A novel vaccine against mosquito-borne Zika virus based on mosquito salivary gland protein AgBR1

基于蚊子唾液腺蛋白AgBR1的新型针对蚊媒寨卡病毒的疫苗

基本信息

批准号：
10685948
负责人：
Erol Fikrig
金额：
$ 97.95万
依托单位：
L2 DIAGNOSTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-21 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685948
关键词：
Active Immunization Adjuvant Aedes Aluminum Aluminum Hydroxide Animal Model Animals Antibodies Antibody Response Antibody titer measurement Antibody-Dependent Enhancement Antigens Arboviruses Arthropods Bite Blood Bolus Infusion CD8-Positive T-Lymphocytes Cavia Cells Clinical Culicidae Dengue Virus Development Disease model Dose Flavivirus Formulation Funding General Population Granulocyte-Macrophage Colony-Stimulating Factor Hamsters Health Human IL8 gene IgE IgG1 Immune Immune Sera Immune response Immunization Immunize Immunocompetent Immunocompromised Host Immunodeficient Mouse Immunoglobulin A Immunoglobulin G Immunoglobulin M Immunologic Deficiency Syndromes Immunologics Inbred BALB C Mice Inbred Mouse Infection Interferon Type II Interleukin-1 beta Interleukin-10 Interleukin-2 Interleukin-4 Interleukin-5 Interleukin-6 Kinetics Licensing Modeling Montanide ISA-51 Mus Pathogenesis Patients Phase Physiological Play Poly I-C Procedures Prophylactic treatment Protein Secretion Proteins Regimen Rodent Rodent Model Role Route Saliva Salivary Salivary Proteins Site Skin T cell response T-Cell Activation T-Lymphocyte TNF gene Testing Titrations Vaccinated Vaccination Vaccine Adjuvant Vaccines Viral Viral Antigens West Nile virus ZIKA ZIKV infection Zika Virus antibody transfer cytokine efficacy evaluation feeding human disease immunogenicity immunoregulation mosquito-borne mouse model nonhuman primate novel strategies novel vaccines pathogen phase 2 study prototype response transmission process vaccine candidate vaccine development vaccine trial vector viral transmission

项目摘要

SUMMARY Arboviruses present a constant threat to human and animal health worldwide. They are transmitted by hematophagous arthropods, primarily mosquitoes. One of them, Aedes aegypti, is the primary vector of several widely spread arboviruses such as Zika, dengue and West Nile viruses, and for most of them, human-licensed vaccines do not exist or are suboptimal. These pathogens are transmitted into the host skin together with saliva during feeding. This saliva contains over one hundred unique proteins which can modulate many physiological functions, facilitating blood feeding. It has been shown that many salivary proteins enhance infectivity and pathogenesis of arboviruses by modulating immune responses at the bite site. The development of blocking therapies against them could be a good approach to reduce viral spread in the infected host. This approach may also overcome issues associated with the use of viral antigens as a vaccine targets, due to their high variability or the possibility of induction of antibody- dependent enhancement episodes. In Phase I, a proof-of-principle has been established for a novel strategy of prophylaxis, targeting one salivary protein secreted in A. aegypti saliva, AgBR1, in which passively and actively immunized immunocompromised murine models were partially protected against Zika virus transmitted via mosquito bites. The degree of protection correlated with the antibody titer reached in the immunized animals. However, the use of immunocompromised models has some limitations, such as the weakness of the antibody response, a fact that limits the maximum protection that can be achieved. In this Phase II application, we will define, optimize, and validate a vaccination regimen. We will circumvent the limitations of the immunocompromised animal model by conducting immunizations in immunocompetent murine hosts. We will test the degree of protection achieved by transferring antibodies and/or immune cells to immunocompromised mice, also studying the role of the cellular branch of the immune response against ZIKV infection, as the cellular immune response against mosquito salivary antigens is poorly understood. In addition, we will perform these vaccination studies in guinea pigs and hamsters, to demonstrate that a strong immune response against AgBR1 can be elicited in species other than mice. We will develop a guinea pig and a hamster model of Zika infection transmitted by A. aegypti mosquito bites, and we will test the immunization efficacy of our vaccine candidates. Lastly, we will analyze the potential efficacy of our vaccine against other Zika- related flaviviruses, such as DENV and WNV, with the aim to generate a pan-flaviviral vaccine candidate which could be used alone or in conjunction with pathogen-specific vaccines.

概括虫媒病毒对全世界人类和动物健康构成持续威胁。它们是通过以下方式传输的食血节肢动物，主要是蚊子。其中之一，埃及伊蚊，是多种疾病的主要传播媒介。广泛传播的虫媒病毒，如寨卡病毒、登革热病毒和西尼罗河病毒，其中大多数都是人类许可的疫苗不存在或不是最理想的。这些病原体与唾液一起传播到宿主皮肤中喂食期间。这种唾液含有一百多种独特的蛋白质，可以调节许多生理功能功能，有利于血液的输送。研究表明，许多唾液蛋白通过调节虫媒病毒的感染性和发病机制。咬伤部位的免疫反应。针对它们的阻断疗法的开发可能是一个很好的选择减少病毒在受感染宿主中传播的方法。这种方法还可以克服与以下相关的问题使用病毒抗原作为疫苗靶标，因为它们具有高度变异性或诱导抗体的可能性依赖性增强发作。在第一阶段，针对一种新的预防策略建立了原理验证，该策略针对一种唾液埃及伊蚊唾液中分泌的蛋白质 AgBR1，其中被动和主动免疫免疫功能低下的小鼠模型得到了部分保护，免受通过蚊子叮咬传播的寨卡病毒的侵害。程度保护作用与免疫动物中达到的抗体滴度相关。然而，使用免疫受损模型有一些局限性，例如抗体反应较弱，这一事实限制了可以实现的最大保护。在这个第二阶段的应用中，我们将定义、优化和验证疫苗接种方案。我们将通过在以下环境中进行免疫接种来规避免疫受损动物模型的局限性：具有免疫能力的小鼠宿主。我们将测试通过转移抗体和/或将免疫细胞注射到免疫功能低下的小鼠中，同时研究免疫反应细胞分支的作用由于对蚊子唾液抗原的细胞免疫反应知之甚少，因此人们对 ZIKV 感染的研究还很有限。此外，我们将在豚鼠和仓鼠中进行这些疫苗接种研究，以证明强有力的疫苗接种除小鼠外，其他物种也可引发针对 AgBR1 的免疫反应。我们将培养一只豚鼠埃及伊蚊叮咬传播寨卡病毒感染的仓鼠模型，我们将测试免疫接种情况我们候选疫苗的功效。最后，我们将分析我们的疫苗针对其他寨卡病毒的潜在功效相关黄病毒，例如登革热病毒和西尼罗河病毒，旨在产生一种泛黄病毒候选疫苗可单独使用或与病原体特异性疫苗联合使用。