Project 1

项目1

基本信息

批准号：
10221139
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
项目类别：
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/10221139
关键词：
Antibodies Antibody Repertoire Antibody Response Antibody-Dependent Enhancement Antigens Area B-Lymphocytes Binding Brazil Collaborations Dangerousness Dengue Dengue Infection Dengue Virus Development Disease Disease Outbreaks Dose Engineering Epitopes Evaluation Fetus Flavivirus Generations Genes Goals Health Hemorrhage Human Immune response Immunization Immunize Individual Infection Lateral Letters Link Liposomes Measures Mexico Modeling Mus Population Pre-Clinical Model Pregnancy Prophylactic treatment Recurrence Reporting Risk Safety Sampling Serum Structure Surface Testing Ursidae Family Vaccinated Vaccine Clinical Trial Vaccine Design Vaccines Viral Viral Antigens Virus Wild Type Mouse Work ZIKA Zika Virus Zika virus vaccine base cross reactivity design env Gene Products experimental study genomic locus humanized mouse immunogenicity in vivo mouse model mutant nanoparticle neutralizing antibody nonhuman primate novel response vaccine candidate vaccine efficacy vaccine evaluation vector mosquito virus envelope

项目摘要

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.

摘要 - 项目 1（PD：Michel Nussenzweig）寨卡病毒（ZIKV）再次出现，对人类健康构成严重威胁。怀孕期间发生感染对胎儿的影响。根据蚊子的分布情况 ZIKV 病毒威胁着全球 40% 的人口。没有治疗或预防措施 ZIKV，这使得疫苗的设计变得紧迫且非常令人渴望。许多候选疫苗已经在寻求使用整个病毒或大部分病毒包膜蛋白作为方法 (E)。尽管这种方法在临床前模型中似乎有效且有前途，但仍存在严重问题由于抗体依赖性增强（ADE）现象和与药物的交叉反应，考虑到安全性登革热病毒（DENV）。这种设计的 ZIKV 疫苗可以引发与交叉反应但不发生交叉反应的抗体。中和登革热病毒，可能使接种疫苗的个体更容易感染严重登革热疾病阿德。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 Nussenzweig 实验室发现了人类抗体，可以通过识别非 ZIKV 来有效中和 ZIKV。 Zika 包膜结构域 III (ZEDIII) 上的重叠表位，并与 Bjorkman 实验室合作，开始在病毒表面结构上定义它们的同源表位。该提案的长期目标是开发和评估优先引发的免疫原靶向 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，博士。 Nussenzweig 将与 Bjorkman 博士合作，表征病毒表面的新型中和表位寨卡病毒。这些信息将被用来设计新型免疫原，优先驱动免疫原的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引发人类 VH3-23/VK1-5 抗体，这些抗体是人类 ZIKV 的反复出现且有效的中和剂。 Nussenzweig 实验室计划 1) 发现更多中和 ZIKV 的抗体，以产生一组额外的非重叠中和病毒表位； 2) 使用此信息来帮助 Bjorkman 实验室设计新的免疫原，优先引发针对此类表位的保护性抗体； 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上人源化小鼠； 5) 使用 ZIKV 易感小鼠模型评估疫苗功效； 6) 评估疫苗交叉通过用 DENV 攻击免疫小鼠来提供保护； 7) 通过挑战接种疫苗来评估 ADE 小鼠接受亚致死剂量的 DENV。总的来说，所提出的实验具有重要的转化意义潜力，预计将产生候选疫苗，用于随后在非人类灵长类动物中的评估模型和疫苗临床试验。