Development of immunology and immunization strategies that induce broadly pro

开发免疫学和免疫策略，广泛诱导

• 批准号: 9089825
• 负责人: Dennis R. Burton
• 金额: $ 1872.06万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089825
• 关键词: AIDS Vaccines; AIDS/HIV problem; Adjuvant Study; Adoption; Affinity; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antigens; B-Lymphocytes; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell Communication; Clinical; Clonal Expansion; Complex; Data; Development; Epitopes; Exposure to; Functional disorder; Generations; Goals; HIV; HIV vaccine; Human; Immunization; Immunoglobulin Somatic Hypermutation; Immunology; Individual; Infection; Knock-in Mouse; Lead; Libraries; Licensing; Macaca; Maps; Membrane; Mission; Modeling; Molecular; Monitor; Mus; Passive Immunization; Plasma Cells; Pre-Clinical Model; Preventive; Procedures; Process; Protocols documentation; Qualifying; Regimen; Research; Research Support; Role; Sampling; Somatic Mutation; Specificity; Structure; Structure of germinal center of lymph node; Study models; Suggestion; T cell response; Time; Vaccines; Viral; Viral Physiology; Virus; base; cohort; design; efficacy evaluation; env Gene Products; human monoclonal antibodies; improved; in vitro Assay; insight; neutralizing antibody; nonhuman primate; novel; product development; response; simian human immunodeficiency virus; vaccine candidate

The overall mission of this CHAVI-ID application is to define immunogens and immunization regimens that induce sustained HIV cross-protective B cell and CD4+ T cell responses in preclinical models and, thereby, guide product development strategies for a preventive human AIDS vaccine. Focus #1 will concentrate on B cell and antibody research to facilitate the development of immunogens and immunization protocols that elicit protective broadly neutralizing antibody responses. Our overall strategy in this focus can be briefly summarized in the following goals: 1) To fully define a comprehensive map of the broadly neutralizing (bn) epitopes of the HIV Env spike. Breakthroughs in generating broadly neutralizing human monoclonal antibodies (bnMAbs) in the last two years are bringing this goal within reach; 2) To determine which of the HIV bnMAbs provide the most effective protection against viral challenge in the non-human primate (NHP) model. At the same time, we shall closely monitor developments in the field, including suggestions that some non-neutralizing antibodies may have protective qualifies that might be exploited in vaccine discovery; 3) To determine which HIV broadly neutralizing Abs (bnAbs) are most readily elicited through natural infection and how and when they are elicited using several large cohorts to which we have unique access; 4) To determine which immunogens and immunization strategies best stimulate HIV bnAb generation in the knock-in mouse and NHP models, drawing upon data collected on bnAbs in goals 1-3 and emerging from Focus #2. As we gather together information on optimal immunogens and immunization strategies, we will move forward with small-scale human trials with the advice and close involvement of our Vaccine Discovery Scientific Research Support Component.

该CHAVI-ID申请的总体使命是确定在临床前模型中诱导持续的HIV交叉保护性B细胞和CD 4 + T细胞应答的免疫原和免疫方案，从而指导预防性人类艾滋病疫苗的产品开发策略。重点#1将集中在B细胞和抗体研究，以促进免疫原和免疫方案的开发，引发保护性广泛中和抗体反应。 我们在这方面的总体策略可以简要地概括为以下目标：1）完全定义HIV Env刺突的广泛中和（bn）表位的综合图谱。过去两年在产生广泛中和人单克隆抗体（bnMAb）方面取得的突破使这一目标触手可及; 2）确定哪种HIV bnMAb在非人灵长类动物（NHP）模型中提供针对病毒挑战的最有效保护。与此同时，我们将密切监测该领域的发展，包括一些非中和抗体可能具有可用于疫苗发现的保护性资格的建议; 3）确定哪些艾滋病毒广泛中和抗体（bnAbs）最容易通过自然感染引起，以及如何以及何时使用我们唯一访问的几个大型队列引起它们; 4）确定哪些免疫原和免疫策略最佳地刺激敲入小鼠和NHP模型中的HIV bnAb产生，利用在目标1-3中收集的关于bnAb的数据和从焦点#2中出现的数据。当我们收集关于最佳免疫原和免疫策略的信息时，我们将在疫苗发现科学研究支持部门的建议和密切参与下推进小规模人体试验。