A Multivalent Lyme Disease Vaccine Targeting Tick-Host-Pathogen Interactions

针对蜱虫宿主病原体相互作用的多价莱姆病疫苗

• 批准号: 8714278
• 负责人: SUKANYA NARASIMHAN
• 金额: $ 30万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714278
• 关键词: Active Immunization; Adjuvant; Antibodies; Antigens; Arthropods; Bite; Black-legged Tick; Borrelia; Borrelia burgdorferi; Collaborations; Complement; Drug Formulations; Ensure; Epitopes; Host Defense; Human; Immune; Immune Sera; Immunity; Impairment; Infection; Interleukin-4; Lectin; Liposomes; Lyme Disease; Lyme Disease Vaccines; Medical; Membrane Proteins; Methods; Modeling; Mus; Names; Order Spirochaetales; OspC protein; Passive Immunization; Pathway interactions; Peptides; Phase; Play; Production; Proteins; Role; Saliva; Salivary; Salivary Proteins; Site; Skin; Splenocyte; Staging; Structure; Ticks; Vaccine Design; Vaccines; Work; base; defense response; density; feeding; inhibitor/antagonist; mouse model; nanoparticulate; novel vaccines; p23 translationally controlled tumor protein; pathogen; peptide based vaccine; phase 2 study; prevent; professor; public health relevance; research study; response; success; tick borne spirochete; transmission process; vaccine delivery; vaccine efficacy

DESCRIPTION (provided by applicant): This proposal seeks to develop a novel vaccine against Lyme disease -- by targeting Ixodes scapularis proteins critical for Borrelia burgdorferi transmission from the tick to mammalian host. Earlier work has identified four tick proteins, Salp15, TRE31, tHRF and TSLPI, that facilitate different steps of spirochete transmission and immunity against these proteins individually provided partial impairment of spirochete transmission to the murine host. Simultaneously targeting these proteins might compromise multiple steps of transmission and effectively thwart transmission. Towards this new strategy to prevent Lyme disease, we will assess the efficacy of vaccine targeting: A. A combination of Borrelia-interacting tick proteins, TRE31, and Salp15, to impair interactions that facilitate spirochete egress from the gut and interactions that ensure spirochete survival in the host respectively; B. A combination of Borrelia-assisting salivary proteins, Tick Salivary Lectin Pathway Inhibitor (TSLPI) and tick histamine release factor (tHRF), that do not physically associate with the spirochete, but play a significant role in enhancing spirochete survival in the host during transmission and in tick engorgement respectively; and C. A combination of Borrelia-interacting (Salp15 and TRE31) and Borrelia-assisting (TSLPI and tHRF) tick proteins to effectively thwart spirochete arrival and survival at the tick bite-site. Such a systematic approach has hitherto not been explored and could in principle also be applicable to thwart other arthropod- borne pathogens. The success of this multipronged derailment approach will provide the basis for the formulation of a multivalent tick antigenic peptide-based vaccine against Lyme disease in Phase II efforts.

描述（由申请人提供）：该提案旨在开发一种针对莱姆病的新型疫苗-通过靶向肩胛硬蜱蛋白质，该蛋白质对于伯氏疏螺旋体从蜱传播到哺乳动物宿主至关重要。早期的工作已经确定了四种蜱蛋白，Salp 15，TRE 31，tHRF和TSLPI，它们促进螺旋体传播的不同步骤，并且针对这些蛋白的免疫单独地提供了螺旋体向鼠宿主传播的部分损害。同时靶向这些蛋白质可能会损害多个传播步骤，并有效地阻止传播。针对这一预防莱姆病的新策略，我们将评估疫苗靶向的有效性：疏螺旋体相互作用蜱蛋白TRE 31和Salp 15的组合，分别削弱促进螺旋体从肠道排出的相互作用和确保螺旋体在宿主中存活的相互作用; B.疏螺旋体辅助唾液蛋白、蜱唾液凝集素途径抑制剂（TSLPI）和蜱组胺释放因子（tHRF）的组合，其不与螺旋体物理结合，但分别在传播期间和蜱充血期间增强螺旋体在宿主中的存活中起重要作用;和C.疏螺旋体相互作用（Salp 15和TRE 31）和疏螺旋体辅助（TSLPI和tHRF）蜱蛋白的组合，可有效阻止螺旋体到达蜱叮咬部位并存活。这种系统的方法迄今尚未被探索，原则上也可以适用于挫败其他节肢动物传播的病原体。这种多管齐下的脱轨方法的成功将为在第二阶段努力中制定基于多价蜱抗原肽的莱姆病疫苗提供基础。