Polyvalent DNA Plus Protein HIV Vaccines

描述（由申请人提供）：本次修订的R 01申请的目标是进一步优化DNA初免和蛋白加强方法，以开发可产生针对靶向HIV-1病毒的广谱中和抗体的改良多价HIV疫苗制剂。该申请基于我们最近的结果，即DNA初免加蛋白质加强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引发针对某些主要HIV分离株的中和抗体应答。当在这种初免/加强疫苗接种方法中使用来自原代HIV-1分离株的Env抗原时，实现了这一点。据信DNA引发有助于最终抗体应答的质量，而蛋白质加强导致高水平抗体应答的快速产生。由于DNA免疫传统上用于细胞介导的免疫应答而不是抗体应答，因此这一意外发现将为DNA免疫在引发针对HIV-1的中和抗体方面带来新的应用。因此，我们的方法在人类HIV疫苗开发中具有令人兴奋的潜力。目标1.进一步扩大针对其他主要病毒分离株的中和抗体的广度，特别是对我们的试验性多价制剂耐药的病毒分离株。目标二。通过优化Env抗原设计和优化免疫程序，开发下一代DNA初免和蛋白加强的HIV疫苗。目标3。研究DNA初免+蛋白加强免疫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+蛋白疫苗奠定基础。目前的应用结合了HIV疫苗开发中的两种重要技术：DNA初免加蛋白质加强疫苗接种方法，该方法已被证明有望产生针对原代HIV-1分离株的中和抗体，以及使用标准化原代病毒组的高通量中和测定。这将使我们能够有效地筛选大量独特的一级Env抗原，以配制有效的多价HIV疫苗，用于下一阶段的临床试验。

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.