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

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

展开

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 Arbovirus在全球范围内对人类和动物健康构成了不断威胁。它们是由造血节肢动物，主要是蚊子。其中之一，艾德斯伊格普蒂（Aedes Aegypti），是几个的主要向量广泛传播寨卡病毒，例如寨卡病毒，登革热和西尼罗河病毒，对于大多数人，人类许可疫苗不存在或次优。这些病原体与唾液一起传播到宿主皮肤中在喂食期间。该唾液包含一百多种独特的蛋白质，可以调节许多生理功能，促进血液喂养。已经表明，许多唾液蛋白通过调节来增强arbovirus的感染性和发病机理咬伤部位的免疫反应。对他们的阻塞疗法的发展可能是一个好减少受感染宿主中病毒传播的方法。这种方法也可能克服与病毒抗原作为疫苗靶标，由于其高变异性或诱导抗体的可能性依赖增强发作。在第一阶段，已经建立了一种原则证明，以实现一种新的预防策略，以一种唾液为目标 A. egypti唾液中分泌的蛋白质AGBR1，其中被动地和主动免疫功能抗体受到免疫功能鼠模型受到了通过蚊子叮咬传播的寨卡病毒的部分保护。程度保护与免疫动物中达到的抗体滴度相关。但是，使用免疫功能低下的模型有一些局限性，例如抗体反应的弱点，这一事实是限制可以实现的最大保护。在此II阶段应用程序中，我们将定义，优化和验证疫苗接种方案。我们将通过在进行免疫接种来规避免疫功能低下的动物模型的局限性免疫能力的鼠宿主。我们将通过转移抗体和/或来测试获得的保护程度免疫细胞对免疫功能低下的小鼠，还研究了免疫反应的细胞分支的作用针对ZIKV感染，因为对蚊子唾液抗原的细胞免疫反应知之甚少。此外，我们将在几内亚猪和仓鼠中进行这些疫苗接种研究，以证明强大的对小鼠以外的物种可以引起对AGBR1的免疫反应。我们将开发一只豚鼠， A. aegypti蚊子叮咬传播的寨卡寨模型，我们将测试免疫我们候选疫苗的功效。最后，我们将分析疫苗对其他Zika-的潜在功效相关的黄病毒，例如DENV和WNV，目的是生成泛氟病毒疫苗的候选者可以单独使用或与病原体特异性疫苗一起使用。