Epitope-focused vaccine strategies against Zika virus

摘要--总体(PI：Michel Nussenzweig) 尽管寨卡病毒(ZIKV)感染通常会导致轻微的疾病，但当它发生时会产生严重的后果 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 高达一半的病例存在像差。ZIKV是一个全球性的挑战；根据疾控中心的数据，近40%的 世界人口生活在对寨卡病毒有能力的蚊媒居住的地区。因此， 需要一种既安全又有效的疫苗来预防寨卡病毒感染。 ZIKV是一种类似登革热(DENV)的黄病毒，可导致严重的人类疾病和死亡。 有4个DENV血清型(DENV1-4)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出血形式的 登革热当对一种血清型产生的抗体是交叉反应且无或很差时 对另一种血清型有中和作用。交叉反应的抗体被认为形成免疫复合体， 增强感染和疾病，这种现象被称为抗体依赖增强 (ADE)。体外和体内实验支持ADE延伸到ZIKV的观点。因此，一个理想的目标 是开发一种ZIKV疫苗，这种疫苗选择性地诱导针对ZIKV中和表位的抗体，而在 同时避免对其他黄病毒，包括DENV，是非中和的和潜在的 增强功能。要做到这一点，需要了解ZIKV的中和抗体反应和结构 了解这些抗体如何识别ZIKV表面蛋白。 该计划项目建立在努森茨韦格、比约克曼和 大米实验室。它的最终目标是发现和表征ZIKV上的一组中和表位 并利用这一信息来设计和测试候选疫苗，以诱导选择性地 瞄准这些中和表位。我们提出了两个由米歇尔博士领导的高度相关的项目 Nussenzweig和Pamela Bjorkman将得到查尔斯·赖斯博士领导的科学核心的支持， 世卫组织将提供病毒学方面的专业知识。在项目1中，以前描述的样本来自异常情况 ZIKV响应器将用于中和记忆B细胞中的抗体发现。项目2将 从结构上表征抗体及其表位，所获得的信息将使理性 候选免疫原的设计和生产。项目2中设计的免疫原将在#年进行评估 项目1使用野生型和基因人源化小鼠预防寨卡病毒的安全性和有效性 和DENV感染。这两个项目的活动都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，以供随后在非人类身上进行评估。 灵长类，因此有很大的翻译潜力。

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.