Project 1

摘要--项目1(PD：Michel Nussenzweig) 寨卡病毒(ZIKV)的重新出现对人类健康构成了严重威胁 怀孕期间发生感染时对胎儿的影响。根据其蚊子的分布情况 作为媒介，ZIKV威胁着多达40%的世界人口。没有治疗或预防的方法来预防 ZIKV，这使得疫苗的设计变得迫切和迫切。许多候选疫苗是 已经在寻求使用整个病毒或大部分病毒包膜蛋白作为一种方法 (E)。尽管这种方法在临床前模型中似乎是有效的和有希望的，但仍然存在严重的担忧 关于抗体依赖增强(ADE)和交叉反应现象的安全性 登革病毒(DENV)。这种设计的ZIKV疫苗可以诱导出与之交叉反应但不发生交叉反应的抗体 中和DENV，可能会使接种疫苗的人更容易感染严重的登革热 艾德。相比之下，专门针对中和表位设计的疫苗更有可能是安全的。这个 努森茨韦格实验室发现，人类抗体通过识别非ZIKV病毒而有效中和ZIKV 寨卡病毒包膜结构域III(ZEDIII)上的重叠表位，并与比约克曼实验室合作 开始在结构上定义它们在病毒表面的同源表位。 这项提案的长期目标是开发和评估优先诱导 针对ZIKV中和表位且不会增强登革热感染的抗体。为了实现这一目标，Dr。 Nussenzweig将与Bjorkman博士合作表征病毒表面的新中和表位 齐科夫。这些信息将被用来设计新的免疫原，优先驱动产生 针对这些表位的中和抗体。例如，将设计和评估候选免疫原 目的诱导人VH3-23/VK1-5抗体，这些抗体是ZIKV在人类体内反复出现的有效中和剂。 Nussenzweig实验室计划1)发现更多中和ZIKV的抗体，以便产生 额外的非重叠中和病毒表位小组；2)利用这些信息帮助比约克曼实验室 设计新的免疫原，优先诱导针对这些表位的保护性抗体；3)评估这些 野生型小鼠的免疫原；4)将最有希望的免疫原的评估扩展到遗传学 人源化小鼠；5)使用ZIKV敏感的小鼠模型评估疫苗效果；6)交叉评估疫苗 通过用DENV攻击免疫小鼠来保护；以及7)通过挑战接种疫苗来评估ADE 注射亚致死剂量DENV的小鼠。总体而言，拟议的实验具有重大的翻译意义 潜在的，并有望导致候选疫苗的后续评估在非人类灵长类动物 模型和疫苗临床试验。

Summary - Project 1 (PD: Michel Nussenzweig) The re-emergence of Zika virus (ZIKV) poses serious threats to human health because of the dire consequences on the fetus when infection occurs during pregnancy. Based on the distribution of its mosquito vector, ZIKV threatens up to 40% of the world's population. There are no treatments or prophylaxis against ZIKV, which makes the design of vaccines urgent and highly desirable. Numerous vaccine candidates are already being pursued that use as an approach the whole virus or large portions of the virus Envelope protein (E). Although this approach seems efficacious and promising in pre-clinical models, serious concerns exist with regard to safety due to the phenomenon of Antibody Dependent Enhancement (ADE) and cross-reactivity with dengue virus (DENV). A ZIKV vaccine of such design could elicit antibodies that cross-react with but do not neutralize DENV, possibly making a vaccinated individual more susceptible to severe dengue disease through ADE. In contrast, a vaccine designed to focus exclusively on neutralizing epitopes is more likely to be safe. The Nussenzweig lab has discovered human antibodies that potently neutralize ZIKV by recognizing non- overlapping epitopes on the Zika Envelope Domain III (ZEDIII), and in collaboration with the Bjorkman lab has started to structurally define their cognate epitopes on the viral surface. The long-term goal of this proposal is to develop and evaluate immunogens that preferentially elicit antibodies that target ZIKV neutralizing epitopes and do not enhance dengue infection. To accomplish this, Dr. Nussenzweig will work with Dr. Bjorkman to characterize novel neutralizing epitopes on the viral surface of ZIKV. This information will be harnessed to design novel immunogens that preferentially drive the generation of neutralizing antibodies to these epitopes. For example, candidate immunogens will be designed and evaluated to elicit human VH3-23/VK1-5 antibodies that are recurrent and potent neutralizers of ZIKV in humans. The Nussenzweig lab plans to 1) discover more antibodies that neutralize ZIKV in order to generate a panel of additional non-overlapping neutralizing viral epitopes; 2) use this information to help the Bjorkman lab design novel immunogens that preferentially elicit protective antibodies to such epitopes; 3) evaluate these immunogens in wild type mice; 4) extend the evaluation of the most promising immunogens to genetically humanized mice; 5) assess vaccine efficacy using ZIKV-susceptible mouse models; 6) evaluate vaccine cross- protection by challenging the immunized mice with DENV; and 7) evaluate ADE by challenging vaccinated mice with sub-lethal doses of DENV. Overall, the proposed experiments bear a significant translational potential, and are expected to result in candidate vaccines for subsequent evaluation in non-human primate models and vaccine clinical trials.