Project 2

项目2

基本信息

批准号：
10454950
负责人：
Pamela J Bjorkman
金额：
$ 50.97万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454950
关键词：
Abbreviations Affinity Antibodies Antibody titer measurement Antibody-Dependent Enhancement Antigen Targeting Antigens Binding Cells Collaborations Complementarity Determining Regions Complex Cryoelectron Microscopy Crystallization Dengue Dengue Virus Development Disease E protein Epitopes Flavivirus Genes Glycoproteins Goals HIV-1 Human Immunoglobulin G Immunoglobulin Genes Immunoglobulins Individual Infection Joints Knowledge Laboratories Lateral Libraries Light Link Liposomes Masks Membrane Membrane Proteins Memory B-Lymphocyte Methods Molecular Sieve Chromatography Mus Paper Polysaccharides Pre-Clinical Model Pregnancy Process Production Reporting Rice Risk Roentgen Rays Safety Somatic Mutation Structure Surface Plasmon Resonance Tertiary Protein Structure Testing Vaccination Vaccine Antigen Vaccines Variant Viral Virion Virus Work X-Ray Crystallography Yeasts ZIKV disease ZIKV infection Zika Virus Zika virus vaccine antigen binding base cross reactivity design efficacy evaluation experience experimental study fetal global health immunogenicity in vivo nanoparticle neutralizing antibody particle protein E rational design research clinical testing screening vaccine strategy virology virus envelope

Abbreviations Affinity Antibodies Antibody titer measurement Antibody-Dependent Enhancement Antigen Targeting Antigens Binding Cells Collaborations Complementarity Determining Regions Complex Cryoelectron Microscopy Crystallization Dengue Dengue Virus Development Disease E protein Epitopes Flavivirus Genes Glycoproteins Goals HIV-1 Human Immunoglobulin G Immunoglobulin Genes Immunoglobulins Individual Infection Joints Knowledge Laboratories Lateral Libraries Light Link Liposomes Masks Membrane Membrane Proteins Memory B-Lymphocyte Methods Molecular Sieve Chromatography Mus Paper Polysaccharides Pre-Clinical Model Pregnancy Process Production Reporting Rice Risk Roentgen Rays Safety Somatic Mutation Structure Surface Plasmon Resonance Tertiary Protein Structure Testing Vaccination Vaccine Antigen Vaccines Variant Viral Virion Virus Work X-Ray Crystallography Yeasts ZIKV disease ZIKV infection Zika Virus Zika virus vaccine antigen binding base cross reactivity design efficacy evaluation experience experimental study fetal global health immunogenicity in vivo nanoparticle neutralizing antibody particle protein E rational design research clinical testing screening vaccine strategy virology virus envelope

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项目摘要

Project Summary - Project 2 (PD: Pamela Bjorkman) Zika virus (ZIKV) infection is an emerging global health concern due to the potential for fetal abnormalities when infection occurs during pregnancy. A ZIKV vaccine should preferentially elicit neutralizing antibodies (Abs) rather than non-neutralizing Abs, which may exacerbate disease caused by ZIKV or related dengue virus strains through the phenomenon of Ab-dependent enhancement (ADE). The Bjorkman lab proposes to use knowledge of the structural basis for Ab neutralization of ZIKV to design potential vaccine immunogens optimized to elicit neutralizing Abs while reducing the risk of ADE by minimizing the production of non- neutralizing Abs. The Nussenzweig, Rice, and Bjorkman laboratories have recently-established a collaboration to isolate and characterize Abs against ZIKV Envelope Domain III (ZEDIII). A group of ZIKV-infected individuals with high ZIKV neutralizing Ab activity have been found to have Abs derived from immunoglobulin genes VH3- 23/VK1-5. Several of these Abs neutralize ZIKV in vivo and are effective in challenge and in treatment experiments in mice. The structural basis for ZIKV neutralization by these Abs has been revealed by the Bjorkman lab in crystal structures of Ab–EDIII complexes. The crystal structures of these Abs bound to ZEDIII and to the counterpart domain of dengue 1 virus (DENV1) revealed a common mechanism of recognition of the ZIKV and DENV1 EDIII lateral ridge. The Bjorkman lab will extend these efforts to solve and compare structures of additional neutralizing Abs bound to their target antigens, both isolated envelope domains and virions, in order to determine which features correlate with neutralizing activity. Complexes of antigen with neutralizing Abs of varying cross-reactivity and potency (isolated by Dr. Nussenzweig and evaluated by Dr. Rice) will be crystallized and their structural features compared to identify viral vulnerabilities as well as characterize epitopes targeted by weak or non-neutralizing antibodies. The Bjorkman lab proposes to use the germline-targeting approach for ZIKV immunogen design to mitigate the potential for ADE, an approach made possible by the identification and characterization of the VH3-23/VK1-5 class of anti-ZIKV Abs. Initial immunogen design efforts will be focused on the lateral ridge epitope, which is recognized by the potent VH3-23/VK1-5 Abs. Yeast library screening methods successfully used for HIV-1 immunogen design will be adapted to identify ZEDIII variants that bind with higher affinity to iGL versions of VH3-23/VK1-5 Abs. Non-neutralizing epitopes will be masked by adding N-linked glycans or altered to reduce immunogenicity. Optimized antigens will be multimerized to generate candidate immunogens. These immunogens will be evaluated for efficacy and safety in pre-clinical models in collaboration with Drs. Nussenzweig and Rice. The goal is to develop immunogens suitable to move towards clinical testing.

项目摘要 - 项目2（PD：Pamela Bjorkman） Zika病毒（ZIKV）感染是胎儿异常的潜力，是一个新兴的全球健康问题当怀孕期间发生感染时。 ZIKV疫苗应优先引起中和抗体（ABS）而不是非中和ABS，这可能加剧由ZIKV或相关登革热病毒引起的疾病通过AB依赖性增强现象（ADE）的菌株。 Bjorkman实验室提案要使用了解ZIKV的AB协商以设计潜在疫苗免疫原的结构基础知识优化以引起中和ABS，同时通过最大程度地减少非 - 的产生来降低ADE风险中和腹肌。 Nussenzweig，Rice和Bjorkman Laboratories最近建立了一个合作，以隔离并表征针对ZIKV包膜III（ZEDII）的ABS。一群ZIKV感染的人已经发现，高ZIKV中和AB活性具有源自免疫球蛋白基因VH3-的ABS 23/vk1-5。其中一些ABS中和体内中和Zikv，在挑战和治疗方面有效小鼠的实验。这些ABS的ZIKV神经化的结构基础已被揭示 Bjorkman实验室在AB – EDIII复合物的晶体结构中。这些ABS的晶体结构与Zediii结合以及登革热1病毒（DENV1）的对应区域揭示了对识别的共同机制 ZIKV和DENV1 EDIII侧脊。 Bjorkman实验室将扩大这些努力来解决和比较与靶抗原结合的其他中和ABS的结构，既有孤立的包膜结构域和病毒体，以确定哪些特征与中和活性相关。抗原的复合物与中和ABS的交叉反应性和效力不同（由Nussenzweig博士分离，并由博士进行评估大米）将结晶且结构特征相比，以确定病毒脆弱性以及表征由弱或非中和抗体靶向的表位。 Bjorkman实验室的提议使用ZIKV免疫设计的种系靶向方法减轻ADE的潜力，通过识别和表征使ADE的潜力成为可能 VH3-23/VK1-5抗ZIKV ABS类。最初的免疫原设计工作将集中在侧脊上 episodeTope，由潜在的VH3-23/VK1-5 ABS认可。酵母库筛查成功用于HIV-1免疫原的设计将适应以识别具有较高亲和力与Igl结合的ZEDIII变种 VH3-23/VK1-5 ABS的版本。通过添加N连接的聚糖或更改，将掩盖非中和表位降低免疫原性。优化的抗原将被多磨合以产生候选免疫原。这些与DRS合作的临床前模型中，将评估免疫原子的效率和安全性。 Nussenzweig和大米。目的是开发适合临床测试的免疫原。