Env Immunogen Design-Rational and Random Designs, and Env Receptor Mimetic Comp..

Env 免疫原设计-理性和随机设计，以及 Env 受体模拟组件。

• 批准号: 7166858
• 负责人: Indresh K Srivastava
• 金额: $ 62.1万
• 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/7166858
• 关键词: AIDS vaccines; antigen antibody reaction; antigens; bioengineering /biomedical engineering; biomimetics; clinical research; epitope mapping; gene deletion mutation; gene expression; genetic screening; glycosylation; guinea pigs; helper T lymphocyte; laboratory mouse; laboratory rabbit; monoclonal antibody; neutralizing antibody; nuclear matrix; protein isoforms; vaccine development; vaccine evaluation; virus characteristic; virus envelope; virus genetics

So far, generation of broadly neutralizing antibody responses against diverse primary HIV isolates has been an elusive target. Therefore, the aim of this project is to design and evaluate novel Env immunogens for their ability to induce broadly neutralizing antibody responses against diverse primary isolates. We previously reported that an Env immunogen (o-gp140SF162DV2) containing a partial deletion in the second variable loop (V2) derived from SF162 (R5 tropic), when used in a DMA prime-protein boost regimen in rhesus macaques, induced neutralizing antibodies against some heterologous subtype B primary isolates as well as protection to the vaccinated animals upon challenge with pathogenic SHIVSF162P4. We plan to continue working on trimeric Env and use four complementary approaches to further enhance the exposure of conserved neutralizing epitopes to improve the efficacy of Env immunogens in inducing broadly neutralizing antibodies and protection in challenge model. In the first, we propose to increase the exposure of conserved neutralizing epitopes involved in receptor and co-receptor binding regions of the Env by introducing deletions in V-regions and "bridging-sheet" following rational and random approaches. In the second, we seek to expose neutralizing epitopes by introducing site specific or global deglycosylation either alone or in combination with b-sheet and/or V- loops. In the third, we seek to expose these epitopes by the use of Env complexed to rationally designed CD4 mimics or other scaffolds. Lastly, we propose to express Env trimer in non-glycosylated form to enhance the exposure of critical neutralizing epitopes that are shielded by extensive glycosylation. We will use subtype B antigens as a model for evaluating the efficacy of various approaches mentioned above. The best approach will be used for optimizing Env antigens from other subtypes e.g. A and C. We will screen candidate immunogens for expression, CD4-binding, and binding to a panel of monoclonal antibodies of known specificities. Once a candidate has met pre-defined criteria, it then will be advanced to immunogenicity studies in rabbits. Neutralizing antibody and cellular responses induced by the lead candidate will be optimized using adjuvants, formulations, and vaccine regimens. The best Env immunogen will be advanced to vaccine/challenge studies in primates. These studies should yield important information for the design of next generation HIV vaccines for future clinical evaluations.

到目前为止，针对多种原发性HIV分离株的广泛中和抗体反应的产生一直是 一个难以捉摸的目标。因此，该项目的目的是设计和评估新颖的ENV免疫原 能够诱导针对多种原发性分离株的抗体反应广泛中和的能力。我们以前 报道了第二个变量中包含部分缺失的ENV免疫原（O-GP140SF162DV2） 在恒河猴中使用的DMA Prime蛋白增强方案中，源自SF162（R5 Tropic）的循环（V2） 猕猴，诱导对某些异源亚型B主要分离株的中和抗体以及 通过致病性SHIVSF162P4挑战时，可以保护接种动物。我们计划继续 从事三聚合物env并使用四种互补方法进一步增强 保守的中和表位，以提高ENV免疫剂在诱导广泛中和的功效 挑战模型中的抗体和保护。首先，我们建议增加保守的暴露 通过引入缺失，中和参与ENV受体和受体结合区域的表位 在有理和随机方法之后，在V区和“桥接”中。在第二个中，我们试图 通过单独或在 结合B片和/或V-循环。在第三个中，我们试图通过使用env来暴露这些表位 复合于合理设计的CD4模拟物或其他支架。最后，我们建议在 非糖基化形式，以增强被屏蔽的关键中和表位的暴露 广泛的糖基化。我们将使用亚型B抗原作为评估各种功效的模型 上面提到的方法。最佳方法将用于优化其他其他方法 子类型，例如A和C。我们将筛选候选免疫原以表达表达，CD4结合并与A结合 已知特异性的单克隆抗体面板。一旦候选人达到预定义的标准， 将在兔子中进行免疫原性研究。中和抗体和细胞反应诱导 将使用辅助候选者，配方和疫苗方案进行优化。最好的环境 免疫原将推进灵长类动物的疫苗/挑战研究。这些研究应该产生重要 用于设计下一代艾滋病毒疫苗的信息，以进行未来的临床评估。