统具有广泛的应用， 许多传染病的疫苗平台，并显示出显着的安全性， 这从它们目前用于人类疫苗接种中得到证实。总体目标体现在三个具体方面： 目的：1）构建一系列具有复制能力的、复制缺陷的重组RABV 和表达B的病毒体。伯氏螺旋体和蜱抗原，2）用于 在鼠模型中的长期免疫原性，和3）鉴定最有效的疫苗 调节B的候选物。并产生保护性免疫。我们还将 进行研究，了解体液和细胞免疫反应的机制， 主机保护。总的来说，这些研究将有助于设计更安全的下一代疫苗， 预防莱姆病的发生。此外，同样的方法可以作为一个范例， 防治其他蜱传感染。 ! ! !