HIV Vaccine Design and Development Team

HIV疫苗设计和开发团队

• 批准号: 6374728
• 负责人: PAUL J MADDON
• 金额: $ 209.05万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2003-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374728
• 关键词: AIDS vaccines; human immunodeficiency virus; vaccine development

The overall goal of this proposal is to develop and bring to human clinical testing a vaccine which induces antibodies that potently and broadly neutralized primary HIV isolates. An effective antiviral antibody response is a desirable feature of prophylactic HIV vaccine to supplement broadly active cellular immune responses as part of a multi-component vaccine strategy. Our vaccine concept is to create oligomeric HIV envelope glycoprotein (env) complexes that provide authentic antigenic mimics of virus-associated env. Although this has been a long-standing goal of HIV vaccine research, authentic oligomers have never been produced as recombinant proteins due to the inherent instability of the non-covalent interaction between gp120 and gp41. However, recent findings in our laboratories demonstrate that this limitation can be overcome by introducing a disulfide bond between the two subunit proteins. As we describe below (and in the Binley et al. Manuscript included in the Appendix), when the introduced cysteine residues are placed in favorable locations, gp120 and gp41 form a stable oligomeric complex whose pattern of antibody reactivity mirrors that of virus- associated env. By stably presenting this antigenically relevant structure to the immune system, this immunogen could in principle induce a neutralizing antibody response superior to that elicited by prior generation env-based vaccines or by natural infection. Our primary approach is to develop a recombinant oligomeric HIV subunit vaccine based on this concept. At present, subunit vaccines provide the most effective means of inducing robust humoral immune responses by delivering the immunogen in a homogeneous, concentrated, and optimally adjuvanted form. However, we recognize that other approaches may provide superior means of delivering the oligomers to the human system. Therefore, we will also examine a nucleic acid-based vaccine approach wherein the oligomers are synthesized in vivo. For this, we have teamed with AlphaVax, Inc. who have developed non- replicating viral vectors based on the Venezuelan Equine Encephalitis (VEE) virus. Although our primary goal is to induce an effective antiviral antibody response, we will also examine cellular immune response elicited by both the subunit and viral vaccines to guide our selection of the optimum construct(s) for further development. Our projects includes an extensive and iterative program for designing and testing these novel immunogens in the best available in vitro and animal models of HIV infection, including the SHIV-macaque model. We seek to develop a safe and efficacious vaccine against HIV for worldwide use in stemming the AIDS epidemic. Therefore, a primary and early focus of our effort will be to prepare vaccine candidates based on envs derived from subtype C viruses. The most promising vaccine candidates will be tested in Phase I/II human clinical trials in both South African and the U.S. Our focused, development-based approach will be carried out by a consortia of distinguished investigators from both industry with experience in all aspects of vaccine design, development and clinical testing.

该提案的总体目标是开发一种疫苗并将其用于人体临床测试，该疫苗可诱导产生有效且广泛中和主要 HIV 分离株的抗体。有效的抗病毒抗体反应是预防性 HIV 疫苗的一个理想特征，可以补充广泛活跃的细胞免疫反应，作为多成分疫苗策略的一部分。我们的疫苗概念是创建寡聚 HIV 包膜糖蛋白 (env) 复合物，提供病毒相关包膜的真实抗原模拟物。尽管这一直是 HIV 疫苗研究的长期目标，但由于 gp120 和 gp41 之间非共价相互作用的固有不稳定性，真正的寡聚物从未以重组蛋白的形式产生。然而，我们实验室的最新研究结果表明，可以通过在两个亚基蛋白之间引入二硫键来克服这一限制。正如我们下面所描述的（以及附录中 Binley 等人的手稿），当引入的半胱氨酸残基被放置在有利的位置时，gp120 和 gp41 形成稳定的寡聚复合物，其抗体反应模式反映了病毒相关环境的反应模式。 。通过向免疫系统稳定地呈现这种抗原相关结构，这种免疫原原则上可以诱导中和抗体反应，该反应优于上一代基于 env 的疫苗或自然感染所引起的反应。我们的主要方法是基于这个概念开发重组寡聚HIV亚单位疫苗。目前，亚单位疫苗通过以均质、浓缩和最佳佐剂形式递送免疫原，提供了诱导强烈体液免疫反应的最有效方法。然而，我们认识到其他方法可能提供将寡聚体递送至人体系统的更好方法。因此，我们还将研究基于核酸的疫苗方法，其中寡聚物在体内合成。为此，我们与 AlphaVax, Inc. 合作，后者开发了基于委内瑞拉马脑炎 (VEE) 病毒的非复制病毒载体。尽管我们的主要目标是诱导有效的抗病毒抗体反应，但我们还将检查亚单位和病毒疫苗引起的细胞免疫反应，以指导我们选择最佳构建体以进行进一步开发。我们的项目包括一个广泛的迭代计划，用于在最佳的 HIV 感染体外和动物模型（包括 SHIV 猕猴模型）中设计和测试这些新型免疫原。我们寻求开发一种安全有效的艾滋病毒疫苗，供全世界使用以遏制艾滋病流行。因此，我们工作的首要和早期重点将是基于 C 亚型病毒衍生的 envs 制备候选疫苗。最有前途的候选疫苗将在南非和美国进行 I/II 期人体临床试验。我们以开发为基础的重点方法将由来自两个行业、在疫苗各个方面都有经验的杰出研究人员组成的联盟来实施设计、开发和临床测试。