Enhancing B cell immunity against HIV-1 using novel vaccine delivery platforms

描述(申请人提供)：开发保护性艾滋病疫苗是全球的当务之急。中和抗体(NAB)能有效预防HIV-1感染。虽然诱导广泛交叉反应的NAB长期以来一直是一个重大的科学挑战，但我们最近产生了一种包含gp41膜近端外部区域(MPER)的迷你蛋白，它可以诱导具有显著广度的NAB。这项提议的主要目标是开发能够增强B细胞免疫反应的新型疫苗递送平台。 这一建议背后的基本假设是，在重复的、明确定义的晶格(多价)中包含相同靶表位的多个副本的聚合抗原能够诱导比单体抗原(单价)更好的B细胞免疫反应，因为它具有以下潜力：(1)诱导T细胞非依赖(TL)和依赖(TD)的B细胞免疫；(2)促进B细胞的激活和成熟；(3)激活更多的B细胞亚群。为了验证这一假设，我们将开发基于纳米结构的新型疫苗递送平台，旨在向B细胞递送多价形式的免疫原和共刺激分子，并促进向树突状细胞和巨噬细胞靶向递送抗原。拟议研究的成功完成将代表着朝着开发保护性艾滋病疫苗的方向取得的重大进展。 拟议的研究计划由两个项目和两个核心组成：项目1的作用是开发疫苗交付平台。项目2的作用是非常详细地评估针对gp41-MPER的B细胞免疫反应。行政核心负责提供组织管理和维护基础设施，以支持财政监测。蛋白质生产核心负责为项目1和2生产和提供高质量的抗原和共刺激分子。这是一个由来自5个机构的7名关键研究人员高度合作的项目。

DESCRIPTION (provided by applicant): There is a global urgency to develop a protective AIDS vaccine. Neutralizing antibodies (Nabs) can provide effective prophylaxis against HIV-1 infections. Although eliciting Nabs that are broadly cross-reactive has long been a major scientific challenge, we have recently generated a mini-protein containing the membrane-proximal external region (MPER) of gp41 that can elicit Nabs with significant breadth. The primary objective of this proposal is to develop novel vaccine delivery platforms that can enhance B cell immune responses. The underlying hypothesis behind this proposal is that a polymeric antigen containing many copies of the same target epitope in a repetitive, well-defined lattice (multivalent) can elicit a superior B cell immune response than a monomeric antigen (monovalent) because of its potential to (1) induce both T cell-independent (Tl) and -dependent (TD) B cell immunity; (2) enhance B cell activation and maturation; and (3) activate a greater diversity of B cell subsets. To test this hypothesis, we will develop novel vaccine delivery platforms based on nanostructures designed to present multivalent forms of immunogens and costimulatory molecules to B cells and to facilitate targeted delivery of antigens to dendritic cells and macrophages. Successful completion of the proposed studies would represent a major advancement towards developing a protective AIDS vaccine. The proposed research Program consists of two Projects and two Cores: The role of Project 1 is to develop vaccine delivery platforms. The role of Project 2 is to evaluate B cell immune responses against gp41- MPER in great detail. The Administrative Core is responsible for providing the organizational management and maintaining infrastructure to support the fiscal monitoring. The Protein Production Core is responsible for producing and providing high quality antigens and costimulatory molecules to Projects 1 and 2. This is a highly collaborative program project of seven key investigators from five institutions.