Multivalent Tick-Microbe targeted Lyme disease vaccines

多价蜱微生物靶向莱姆病疫苗

基本信息

批准号：
10442534
负责人：
UTPAL PAL
金额：
$ 71.7万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442534
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 vaccine platform vector vector tick vector vaccine

项目摘要

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概要/摘要莱姆病在世界许多地区仍然是一种流行的蜱传感染。仅在美国，每年发生超过30万例新病例。该感染是由伯氏疏螺旋体引起的 lato，是一组非典型细胞外细菌病原体，通过复杂的机制在自然界中生存涉及蜱（属于肩胛硬蜱复合体）和一系列脊椎动物的地方性动物感染周期宿主，最常见的是野生啮齿动物。尽管过去几年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不断出现，很大程度上是由于缺乏有效的控制蜱虫感染措施、缺乏人类疫苗、诊断困难和临床并发症与使用现有抗菌药物的治疗相关。具体来说，几个月后标准护理抗生素治疗中，一部分患者可能会经历一系列持续或复发的症状症状，称为慢性莱姆病或治疗后莱姆病综合症，进一步治疗方案仍然不可用。因此，疫苗的研发非常有必要对抗莱姆病。该项目的目标是开发一种新颖的疫苗接种运动，包含来自莱姆病病原体和蜱载体的选定抗原，由良好表达建立病毒载体系统。该方法包含了一组新的疫苗靶点，这些靶点已表达在微生物表面或朝向蜱肠道的腔表面。正如最近发布的和初步数据显示，对这些目标进行免疫可以在哺乳动物中产生保护性免疫力。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针对许多传染病的有效疫苗平台，并显示出卓越的安全性，例如从它们目前用于人类疫苗接种中可以看出。总体目标具体体现在三个方面目标：1) 构建一组具有复制能力、复制缺陷的重组 RABV 和表达伯氏疏螺旋体和蜱抗原的病毒粒子，2) 疫苗构建体的表征小鼠模型中的长期免疫原性，以及 3) 鉴定最有效的疫苗调节伯氏疏螺旋体感染并产生保护性免疫力的候选者。我们也会进行研究以了解相关体液和细胞免疫反应的机制具有主机保护功能。总体而言，这些研究将有助于设计更安全的下一代疫苗预防莱姆疏螺旋体病的发生。此外，同样的方法可以作为以下范例：对抗其他蜱传感染。！！！