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: 9173245
• 负责人: Joseph J Campo
• 金额: $ 38.54万
• 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/9173245
• 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.); Control Groups; DBL Oncoprotein; Data; Data Set; Development; Europe; Evaluation; Formulation; Future; Generations; Genome; Geographic Locations; Goals; Human; Immune; Immune Sera; Immune response; Immune system; Immunoglobulin G; Incidence; Infection; Integrins; Laboratory culture; Left; Life; Ligands; Lipoproteins; Lyme Arthritis; Lyme Disease; Lyme Disease Vaccines; Monitor; Morbidity - disease rate; Mus; Nature; Needles; North America; OspA protein; Passive Immunity; Passive Immunization; Phase; Plasmids; Population; Populations at Risk; Predisposition; Protein Microchips; Proteins; Proteome; Recombinants; Refractory; Research; Safety; Serum; Subunit Vaccines; Surface; Symptoms; Testing; Ticks; Time; VDAC1 gene; Vaccinated; Vaccination; Vaccines; Variant; Work; base; cytokine; extracellular; feeding; high risk; in vivo; interest; killings; mouse model; mutant; novel; novel strategies; novel vaccines; pathogen; post-market; research study; 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.

伯氏疏螺旋体、加里尼伯氏疏螺旋体和阿夫泽利伯氏疏螺旋体在不同的地理位置都是莱姆病的病原。如果