Polyvalent DNA Plus Protein HIV Vaccines

描述(由申请人提供)：这项修订的R01申请的目标是进一步优化DNA初级和蛋白质增强方法，以开发能够产生针对目标HIV-1病毒的广泛中和抗体的改进的多价艾滋病毒疫苗配方。这一应用是基于我们最近的结果，即DNA Prime+Protein Boost免疫方法在临床前动物和早期人类临床研究的多个分支中有效地诱导针对某些初级HIV分离株的中和抗体反应。这是在这种初级/增强疫苗接种方法中使用来自HIV-1初级分离株的Env抗原时实现的。人们认为DNA启动有助于提高最终抗体反应的质量，而蛋白质Boost则导致快速产生高水平的抗体反应。由于DNA免疫传统上用于细胞免疫反应，而不是抗体反应，这一意想不到的发现将为DNA免疫在诱导抗HIV-1中和抗体方面带来新的应用。因此，我们的方法在人类HIV疫苗开发方面具有令人兴奋的潜力。目的1.进一步扩大针对其他初级病毒分离株的中和抗体的广度，特别是那些对我们的试点多价制剂具有抗药性的病毒分离株。目的2.利用优化的包膜抗原设计和优化的免疫程序，研制新一代DNA主剂和蛋白质增强HIV疫苗。目的3.研究DNA Prime Plus Protein Boost策略的免疫学机制和抗体亲和力成熟过程，为开发更有效的多价DNA Plus Protein疫苗奠定基础。目前的应用结合了HIV疫苗开发中的两项重要技术：DNA Prime+Protein Boost疫苗接种方法，该方法已显示出在产生针对HIV-1初级分离株的中和抗体方面的前景，以及使用标准化的初级病毒面板进行高通量中和分析。这将使我们能够有效地筛选大量独特的初级Env抗原，为下一阶段的临床测试制定有效的多价HIV疫苗。

DESCRIPTION (provided by applicant): The goal of this revised R01 application is to further optimize the DNA prime and protein boost approach for the development of improved polyvalent HIV vaccine formulations that can generate broad neutralizing antibodies against targeted HIV-1 viruses. This application is based on our recent results that the DNA prime plus protein boost immunization approach was effective in eliciting neutralizing antibody responses against certain primary HIV isolates across multiple clades from both preclinical animal and early phase human clinical studies. This was achieved when the Env antigens from primary HIV-1 isolates were used in this prime/boost vaccination approach. It is believed that DNA priming contributes to the quality of the final antibody responses while the protein boost leads to a quick production of high level antibody responses. Because DNA immunization has been traditionally used for cell mediated immune responses rather than antibody responses, this unexpected finding will bring novel applications to DNA immunization in eliciting neutralizing antibodies against HIV-1. Therefore our approach has exciting potential in human HIV vaccine development. Aim 1. To further expand the breadth of neutralizing antibodies against additional primary viral isolates especially those resistant to our pilot polyvalent formulations. Aim 2. To develop the next generation DNA prime and protein boost HIV vaccines by using optimized forms of Env antigen designs and optimized immunization schedules. Aim 3. To study the immunological mechanism and the antibody affinity maturation process that may contribute to the efficacy of DNA prime plus protein boost strategy so that more effective polyvalent DNA plus protein vaccines can be developed. The current application combines two important technologies in HIV vaccine development: the DNA prime plus protein boost vaccination approach which has been shown promise in generating neutralizing antibodies against primary HIV-1 isolates and the high throughput neutralization assays with standardized primary viral panels. This will allows us to effectively screen a large number of unique primary Env antigens to formulate the effective polyvalent HIV vaccines for the next phase of clinical testing.