Improved Mimotope Structures and Scaffolds for Prime-Boost Strategies

改进的 Mimotope 结构和支架用于 Prime-Boost 策略

• 批准号: 7166859
• 负责人: David Davis
• 金额: $ 41.4万
• 依托单位: NOVARTIS VACCINES AND DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7166859
• 关键词: AIDS vaccines; B lymphocyte; HIV envelope protein; Macaca; antigen antibody reaction; antigens; bioengineering /biomedical engineering; biological models; biomimetics; clinical research; epitope mapping; human immunodeficiency virus 1; laboratory rabbit; neutralizing antibody; simian immunodeficiency virus; transfection /expression vector; vaccine development; vaccine evaluation; vector vaccine; viruslike particle

Overcoming the obstacles of eliciting broadly neutralizing antibodies (NAb) to HIV-1 will be a major step forward to developing a successful AIDS vaccine. The long-term objectives of project 2 are to design, evaluate and select novel HIV-1 enveloped based immunogens which are capable of inducing broad neutralizing antibodies which will have a protective effect in vaccinated individuals. The challenge and reason for this B-cell epitope focused approach is that HIV-1 has developed multiple mechanisms to shield itself and evade the antiviral effects of many antibodies. By far most host antibodies directed to the envelope (Env) of HIV-1 are ineffective in eliciting broad Nab responses. There are however several conserved B-cell epitopes which are rarely exposed, but when recognized by the host are able to elicit a broad Nab response. Here we aim to develop vaccine immunogens which together will focus the antibody response to highly conserved Env epitopes. Specifically our aims are to: 1. To improve the presentation of conformational Nab B-cell epitopes (mimotopes) for optimal presentation in vivo by; a) Combinatorial Synthesis and "Click" chemistry through direct collaboration and interaction with Core D, and, b) Engineered virus-like particles (VLPs) expressing Nab epitopes. Experience in VLPs expressing HIV peptides will include p55 Gag as well as Hepatitis B particles (Univ Regensburg, this project). 2. To identify the optimal vaccine platforms (protein, peptide, and/or viral vector) and regimen for either priming or boosting conformationaly dependent epitope specificities. This will be facilitated by close interaction with the vaccine technologies core (B) as well as complementary Env structures developed in projects 1 and 3. 3. To determine how many Nab peptide epitopes can optimally be combined in a prime boost immunization protocol to ultimately generate robust neutralizing antibody responses in an outbred population, evaluated first in rabbits and subsequently more stringently in non-human-primates models (Core C). 4. To determine "proof of principle" protective efficacy of these optimized mimotope-based vaccine regimens in the SHIV rhesus macaque vaccine challenge model. The best combination of NAb B-cell epitope presenting structures and delivery systems will be revealed in heterologous and mucosal challenge studies.

克服广泛中和抗体（NAB）的障碍将是一个主要的步骤 转发开发成功的艾滋病疫苗。项目2的长期目标是设计， 评估并选择能够诱导广泛的基于基于的HIV-1的新型HIV-1 中和抗体将对接种的个体具有保护作用。挑战和 这种B细胞表位的原因是HIV-1开发了多种机制来屏蔽 本身并逃避许多抗体的抗病毒作用。到目前为止，大多数针对信封的宿主抗体 HIV-1（ENV）在引起广泛的NAB响应方面无效。但是有几个保守的B细胞 很少暴露的表位，但是当宿主认可时，能够引起广泛的NAB反应。 在这里，我们旨在开发疫苗免疫原，将抗体反应集中于高度 保守的ENV表位。特别是我们的目标是： 1。提高构象NAB B细胞表位（MIMOTOPES）的表现，以最佳呈现 体内a）通过直接协作和与与 核心D，b）表达NAB表位的工程性病毒样颗粒（VLP）。有VLP的经验 表达HIV肽将包括P55插孔以及乙型肝炎颗粒（Univ Regensburg，此 项目）。 2。确定最佳疫苗平台（蛋白质，肽和/或病毒载体）和方案 启动或增强构型依赖性表位特异性。这将通过关闭来促进 与疫苗技术核心（b）以及在中发展的互补环境结构的相互作用 项目1和3。 3。确定可以最佳地组合数量的NAB肽表位数 评估的方案最终产生强大的中和抗体反应，并评估 首先在兔子中，随后更严格地在非人类 - 纯化的模型（核心C）中。 4。确定这些优化模仿疫苗方案的“原理证明”保护功效 在Shiv Rhesus猕猴疫苗挑战模型中。 NAB B细胞表位的最佳组合 在异源和粘膜挑战研究中将揭示出结构和输送系统。