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: 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
• 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

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）的最近出现和破坏性影响清楚地表明了Arboviral 出现继续违抗准确的预测，并暴露了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严重加剧了 疫苗接种仍然是可用的疫苗，治疗和可靠的控制措施。 可靠的预防和控制爆发策略，但疫苗开发本质上涉及权衡取舍 在安全性和免疫原性之间。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A的快速和长期免疫原性相结合 实时疫苗。我们已经建立了一个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）。初步数据表明，ARPV的主机限制明显在稍后 复制周期比其他ISFV所述的复制周期，并且能够进入脊椎动物细胞并开发A 在没有基因组复制的情况下，可靠的免疫反应。开发了ARPV/ZIKV嵌合体进行测试 我们的假设是ARPV/ZIKV疫苗接种产生快速而强大的先天，体液和细胞介导的 免疫反应会引起对随后的ZIKV挑战的免疫力进行消毒。初步研究表明 单剂量的ARPV/ZIKV产生强大的自适应ZIKV特异性免疫反应，完全完全 保护小鼠免受病毒血症，体重减轻和死亡率的侵害，同时证明体内特殊的安全性。这 平台之所以出色，是因为嵌合体的基本复制的安全性提高 脊椎动物细胞缺陷，由于缺乏灭活要求而增加免疫原性，并有效 基因组传递到靶细胞。这种创新和必不可少的R01旨在评估安全性， 通过三个目的，ARPV/ZIKV疫苗接种的免疫原性的保护效率和机制： 1。确定ARPV/ZIKV免疫对防止ZIKV诱导的鼠类疾病的效率 恒河猕猴模型。 2。阐明了疫苗诱导的潜在疫苗诱导的ZIKV诱导的疾病的相关性。 接种的鼠模型。 3。在体外和体内评估该疫苗候选者的安全性，并阐明机制 其免疫原性的基础。 这项研究将产生一种安全，高效，单剂量ZIKV疫苗，理想地适合负担得起 控制爆炸性爆发，通常会影响资源有限的区域。我们平台的抗原优势 将提高有效性，有效地结合了复制缺陷性病毒样颗粒的安全性或 具有抗原优势的核酸疫苗，以及活衰减的快速，长期的免疫原性 疫苗。该平台也可以轻松地转化为其他人类或兽医重要性的黄病毒。