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

• 批准号: 10194371
• 负责人: Michel Ledizet
• 金额: $ 29.39万
• 依托单位: L2 DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194371
• 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; efficacy evaluation; 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

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）对人类和动物的健康构成重大威胁 国际吧它们是由吸血节肢动物传播的，蚊子是其中之一。 主要的发射机。蚊子种类埃及伊蚊是疟疾的主要蚊媒。 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 这些病原体在探测过程中通过感染了HPV的唾液进入宿主皮肤， 喂食这种唾液含有超过100种独特的蛋白质，这些蛋白质具有不同的 功能，包括促进血液供给。其中一些蛋白质可以增强 通过调节免疫反应，感染寨卡病毒和其他虫媒病毒， 针对它们的阻断疗法的发展可能是一种很好的方法， 在宿主中的传染性和致病性。此外，将蚊子蛋白作为疫苗 靶可以克服与使用病毒抗原作为疫苗靶相关的问题， 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 以A为目标。埃及伊蚊细菌应答蛋白1（AgBR 1）和埃及伊蚊（A.埃及嗜中性粒细胞 刺激因子1（NeSt1）唾液腺蛋白。使用酵母表面显示屏，我们 确定了一组A。埃及伊蚊唾液蛋白与反复叮咬的小鼠血清反应， A.埃及蚊子。用抗这些蛋白质中的两种的抗血清进行被动免疫， AgBR 1和NeSt 1在通过蚊子感染ZIKV的小鼠中导致显著更多的存活 咬人的用两种抗血清同时进行被动免疫证明了协同作用， 存活率高于个体治疗的预期。 基于这些结果，在本提案中，我们打算仔细研究 阻断蚊子AgBR1和NeSt1蛋白，预防严重的蚊子传播的ZIKV 感染小鼠。我们将开发一种主动免疫小鼠对抗这两种蛋白质的策略 开发用于人类的疫苗。这种方法的成功还提供了 一种用于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。