Project 1

项目1

• 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
• 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

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.

总结-项目1（PD：Michel Nussenzweig） 寨卡病毒（ZIKV）的重新出现对人类健康构成严重威胁，因为它具有可怕的 怀孕期间发生感染时对胎儿的影响。根据蚊子的分布 ZIKV威胁着世界上40%的人口。没有治疗或预防措施， ZIKV，这使得疫苗的设计变得迫切和非常可取。许多候选疫苗 作为一种方法，使用整个病毒或病毒包膜蛋白的大部分， （E）.尽管这种方法在临床前模型中似乎有效且有前景，但存在严重的问题， 由于抗体依赖性增强（ADE）现象和与 登革病毒（DENV）。这种设计的ZIKV疫苗可以引发与免疫原性抗体交叉反应但不与免疫原性抗体交叉反应的抗体。 中和DENV，可能使接种疫苗的个体更容易感染严重的登革热疾病， ADE。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。的 Nussenzweig实验室发现了人类抗体，通过识别非ZIKV， Zika Envelope Domain III（ZEDIII）上的重叠表位，并与Bjorkman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引发免疫反应的免疫原。 靶向ZIKV中和表位并且不增强登革热感染的抗体。为了做到这一点，博士。 Nussenzweig将与Bjorkman博士合作，对病毒表面的新型中和表位进行表征。 ZIKV。这些信息将被用来设计新的免疫原，优先驱动免疫原的产生。 中和这些表位的抗体。例如，将设计和评估候选免疫原， 以引发人VH 3 -23/VK 1 -5抗体，所述人VH 3 -23/VK 1 -5抗体是人中ZIKV的复发性和有效中和剂。 Nussenzweig实验室计划1）发现更多中和ZIKV的抗体，以产生一种新的抗体。 一组额外的非重叠中和病毒表位; 2）使用此信息帮助Bjorkman实验室 设计新的免疫原，优先引发针对这些表位的保护性抗体; 3）评估这些 野生型小鼠中的免疫原; 4）将最有希望的免疫原的评估扩展到遗传学上， 人源化小鼠; 5）使用ZIKV易感小鼠模型评估疫苗功效; 6）评估疫苗交叉免疫效应; 7）评估疫苗交叉免疫效应。 通过用DENV攻击免疫的小鼠来评估ADE;以及7）通过用DENV攻击免疫的小鼠来评估ADE。 用亚致死剂量的登革病毒感染小鼠。总的来说，拟议的实验承担了重大的翻译 潜在的，并预计产生候选疫苗，用于随后在非人灵长类动物中进行评价 模型和疫苗临床试验。