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: 8876575
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876575
• 关键词: Active Immunization; Adjuvant; Antibodies; Antigens; Arthropods; Bite; Black-legged Tick; Borrelia; Borrelia burgdorferi; Collaborations; Complement; Drug Formulations; Ensure; Epitopes; Health; 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; research study; response; success; tick borne spirochete; transmission process; vaccine delivery; vaccine development; 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)：这项提案寻求开发一种新的莱姆病疫苗--通过靶向对伯氏疏螺旋体从扁虱传播到哺乳动物宿主至关重要的肩部硬蜱蛋白。早期的工作已经确定了四种Tick蛋白，Salp15，TRE31，tHRF和TSLPI，它们促进了螺旋体传播的不同步骤，并且对这些蛋白的免疫单独提供了对螺旋体向小鼠宿主传播的部分损害。同时以这些蛋白质为靶点可能会损害多个传播步骤，并有效地阻碍传播。在这一预防莱姆病的新策略中，我们将评估疫苗靶向的有效性：a.与疏螺旋体相互作用的扁虱蛋白TRE31和Salp15的组合，分别破坏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.协助疏螺旋体的唾液蛋白、扁虱唾液凝集素途径抑制物(TSLPI)和扁虱组胺释放因子(THRF)的组合，它们在物理上与螺旋体无关，但在传播期间和扁虱充血时分别在提高螺旋体在宿主中的存活方面发挥重要作用；以及C.结合疏螺旋体(Salp15和TRE31)和协助疏螺旋体(TSLPI和tHRF)扁虱蛋白的组合，有效地阻止螺旋体到达并在扁虱叮咬部位存活。到目前为止，这种系统的方法还没有被探索过，原则上也可以适用于阻止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第二阶段的莱姆病多价硬蜱抗原肽疫苗的研制奠定基础。