Identification of protective Lyme disease antigens using live attenuated vaccines

使用减毒活疫苗鉴定保护性莱姆病抗原

基本信息

批准号：
9917694
负责人：
Jenifer L Coburn
金额：
$ 37.82万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-19 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917694
关键词：
Adoptive Cell Transfers Alleles Animal Model Antibiotic Therapy Antibody Response Antigens Arthritis Asia Attenuated Attenuated Live Virus Vaccine Bacteria Blood Circulation Borrelia Borrelia afzelii Borrelia burgdorferi Borrelia burgdorferi Group Borrelia garinii Case Study Cells Centers for Disease Control and Prevention (U.S.)Complement Control Groups DBL Oncoprotein Data Data Set Development Europe Evaluation Formulation Future Generations Genome Geographic Locations Geography Goals Human Immune Immune Sera Immune response Immune system Immunize Immunoglobulin G Incidence Infection Integrins Laboratory culture Left Ligands Lipoproteins Lyme Arthritis Lyme Disease Lyme Disease Vaccines Monitor Morbidity - disease rate Mus Nature Needles North America OspA protein OspA vaccine Passive Immunity Passive Immunization Pathogenicity Phase Plasmids Populations at Risk Predisposition Primary Infection Protein Microchips Proteins Proteome Recombinants Refractory Research Safety Subunit Vaccines Surface Symptoms Testing Ticks Time VDAC1 gene Vaccinated Vaccination Vaccines Variant Work base cytokine experimental study extracellular high risk population in vivo interest mouse model mutant novel novel strategies novel vaccines pathogen pathogenic bacteria post-market response tick bite tool vaccine safety vector-borne

项目摘要

Borrelia burgdorferi, B. garinii and B. afzelii are all agents of Lyme disease in different geographic locations. If left untreated, Lyme disease can cause significant and long-term morbidity, which may continue after appropriate antibiotic therapy has been administered and live bacteria are no longer detectable. There was a Lyme disease vaccine available for human use from 1998 to 2002, but that vaccine is no longer available. The vaccine targeted an abundant B. burgdorferi surface lipoprotein, OspA, which is produced by the bacteria primarily while they reside in the tick and in laboratory culture. This vaccine protected against infection when bloodstream anti-OspA titer was sufficiently high, but was comprised of only a single OspA variant. Ultimately, this vaccine afforded ~80% effective protection in the large phase three trial and in subsequent post-market monitoring, likely at least in part due to the diversity of OspA sequences that was later revealed by genome and ospA allele sequencing. There was also concern regarding the safety of this vaccine among some groups, as reactivity to OspA was associated with Lyme arthritis, particularly the treatment-refractory arthritis, although no increase in arthritis was seen in humans who received the vaccine compared to control groups. The increasing incidence and geographic spread of Lyme disease, however, is renewing interest in vaccination of at-risk populations, and is fueled by recent analyses of several data sets that indicate that the Lyme disease case numbers in the USA may actually be up to ten times higher than the number of cases reported to the CDC. We took the novel approach of vaccinating mice with two targeted mutant strains of B. burgdorferi that are avirulent in mice. Mice vaccinated with both strains were protected against challenge by the parental strain and a heterologous B. burgdorferi strain by either needle inoculation or tick bite. Sera from vaccinated mice were also protective (conferred “passive immunity”). In ticks, the homologous strain was eliminated but the heterologous strain was not, suggesting that the vaccines generated a response against antigens that are produced by the bacteria both early in mammalian infection and in the tick. Partial protection was also conferred against B. garinii infection. Our hypothesis is that the live attenuated vaccine strains provide unique tools to identify novel protective antigens. To further characterize the protective response raised against the live attenuated vaccines, we propose to 1) Identify antigens that are recognized by the sera of vaccinated mice; 2) Produce and test recombinant versions of these antigens as subunit vaccines; and 3) Analyze the immune response in immunized mice and evaluate association with susceptibility to arthritis upon challenge with infectious B. burgdorferi. These experiments will test the novel hypothesis that live attenuated B. burgdorferi strains can be informative regarding identification of protective antigens produced by the bacteria and recognized by the mouse immune system in vivo. The approaches we will take will illuminate new candidate antigens that are effective and safe for future development of Lyme disease vaccines.

伯氏疏螺旋体、加氏疏螺旋体和阿氏疏螺旋体都是不同地理位置的莱姆病病原体。如果不及时治疗，莱姆病可能会导致严重的长期发病，并且这种情况可能会在发病后持续存在。已进行适当的抗生素治疗，并且不再检测到活细菌。莱姆病疫苗从 1998 年到 2002 年可供人类使用，但该疫苗已不再可用。疫苗针对的是细菌产生的丰富的伯氏疏螺旋体表面脂蛋白 OspA 主要是当它们居住在蜱虫和实验室培养物中时，这种疫苗可以防止感染。血流抗 OspA 滴度足够高，但最终仅由单一 OspA 变体组成。该疫苗在大型三期试验和随后的上市后提供了约 80% 的有效保护监测，可能至少部分是由于后来基因组揭示的 OspA 序列的多样性 ospA 等位基因测序也引起了一些群体对该疫苗安全性的担忧，因为对 OspA 的反应性与莱姆关节炎有关，特别是治疗难治性关节炎，尽管与对照组相比，接种疫苗的人的关节炎没有增加。然而，莱姆病的发病率和地域传播不断增加，重新燃起了人们对莱姆病疫苗接种的兴趣。最近对几个数据集的分析表明莱姆病美国的病例数实际上可能比向美国报告的病例数高十倍 CDC。我们采用了新方法，给小鼠接种了两种目标伯氏疏螺旋体突变株。接种这两种菌株的小鼠均无毒力，可免受亲代菌株的攻击。以及通过针头接种或蜱虫叮咬获得的异源伯氏疏螺旋体菌株。也具有保护性（赋予“被动免疫力”）。异源菌株则不然，这表明疫苗产生了针对抗原的反应，该细菌在哺乳动物感染早期和蜱中也产生了部分保护。我们的假设是减毒活疫苗株可提供针对 B. garinii 感染的作用。识别新型保护性抗原的独特工具，以进一步表征所产生的保护性反应。针对减毒活疫苗，我们建议 1) 鉴定被疫苗血清识别的抗原 2) 生产和测试这些抗原的重组版本作为亚单位疫苗；以及 3) 分析免疫小鼠的免疫反应并评估与关节炎易感性的关系用传染性伯氏疏螺旋体进行挑战这些实验将检验活的减毒伯氏疏螺旋体的新假设。伯氏杆菌菌株可对细菌产生的保护性抗原进行信息性鉴定并被小鼠体内免疫系统识别，我们将采取的方法将阐明新的方法。对莱姆病疫苗的未来开发有效且安全的候选抗原。