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: 9316758
• 负责人: Dennis R. Burton
• 金额: $ 24.02万
• 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: 2016-04-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316758
• 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.

这种CHAVI-ID应用的总体任务是定义免疫原和免疫方案，这些免疫原则和免疫方案在临床前模型中诱导HIV持续的HIV交叉保护B细胞和CD4+ T细胞反应，从而指导预防性人类AIDS疫苗的产品开发策略。 Focus＃1将集中于B细胞和抗体研究，以促进免疫原和免疫方案的发展，从而引发保护性广泛中和抗体反应。 我们在此重点中的总体策略可以在以下目标中进行简要总结：1）完全定义了HIV Env Spike的广泛中和（BN）表位的全面图。在过去两年中，突破性中和人类单克隆抗体（BNMAB）的突破正在实现这一目标； 2）确定哪些HIV BNMAB在非人类灵长类动物（NHP）模型中提供了防止病毒挑战的最有效保护。同时，我们将密切监视该领域的发展，包括一些建议，即某些非中和抗体可能具有在疫苗发现中可能利用的保护符合条件； 3）确定哪些HIV广泛中和ABS（BNAB）最容易通过自然感染引起，以及如何以及何时使用几个我们具有独特访问的大型同类群体引起它们； 4）确定哪些免疫原和免疫策略最能刺激敲入小鼠和NHP模型中的HIV BNAB产生，借鉴了目标1-3中BNAB的数据，并从焦点＃2中出现。当我们聚集有关最佳免疫原子和免疫策略的信息时，我们将进行小规模的人类试验，并与我们的疫苗发现科学研究支持部分的建议和密切参与。