Vaccination against Zika virus infection using mosquito NeSt1 protein

使用蚊子 NeSt1 蛋白预防寨卡病毒感染的疫苗

基本信息

批准号：
10081573
负责人：
Michel Ledizet
金额：
$ 29.92万
依托单位：
L2 DIAGNOSTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-16 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081573
关键词：
Active Immunization Adjuvant Aedes Aluminum Hydroxide Animal Model Animals Antibodies Antibody Response Arboviruses Arthropods Bacteria Bite Blood Cells Culicidae Dengue Dengue Virus Development Dose Drosophila genus Flavivirus Goals Health Human Immune Sera Immune response Immunity Immunization Immunize Individual Infection Insecta Mediating Medical Methods Mus Passive Immunization Pathogenesis Phase Physiological Post-Translational Protein Processing Proteins Recombinant Proteins Recombinants Regimen Saliva Salivary Proteins Schedule Serum Skin Structure Subcutaneous Injections Surface System Time Vaccination Vaccines Viral Antigens Viremia Virus Virus Diseases West Nile virus Yeasts ZIKA ZIKV disease ZIKV infection Zika Virus arthropod-borne base experimental study feeding glycosylation mortality mosquito-borne mouse model neutrophil novel pathogen phase 2 study prevent protective effect success synergism transmission-blocking vaccine vaccine candidate vaccine development vector mosquito viral transmission

项目摘要

Arthropod-borne viruses (arboviruses) present a substantial threat to human and animal health worldwide. They are transmitted by hematophagous arthropods, in which mosquitoes are one of the main transmitters. The mosquito specie, Aedes aegypti, is the primary mosquito vector of several widely spread arboviruses as zika, dengue or West Nile viruses. Mosquitoes transmit these pathogens by inoculating virus-infected saliva into host skin during probing and feeding. This saliva contains over one hundred unique proteins and these proteins have diverse functions, including facilitating blood feed. Some of these proteins are known to enhance infectivity and pathogenesis in Zika and other arboviruses by modulating immune responses, and the development of blocking therapies against them could be a good approach to reduce infectivity and pathogenesis in the host. In addition, focusing on mosquito proteins as vaccine targets can overcome the problems associated with the use of viral antigens as a vaccine targets, due to their high variability. In this proposal, we will develop a novel transmission-blocking vaccine against Zika virus (ZIKV) by targeting A. aegypti bacteria responsive protein 1 (AgBR1) and A. aegypti neutrophil stimulating factor 1 (NeSt1) salivary gland protein. Using a yeast surface display screen, we identified a set of A. aegypti salivary proteins that react with sera from mice repeatedly bitten by A. aegypti mosquitoes. Passive immunization with antiserum against two of these proteins, AgBR1 and NeSt1, resulted in significantly more survival in mice infected with ZIKV by mosquito bite. Simultaneous passive immunization with both antisera demonstrated a synergy resulting in higher survival than expected from the individual treatments. Based on these results, in this proposal we intend to carefully examine the protective effects of blocking the mosquito AgBR1 and NeSt1 proteins in preventing severe mosquito-borne ZIKV infection in mice. We will develop a strategy for actively immunizing mice against both proteins towards the development of a vaccine for use in humans. The success of this approach also offers a functional paradigm for developing vaccines against other flaviviruses and other arthropod- borne pathogens of medical importance.

节肢动物传播的病毒（虫媒病毒）对人类和动物健康构成重大威胁全世界。它们通过食血节肢动物传播，其中蚊子是其中之一主要发射机。埃及伊蚊是蚊子的主要媒介几种广泛传播的虫媒病毒，如寨卡病毒、登革热病毒或西尼罗河病毒。蚊子传播这些病原体通过在探测过程中将感染病毒的唾液接种到宿主皮肤中来消除喂养。这种唾液含有一百多种独特的蛋白质，这些蛋白质具有不同的特性功能，包括促进血液供给。已知其中一些蛋白质可以增强通过调节免疫反应来研究寨卡病毒和其他虫媒病毒的感染性和发病机制，以及针对它们的阻断疗法的开发可能是减少宿主的传染性和发病机制。此外，重点关注蚊子蛋白作为疫苗靶标可以克服与使用病毒抗原作为疫苗靶标相关的问题，由于其高度可变性。在这项提案中，我们将开发一种针对寨卡病毒（ZIKV）的新型传播阻断疫苗通过靶向埃及伊蚊细菌反应蛋白 1 (AgBR1) 和埃及伊蚊中性粒细胞刺激因子 1 (NeSt1) 唾液腺蛋白。使用酵母表面显示屏，我们鉴定出一组埃及伊蚊唾液蛋白，这些蛋白可与反复被埃及伊蚊咬伤的小鼠血清发生反应 A. 埃及蚊子。使用针对其中两种蛋白质的抗血清进行被动免疫， AgBR1 和 NeSt1 使蚊子感染 ZIKV 的小鼠的存活率显着提高咬。同时使用两种抗血清进行被动免疫显示出协同作用，从而导致个体治疗的存活率高于预期。基于这些结果，在本提案中，我们打算仔细研究以下物质的保护作用：阻断蚊子 AgBR1 和 NeSt1 蛋白可预防严重的蚊媒 ZIKV 小鼠感染。我们将制定一种策略，使小鼠主动免疫这两种蛋白质致力于开发用于人类的疫苗。这种方法的成功还提供了开发针对其他黄病毒和其他节肢动物的疫苗的功能范例具有医学重要性的病原体。