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

• 批准号: 10176402
• 负责人: Albert J. Auguste
• 金额: $ 39.56万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10176402
• 关键词: Adjuvant; Affect; Americas; Arboviruses; Area; Attenuated Vaccines; 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 access; vaccine candidate; vaccine development; vaccine efficacy; vaccine trial; vaccine-induced immunity; vector vaccine; viral transmission

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 爆发。新兴黄病毒的医学和兽医重要性因 缺乏可用的疫苗、治疗方法和可靠的控制措施。疫苗接种仍然是最重要的 疫情防控的可靠策略，但疫苗开发本质上涉及权衡 安全性和免疫原性之间。本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 减毒活疫苗。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）、阿里波病毒（ARPV）。初步数据显示 ARPV 的宿主限制明显晚于 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 在没有基因组复制的情况下产生强大的免疫反应。开发了 ARPV/ZIKV 嵌合体来测试 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。 免疫反应，引发针对随后的 ZIKV 攻击的灭菌免疫力。初步研究表明 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。这 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 基因组递送至靶细胞。这一创新且重要的 R01 旨在评估安全状况， 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 疾病的潜在保护作用的相关性 接种疫苗的小鼠模型。 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 控制通常影响资源有限地区的爆炸性疫情。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 疫苗。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。