Epitope-focused vaccine strategies against Zika virus

针对寨卡病毒的针对表位的疫苗策略

• 批准号: 10221136
• 负责人: Michel C Nussenzweig
• 金额: $ 81.67万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-31 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221136
• 关键词: Affinity; Animal Model; Antibodies; Antibody Response; Antibody-Dependent Enhancement; Antigen-Antibody Complex; Antigens; Binding; Centers for Disease Control and Prevention (U.S.); Collaborations; Dengue; Development; Disease; Disease susceptibility; E protein; Engineering; Epitopes; Evaluation; Flavivirus; Genes; Goals; HIV Antibodies; Health; Hemorrhage; Human; Immune response; Immunization; Immunology; In Vitro; Individual; Infection; Infection prevention; Knowledge; Laboratories; Lateral; Lead; Masks; Medical; Membrane Proteins; Memory B-Lymphocyte; Methods; Microcephaly; Molecular; Mus; Population; Pregnancy; Production; Prophylactic treatment; Publishing; Recurrence; Rice; Roentgen Rays; Safety; Sampling; Serological; Serotyping; Serum; Structure; Surface; Testing; Time; Vaccines; Vertical Disease Transmission; Viral; Virion; Virus; Wild Type Mouse; Work; ZIKA; ZIKV infection; Zika Virus; Zika virus vaccine; antigen binding; base; cross reactivity; design; experience; experimental study; fetal; human disease; human mortality; humanized mouse; in vivo; member; neutralizing antibody; nonhuman primate; particle; prevent; programs; protein E; response; secondary infection; structural biology; synergism; vaccine candidate; vaccine development; vector mosquito; virology; virus envelope

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.

摘要 - 总体（PI：Michel Nussenzweig） 虽然寨卡病毒 (ZIKV) 感染通常会导致轻微的疾病，但当它感染时，就会产生严重的后果。 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障碍 多达近一半的病例存在畸变。 ZIKV 是一项全球性挑战；根据 CDC 的数据，近 40% 世界人口生活在具有寨卡病毒传播能力的蚊媒栖息地。所以， 需要一种既安全又有效的疫苗来预防 ZIKV 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。 DENV 有 4 种血清型 (DENV1-4)，它们在抗原上彼此非常相似，并且与 ZIKV 非常相似。这 相似性可以带来交叉保护，但也可能导致严重的出血性形式 当针对其中一种血清型而引发的抗体具有交叉反应性且无交叉反应性或交叉反应性较差时，就会发生登革热 中和另一种血清型。交叉反应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 （阿德）。体外和体内实验支持 ADE 扩展到 ZIKV 的观点。因此，一个理想的目标 是开发一种 ZIKV 疫苗，选择性地引发针对 ZIKV 中和表位的抗体，同时 同时避免接触其他黄病毒，包括登革热病毒，这些病毒是非中和性的，并且可能具有潜在的中和作用。 增强。这样做需要了解中和抗体对 ZIKV 的反应以及结构 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。其最终目标是发现并表征 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，以产生选择性的抗体 靶向此类中和表位。我们提出了由博士领导的两个高度相关的项目。米歇尔 Nussenzweig 和 Pamela Bjorkman 将得到 Charles Rice 博士领导的科学核心的支持， 谁将提供病毒学方面的专业知识。在项目 1 中，之前对来自特殊样本的特征进行了表征 ZIKV 应答器将用于中和从记忆 B 细胞中发现的抗体。项目2将 从结构上表征抗体及其表位，所获得的信息将能够进行合理的分析 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来安全有效地预防 ZIKV 和登革热病毒感染。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，以便随后在非人类身上进行评估 灵长类动物，因此具有显着的转化潜力。