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

描述（由申请人提供）：全球迫切需要开发一种保护性艾滋病疫苗。中和抗体（Nabs）可以有效预防HIV-1感染。虽然引发广泛交叉反应的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含有gp 41的膜近端外部区域（MPER）的迷你蛋白，可以引发具有显著宽度的Nab。该提案的主要目的是开发能够增强B细胞免疫应答的新型疫苗递送平台。 这一提议背后的基本假设是，在重复的、明确定义的晶格中含有相同靶表位的许多拷贝的聚合抗原（多价）可以引发比单体抗原更优越的上级B细胞免疫应答（单价），因为其具有（1）诱导T细胞非依赖性（T1）和T细胞依赖性（TD）B细胞免疫;（2）增强B细胞活化和成熟;和（3）激活更大多样性的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，该纳米结构设计用于向B细胞呈现多价形式的免疫原和共刺激分子，并促进抗原向树突状细胞和巨噬细胞的靶向递送。成功完成拟议的研究将是在研制艾滋病保护性疫苗方面取得的重大进展。 拟议的研究计划包括两个项目和两个核心：项目1的作用是开发疫苗输送平台。项目2的作用是非常详细地评估针对gp 41- MPER的B细胞免疫应答。行政核心负责提供组织管理和维护支持财政监测的基础设施。蛋白质生产核心负责为项目1和项目2生产和提供高质量的抗原和共刺激分子。这是一个由来自五个机构的七名主要研究人员组成的高度合作的项目。

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.