A Novel Strategy for Generating Safe and Effective Flavivirus Vaccines

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 突发事件继续挑战准确的预测，暴露出我们无法迅速做出反应和控制 疫情爆发。新出现的黄病毒在医学和兽医上的重要性因 缺乏可用的疫苗、治疗方法和可靠的控制措施。疫苗接种仍然是最多的 疫情预防和控制的可靠战略，但疫苗开发本质上涉及权衡 安全性和免疫原性之间的关系。这项研究将开发一个平台，通过以下方式克服这些权衡 将非复制平台的安全优势与疫苗快速、持久的免疫原性相结合 减毒活疫苗。我们已经开发了一种独特的嵌合病毒平台，该平台基于一种新的昆虫特异性 黄病毒(ISFV)、ARIPO病毒(ARPV)。初步数据显示，ARPV的主机限制明显晚于 复制周期比描述的其他ISFV更长，并且能够进入脊椎动物细胞并发展成 在没有基因组复制的情况下产生强大的免疫反应。开发了一种ARPV/ZIKV嵌合体来测试 我们的假设是，ARPV/ZIKV疫苗接种会产生一种快速而强大的先天性、体液和细胞介导的 引起对后续ZIKV挑战的灭菌免疫力的免疫反应。初步研究表明 单剂ARPV/ZIKV可产生强大的适应性ZIKV特异性免疫反应，完全 保护小鼠免受病毒血症、体重减轻和死亡的影响，同时在体内显示出非凡的安全性。这 平台之所以优越，是因为嵌合体由于其基本的复制而增加了安全性 脊椎动物细胞的缺陷，由于缺乏灭活要求而增强的免疫原性，以及有效 将基因组传递到靶细胞。这款创新而必要的R01旨在评估安全配置文件， ARPV/ZIKV疫苗通过三个目的保护效力和免疫原性的机制： 1.检测ARPV/ZIKV免疫对小鼠ZIKV诱导的疾病的预防作用 猕猴模型。 2.阐明疫苗对ZIKV诱导的ARPV/ZIKV疾病的潜在保护作用 接种疫苗的小鼠模型。 3.评价该候选疫苗的体内外安全性，并阐明其作用机制 它的免疫原性。 这项研究将产生一种安全、有效、单剂ZIKV疫苗，将非常适合以负担得起的价格 控制爆炸性疫情，这通常影响到资源有限的地区。我们平台的抗原性优势 将导致增强的疗效，有效地结合了复制缺陷病毒样颗粒或 核酸疫苗具有抗原性优越、快速、长寿、免疫原性活减毒等优点 疫苗。这个平台也可以很容易地翻译成其他对人类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.