HIV Vaccine Design and Development Team

该提案的总体目标是开发并将一种疫苗用于人类临床试验，该疫苗诱导的抗体可有效和广泛地中和主要HIV分离株。有效的抗病毒抗体应答是预防性HIV疫苗的理想特征，以补充广泛活跃的细胞免疫应答，作为多组分疫苗策略的一部分。我们的疫苗概念是创造寡聚体HIV包膜糖蛋白（env）复合物，提供病毒相关env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gp 120和gp 41之间的非共价相互作用的固有不稳定性，真实的寡聚体从未被生产为重组蛋白。然而，我们实验室最近的发现表明，通过在两个亚基蛋白质之间引入二硫键可以克服这种限制。正如我们在下文（以及在附录中包括的Binley et al. Mandelipt）中所述，当引入的半胱氨酸残基位于有利位置时，gp 120和gp 41形成稳定的寡聚复合物，其抗体反应性模式反映了病毒相关env的反应性模式。通过将这种抗原相关结构稳定地呈递给免疫系统，这种免疫原原则上可以诱导中和抗体应答，其上级于由前代基于env的疫苗或由自然感染引起的中和抗体应答。我们的主要方法是基于这一概念开发重组寡聚体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，提供了诱导强体液免疫应答的最有效手段。然而，我们认识到，其它方法可以提供将寡聚体递送至人类系统的上级手段。因此，我们还将研究基于核酸的疫苗方法，其中寡聚体在体内合成。为此，我们与AlphaVax，Inc.合作。他们开发了基于委内瑞拉马脑炎（VEE）病毒的非复制型病毒载体。虽然我们的主要目标是诱导有效的抗病毒抗体应答，但我们也将检查亚单位和病毒疫苗引起的细胞免疫应答，以指导我们选择最佳构建体用于进一步开发。我们的项目包括一个广泛的和迭代的程序，用于设计和测试这些新的免疫原在最好的体外和动物模型的艾滋病毒感染，包括SHIV猕猴模型。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，以遏制艾滋病的流行。因此，我们努力的主要和早期重点将是基于来自C亚型病毒的env制备候选疫苗。最有希望的候选疫苗将在南非和美国进行I/II期人体临床试验，我们专注于开发的方法将由来自两个行业的杰出研究人员组成的联盟进行，他们在疫苗设计，开发和临床试验的各个方面都有经验。

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.