Anti-flavivirus B cell response analysis to aid vaccine design

抗黄病毒 B 细胞反应分析有助于疫苗设计

• 批准号: 10636329
• 负责人: Yuxing Li
• 金额: $ 78.48万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-06 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636329
• 关键词: Address; Adjuvant; Adult; Affect; Animal Model; Animals; Antibodies; Antibody Formation; Antibody Response; Antibody-Dependent Enhancement; Antigens; Area; B cell repertoire; B-Lymphocytes; Binding; Bite; Cell Separation; Cells; Clinical Research; Cross Reactions; Cryoelectron Microscopy; Culicidae; Dengue; Dengue Infection; Dengue Virus; Development; E protein; Epidemic; Epitopes; Event; Family; Feedback; Fetal Death; Fetus; Flavivirus; Flavivirus Infections; Future; Glycoproteins; Guillain Barré Syndrome; Human; Immune; Immune response; Immunity; Immunization; Immunize; Immunoglobulin Genes; Immunologic Stimulation; In Vitro; Infection; Infectious Agent; Investigation; Lead; Mediating; Membrane; Morbidity - disease rate; Mus; Mutation; Outcome; Outcome Study; Pregnancy; Pregnant Women; Process; Protein Engineering; Resolution; Risk; Sequence Homology; Series; Sexual Transmission; Structure; Symptoms; Transgenic Organisms; Vaccine Design; Vaccines; Vertical Transmission; Viral; Virus; X-Ray Crystallography; ZIKA; ZIKV infection; Zika Virus; Zika virus vaccine; cross reactivity; design; dimer; disorder prevention; emerging pathogen; env Gene Products; fetal; global health; immunogenicity; improved; in vitro Assay; in vivo; innovation; insight; member; mouse model; neutralizing antibody; next generation; nonhuman primate; novel; novel vaccines; pathogen; pathogenic virus; prevent; programs; prototype; response; transmission process; vaccine candidate; virus envelope

Zika virus (ZIKV) is a member of flavivirus family that emerged as an infectious agent causing global health crisis during recent epidemics. ZIKV infection can cause Guillain-Barré syndrome in adults, and severe fetal neuromalformations and fetal death during pregnancy. ZIKV infection is primarily transmitted by mosquito bite, while sexual transmission and vertical transmission from infected pregnant women to fetus also contribute to the recent epidemic. Ideally, an effective ZIKV vaccine should provide sterilizing immunity that blocks the initial viral dissemination to prevent subsequent infection-caused morbidity. Currently, there is no approved ZIKV vaccine for disease prevention. The membrane (M) and envelope protein (E) expressed as prM-E form is a common antigen choice for current vaccine candidates against ZIKV, as neutralizing antibodies (nAb) against prM-E can prevent viral entry. However, such nascent PrM-E based ZIKV vaccines can increase the infectiousness of the dengue virus (DENV), another flavivirus of which endemic area largely overlaps with ZIKV. Due to the high degree of sequence homology between the E proteins of ZIKV and DENV, the ZIKV prM-E vaccine may stimulate the production of antibodies that are non-neutralizing but cross-reactive with the DENV E protein. In the event of a subsequent dengue virus infection, antibody-dependent enhancement (ADE) can occur when the suboptimal anti- ZIKV antibodies bind to the DENV virus, which thereby enhance the entry of DENV into host cells and exacerbate dengue symptoms. Strategies to prevent the induction of ADE-prone antibodies have been described recently for modified ZIKV immunogens, which unfortunately display suboptimal protection efficacy in small animals. Here, we focus on applying structure-based vaccine design to develop novel vaccine candidates with improved immunogenicity and reduced ADE potential for DENV infection. In preliminary study, our lead vaccine candidate formulated in optimized adjuvant showed nearly complete protection in immune mice challenged with ZIKV, and abolished ADE potential assessed by in vitro assays. Potent monoclonal ZIKV nAbs targeting the major ZIKV E protein nAb determinants including the quaternary E-dimer dependent epitope isolated from immune mice confirmed the design rationale. In this application, we will extend our effort via further immunogen designs guided by B cell/antibody response analysis and structural investigation of ZIKV E protein-antibody interactions to improve our lead vaccine candidate aiming at achieving sterilizing immunity, to evaluate in small animal models. If succeeds, this study will contribute to (i) the development of an effective and safe ZIKV vaccine, and (ii) deepening our understanding of immune response to flavivirus infections and immunizations.

Zika病毒（ZIKV）是Flavivivirus家族的成员 最近情节中的全球健康危机。 ZIKV感染会导致Guillain-Barré综合征 ZIKV感染 主要是由蚊子咬伤的，而性传播和垂直传播 感染的孕妇对胎儿也有助于最近的流行病。理想情况下，有效的zikv 疫苗应提供消毒免疫，以阻止初始病毒传播以防止 随后引起感染引起的发病率。目前，没有批准的ZIKV疫苗用于疾病 预防。表示为PRM-E形式的膜（M）和包膜蛋白（E）是一种常见 当前针对ZIKV的当前疫苗的抗原选择为中和抗体（NAB） 反对PRM-E可以防止病毒进入。但是，这种新生的基于PRM-E的ZIKV疫苗可以 增加登革热病毒（DENV）的感染性，这是另一个黄病毒的内在区域 Zikv在很大程度上重叠。由于E蛋白之间的序列同源性高度高 ZIKV和DENV的ZIKV PRM-E疫苗可能会刺激抗体的产生 与DENVE蛋白质非中和但交叉反应。如果随后发生登革热 病毒感染，抗体依赖性增强（ADE），当 ZIKV抗体与DENV病毒结合，从而增强DENV进入宿主细胞 和加剧粉丝。防止诱导ADE易发抗体的策略 最近已描述了修改的ZIKV免疫原子，不幸的是显示 小动物的次优效率。在这里，我们专注于应用基于结构的 疫苗设计以开发具有改善免疫原性并降低的新型疫苗候选物 ADE可能引起DENV感染。在初步研究中，我们的铅疫苗候选者在 优化可调节的可调节几乎显示在受ZIKV挑战的免疫小鼠中， 并通过体外评估评估了ADE潜力。有效的单克隆ZIKV NABS靶向 主要的zikv e蛋白NAB决定包括第四纪电子二聚体依赖性发作 从免疫小鼠中分离出来证实了设计基本原理。在此应用程序中，我们将扩展我们的 通过B细胞/抗体响应分析和结构的进一步免疫设计的努力 研究ZIKV E蛋白质抗体相互作用以改善我们的铅疫苗候选目标 实现灭菌性免疫力，以评估小动物模型。如果成功，这项研究将 为（i）开发有效且安全的ZIKV疫苗，以及（ii）加深我们 了解对黄素感染和免疫抑制的免疫响应。