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

• 批准号: 9275338
• 负责人: Jenifer L Coburn
• 金额: $ 37.83万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-19 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275338
• 关键词: Adoptive Cell Transfers; Alleles; Animal Model; Antibiotic Therapy; Antibody Response; Antigens; Arthritis; Asia; Attenuated; Attenuated Live Virus Vaccine; Bacteria; Bite; Blood Circulation; Borrelia; Borrelia burgdorferi; Borrelia burgdorferi Group; 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; killings; mouse model; mutant; novel; novel strategies; novel vaccines; pathogen; post-market; response; tool; vaccine safety; vector

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.

Borrelia Burgdorferi，B。Garinii和B. afzelii都是不同地理位置的莱姆病的药物。如果 未经治疗的莱姆病可能会引起显着和长期发病率，这可能会在 已经进行了适当的抗生素治疗，并且不再可检测到活细菌。有一个 莱姆病疫苗从1998年到2002年可用于人类使用，但该疫苗不再可用。这 疫苗针对丰富的B. burgdorferi表面脂蛋白OSPA，由细菌产生 主要是居住在壁虱和实验室文化中的同时。当这种疫苗免受感染的疫苗时 血流抗OSPA滴度足够高，但仅完成了单个OSPA变体。最终， 该疫苗在大型三期试验中提供了约80％的有效保护 监测，可能至少部分是由于oSPA序列的多样性，后来由基因组揭示 和OSPA等位基因测序。在某些群体中，这种疫苗的安全性也令人担忧， 由于对OSPA的反应性与莱姆关节炎，特别是治疗性关节炎有关，尽管 与对照组相比，接受疫苗的人类没有观察到关节炎的增加。 然而，莱姆病的发病率和地理扩散增加是对疫苗接种的重新兴趣 处于危险的人群，并通过对几个数据集的分析助长了，这些数据集表明莱姆病 美国的案件号实际上可能比报告给报道的案件数量高出十倍 CDC。我们采用了新的方法，用两个靶向的b。brgdorferi靶向突变菌株接种小鼠， 在小鼠中是无毒的。用两种菌株接种疫苗的小鼠受到父母菌株的挑战的保护 以及通过针接种或tick咬咬伤的异源B. burgdorferi菌株。接种小鼠的血清 也受到保护（授予“无源免疫史”）。在壁虱中，消除了同源菌株，但 异源菌株没有，表明该疫苗针对抗原产生了反应 由细菌在哺乳动物感染和tick中产生。部分保护也是 反对Garinii感染。我们的假设是活疫苗菌株提供 识别新型保护抗原的独特工具。为了进一步表征受保护的响应 针对活疫苗，我们建议1）确定由血清识别的抗原 接种小鼠； 2）生产并测试这些抗原作为亚基疫苗的重组版本； 3） 分析免疫的小鼠中的免疫响应，并评估与关节炎易感性的关联 挑战感染性B. Burgdorferi。这些实验将检验活体减弱的新假设。 关于鉴定细菌产生的保护抗原 并由小鼠免疫系统在体内识别。我们将采取的方法将阐明新的 候选抗原，可有效且可安全，可对莱姆病疫苗的未来开发。