Epitope-focused vaccine strategies against Zika virus

总结-总体（PI：Michel Nussenzweig） 虽然寨卡病毒（ZIKV）感染通常会导致轻微的疾病，但当它发生时，它会产生严重的后果。 发生在怀孕期间。垂直传播可导致胎儿死亡，小头畸形或其他发育 近一半的病例出现了畸变。ZIKV是一个全球性的挑战;根据CDC的数据，近40%的 世界人口生活在蚊子媒介居住的区域，蚊子媒介能够感染ZIKV。因此，我们认为， 需要一种既安全又有效地预防ZIKV感染的疫苗。 ZIKV是一种类似登革热（DENV）的黄病毒，其导致严重的人类疾病和死亡。 存在4种DENV血清型（DENV 1 -4），它们在抗原性上彼此非常相似并且与ZIKV非常相似。这 相似性可以提供交叉保护，但它也可能导致严重的出血性形式， 当响应于血清型之一而引发的抗体是交叉反应性的并且是无反应性的或弱反应性的时， 中和到另一种血清型。交叉反应性抗体被认为形成免疫复合物， 增强感染和疾病，这种现象被称为抗体依赖性增强 （ADE）。体外和体内实验支持ADE延伸至ZIKV的观点。因此， 是开发一种ZIKV疫苗，其选择性地激发针对ZIKV的中和表位的抗体，而在 同时避免那些对其他黄病毒，包括登革病毒，是非中和和潜在的 增强。这样做需要了解对ZIKV的中和抗体应答和结构 了解这些抗体如何识别ZIKV表面蛋白。 该计划项目建立在Nussenzweig，Bjorkman和 水稻实验室其最终目标是发现和表征ZIKV上的一组中和表位， 表面，并利用这些信息来设计和测试候选疫苗，以引发抗体， 靶向这些中和表位。我们提出了两个高度相关的项目由米歇尔博士领导 Nussenzweig和Pamela Bjorkman将得到由Charles Rice博士领导的科学核心的支持， 他将提供病毒学方面的专业知识在项目1中，先前表征的样品来自特殊的 ZIKV应答者将用于从记忆B细胞发现中和抗体。项目2将 在结构上表征抗体及其表位，所获得的信息将使合理的 候选免疫原的设计和生产。项目2中设计的免疫原将在 项目1使用野生型和基因人源化小鼠用于保护免受ZIKV的安全性和功效 和DENV感染。这两个项目的活动将得到病毒学和行政核心的支持。 拟议的实验旨在开发候选疫苗，用于随后在非人类中进行评估。 灵长类动物，因此具有显著的翻译潜力。

Summary - Overall (PI: Michel Nussenzweig) Although Zika virus (ZIKV) infection typically leads to a mild disease, it produces grim consequences when it occurs during pregnancy. Vertical transmission can lead to fetal demise, microcephaly or other developmental aberrations in up to nearly half of the cases. ZIKV is a global challenge; according to the CDC, nearly 40% of the world population lives in regions inhabited by the mosquito vectors that are competent for ZIKV. Therefore, a vaccine is needed that is both safe and efficacious in preventing ZIKV infection. ZIKV is a flavivirus like dengue (DENV), which is responsible for severe human disease and mortality. There are 4 serotypes of DENV (DENV1-4) that are antigenically very similar to each other and to ZIKV. This similarity can confer cross-protection, but it may also be responsible for causing a severe hemorrhagic form of dengue when antibodies elicited in response to one of the serotypes are cross-reactive and non- or poorly neutralizing to another serotype. The cross-reactive antibodies are thought to form immune complexes that enhance the infection and the disease, a phenomenon that is referred to as Antibody Dependent Enhancement (ADE). In vitro and in vivo experiments support the view that the ADE extends to ZIKV. Thus, a desirable goal is to develop a ZIKV vaccine that selectively elicits antibodies to neutralizing epitopes of ZIKV, while at the same time avoiding those to other flaviviruses, including DENV, that are non-neutralizing and potentially enhancing. Doing so requires an understanding of the neutralizing antibody response to ZIKV and structural understanding of how these antibodies recognize ZIKV surface proteins. This Program Project builds upon an established collaboration between the Nussenzweig, Bjorkman, and Rice laboratories. Its ultimate goal is to discover and characterize a panel of neutralizing epitopes on the ZIKV surface, and to use this information to design and test candidate vaccines to elicit antibodies that selectively target such neutralizing epitopes. We propose two highly interrelated projects led by Drs. Michel Nussenzweig and Pamela Bjorkman, which will be supported by a Scientific Core led by Dr. Charles Rice, who will provide the expertise in virology. In Project 1, previously characterized samples from exceptional ZIKV responders will be used for neutralizing antibody discovery from memory B cells. Project 2 will characterize the antibodies and their epitopes structurally, and the information obtained will enable the rational design and production of candidate immunogens. The immunogens designed in Project 2 will be evaluated in Project 1 using wild type and genetically humanized mice for safety and efficacy in protection against ZIKV and DENV infection. Activities in both projects will be supported by the Virology and Administrative Cores. The proposed experiments aim at developing vaccine candidates for subsequent evaluation in non-human primates, and as such have significant translational potential.