A Novel Strategy for Generating Safe and Effective Flavivirus Vaccines

寨卡病毒（ZIKV）的最近出现和破坏性影响清楚地表明， 新出现的情况继续挑战准确的预测，并暴露出我们无法迅速作出反应和控制 爆发。新出现的黄病毒的医学和兽医学重要性因以下因素而显著加剧： 缺乏可用的疫苗、疗法和可靠的控制措施。接种疫苗仍然是最重要的 预防和控制疫情的可靠战略，但疫苗开发本质上涉及权衡 安全性和免疫原性之间。这项研究将开发一个平台，以克服这些权衡， 将非复制平台的安全性优势与免疫原性的快速和长寿命的免疫原性相结合， 减毒活疫苗。我们已经开发了一种独特的嵌合病毒平台， 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 与其它ISFV所描述的复制周期不同， 在没有基因组复制的情况下产生强大的免疫应答。开发了ARPV/ZIKV嵌合体以测试 我们假设ARPV/ZIKV疫苗接种产生快速和强大的先天性、体液和细胞介导的免疫应答， 免疫应答增强针对随后ZIKV攻击的消除免疫。初步研究表明 单剂量ARPV/ZIKV产生了强大的适应性ZIKV特异性免疫应答， 保护小鼠免于病毒血症、体重减轻和死亡，同时在体内显示出优异的安全性。这 平台是上级的，因为凭借其基本复制，嵌合体的安全性增加 脊椎动物细胞中的缺陷，由于缺乏灭活要求而增加的免疫原性，以及有效的 将基因组递送至靶细胞。这一创新和必要的R 01旨在评估安全性， ARPV/ZIKV疫苗免疫原性的保护效力和机制通过三个目的： 1.确定ARPV/ZIKV免疫在鼠和小鼠中预防ZIKV诱导的疾病的功效。 恒河猴模型。 2.阐明ARPV/ZIKV中疫苗诱导的针对ZIKV诱导的疾病的保护的潜在相关性 接种的鼠模型。 3.评价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。 这项研究将产生一种安全、有效、单剂量的ZIKV疫苗，它将非常适合于负担得起的疾病。 控制通常影响资源有限地区的爆炸性疾病爆发。我们平台的抗原优势 将导致增强的功效，有效地结合复制缺陷型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， 疫苗。这个平台也可以很容易地翻译成其他人或兽医重要的黄病毒。

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.