A Novel Strategy for Generating Safe and Effective Flavivirus Vaccines

生产安全有效的黄病毒疫苗的新策略

基本信息

批准号：
10033124
负责人：
Albert J. Auguste
金额：
$ 38.68万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10033124
关键词：
Adjuvant Affect Americas Area Attenuated Live Virus Vaccine Biological Blood Transfusion Body Weight decreased Cells Central America Chimera organism Chimeric Proteins Complementary DNA Country Data Defect Defective Viruses Dengue Fever Detection Disease Outbreaks Dose E protein Ensure Equilibrium Event Flavivirus Genome Genomics Geography Goals Guillain-Barré Syndrome Health Human Immune Immune response Immunity Immunization In Vitro In complete remission Inactivated Vaccines Insecta Japanese Encephalitis Vaccines Knowledge Kyasanur Forest Disease Longevity Macaca Macaca mulatta Measures Medical Membrane Proteins Modeling Morbidity - disease rate Mus Natural Immunity Nucleic Acid Vaccines Pathogenesis Pathogenicity Pattern recognition receptor Penetration Perinatal Prevention Production Regimen Reporting Resources Risk Role Route Safety Signal Transduction South America Southeastern Asia Testing Therapeutic Tick-Borne Encephalitis Translating Translations Vaccinated Vaccination Vaccines Vertebral column Viral Viremia Virus Virus Diseases Virus Replication Virus-like particle Yellow Fever ZIKV infection Zika Virus Zika virus vaccine adaptive immune response base biodefense burden of illness cell mediated immune response combat congenital zika syndrome dosage env Gene Products immunogenicity in vivo innovation mortality mouse model novel novel strategies pathogen prevent protective efficacy safety study success transmission process vaccine candidate vaccine development vaccine efficacy vaccine trial vaccine-induced immunity vector vaccine viral transmission

项目摘要

The recent emergence and devastating impact of Zika virus (ZIKV) clearly demonstrates that arboviral emergence continues to defy accurate prediction and exposes our inability to rapidly respond to and control outbreaks. The medical and veterinary importance of emerging flaviviruses is significantly exacerbated by the absence of available vaccines, therapeutics, and reliable control measures. Vaccination remains the most reliable strategy for outbreak prevention and control, but vaccine development intrinsically involves trade-offs between safety and immunogenicity. This study will develop a platform to overcome these trade-offs by combining the safety advantages of non-replicating platforms with the rapid and long-lived immunogenicity of a live-attenuated vaccine. We have developed a unique chimeric virus platform based on a novel insect-specific flavivirus (ISFV), Aripo virus (ARPV). Preliminary data shows ARPV’s host restriction is noticeably later in the replication cycle than described for other ISFVs and is capable of entering vertebrate cells and developing a robust immune response in the absence of genomic replication. An ARPV/ZIKV chimera was developed to test our hypothesis that ARPV/ZIKV vaccination produces a rapid and robust innate, humoral, and cell-mediated immune response that elicits sterilizing immunity against subsequent ZIKV challenge. Preliminary studies show a single dose of ARPV/ZIKV produces a robust adaptive ZIKV-specific immune response that completely protects mice from viremia, weight loss, and mortality, while demonstrating exceptional safety in vivo. This platform is superior because of the increased safety of the chimera by virtue of its fundamental replication defect in vertebrate cells, increased immunogenicity due to a lack of inactivation requirements, and efficient genome delivery to target cells. This innovative and essential R01 aims to evaluate the safety profile, protective efficacy and mechanisms underlying the immunogenicity of ARPV/ZIKV vaccination via three aims: 1. Determine the efficacy of ARPV/ZIKV immunization for preventing ZIKV-induced disease in murine and rhesus macaque models. 2. Elucidate the correlates underlying vaccine-induced protection from ZIKV-induced disease in ARPV/ZIKV vaccinated murine models. 3. Evaluate the safety profile of this vaccine candidate in vitro and in vivo, and elucidate the mechanism underlying its immunogenicity. This study will generate a safe, efficacious, single-dose ZIKV vaccine that will be ideally suited to affordably control explosive outbreaks, which typically affect resource-limited regions. Our platform’s antigenic superiority will result in enhanced efficacy, effectively combining the safety of replication-defective virus-like particles or nucleic acid vaccines with the antigenic superiority, and rapid, long-lived immunogenicity of live-attenuated vaccines. This platform can also be readily translated to other flaviviruses of human or veterinary importance.

寨卡病毒 (ZIKV) 最近的出现和破坏性影响清楚地表明，虫媒病毒的出现继续挑战准确的预测，并暴露出我们无法快速响应和控制新型黄病毒的医学和兽医重要性因疫情而显着加剧。缺乏可用的疫苗、治疗方法和可靠的控制措施仍然是最严重的问题。疫情防控的可靠策略，但疫苗开发本质上涉及权衡这项研究将开发一个平台来克服这些权衡。将非复制平台的安全优势与快速且持久的免疫原性相结合我们开发了一种基于新型昆虫特异性的独特嵌合病毒平台。黄病毒 (ISFV)、Aripo 病毒 (ARPV) 初步数据显示 ARPV 的宿主限制明显较晚。复制周期比其他 ISFV 描述的要长，并且能够进入脊椎动物细胞并形成开发了 ARPV/ZIKV 嵌合体来测试在没有基因组复制的情况下的强大免疫反应。我们的假设是 ARPV/ZIKV 疫苗接种会产生快速而强大的先天性、体液性和细胞介导的免疫反应初步研究表明，这种免疫反应可引发针对随后的 ZIKV 攻击的灭菌免疫力。单剂 ARPV/ZIKV 会产生强大的适应性 ZIKV 特异性免疫反应，保护小鼠免受病毒血症、体重减轻和死亡，同时表现出卓越的体内安全性。平台之所以优越，是因为嵌合体凭借其基本复制而提高了安全性脊椎动物细胞的缺陷，由于缺乏灭活要求而增加的免疫原性，以及有效的这种创新且重要的 R01 旨在评估安全性， ARPV/ZIKV 疫苗接种的保护功效和免疫原性机制通过以下三个目标实现： 1. 确定 ARPV/ZIKV 免疫对于预防小鼠和小鼠中 ZIKV 引起的疾病的功效恒河猴模型。 2. 阐明疫苗对 ARPV/ZIKV 引起的 ZIKV 疾病的保护作用的相关性小鼠模型。 3. 评估该候选疫苗的体外和体内安全性，并阐明其机制其免疫原性的基础。这项研究将产生一种安全、有效、单剂量的 ZIKV 疫苗，非常适合经济实惠的人群控制爆炸性疫情，这通常会影响我们平台的抗原优势。将导致功效增强，有效结合复制缺陷病毒样颗粒的安全性或核酸疫苗具有减毒活疫苗的抗原优势和快速、长效的免疫原性该平台还可以很容易地转化为对人类或兽医具有重要意义的其他黄病毒。