HIV Vaccine Design and Development Team

这项提议的总体目标是开发一种疫苗，并将其用于人类临床测试，该疫苗能够诱导抗体，有效并广泛地中和初级艾滋病毒分离株。作为多组分疫苗策略的一部分，有效的抗病毒抗体反应是预防性艾滋病毒疫苗的一个理想特征，以补充广泛活跃的细胞免疫反应。我们的疫苗概念是创建低聚HIV包膜糖蛋白(Env)复合体，提供真实的病毒相关env抗原模拟。尽管这是HIV疫苗研究的一个长期目标，但由于gp120和gp41之间非共价相互作用的内在不稳定性，真正的低聚物从未作为重组蛋白产生。然而，我们实验室最近的发现表明，通过在两个亚单位蛋白质之间引入二硫键可以克服这一限制。如下所述(以及在Binley等人中)。当引入的半胱氨酸残基被放置在合适的位置时，gp120和gp41形成了稳定的寡聚复合体，其抗体反应模式反映了病毒相关的env的模式。通过稳定地将这种抗原性相关的结构呈现给免疫系统，这种免疫原原则上可以诱导出比上一代基于包膜的疫苗或自然感染更好的中和抗体反应。我们的主要方法是基于这一概念开发重组寡聚HIV亚单位疫苗。目前，亚单位疫苗通过以均一、集中和最佳佐剂的形式递送免疫原，提供了诱导强大体液免疫反应的最有效手段。然而，我们认识到，其他方法可能提供更好的方法将低聚物输送到人体系统。因此，我们还将研究一种基于核酸的疫苗方法，其中寡聚体是在体内合成的。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反应，但我们也将检测亚基疫苗和病毒疫苗引起的细胞免疫反应，以指导我们选择进一步开发的最佳构建体(S)。我们的项目包括一个广泛和迭代的计划，用于在最好的艾滋病毒感染体外和动物模型中设计和测试这些新型免疫原，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，在全球范围内用于遏制艾滋病的流行。因此，我们努力的一个主要和早期的重点将是根据来自C亚型病毒的env准备候选疫苗。最有希望的候选疫苗将在南非和美国的I/II阶段人体临床试验中进行测试。我们专注于开发的方法将由来自这两个行业的具有疫苗设计、开发和临床测试所有方面经验的杰出研究人员组成的财团实施。

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.