Optimization of HIV vaccines for the induction of cross-reactive antibodies

描述（由申请人提供）： U19申请的目标是进一步推进DNA初免/蛋白质加强方法，以专注于广泛反应性抗体反应的开发。该建议是基于我们最近的1期研究结果而制定的，该研究结果表明，候选艾滋病疫苗首次在同一人体临床试验中诱导针对选定的主要HIV-1分离株的细胞介导免疫和中和抗体应答。这也是DNA免疫首次在人类志愿者中有效引发高水平抗体应答。目前的提案代表了一项关键进展，即我们能够使用高度可重复的疫苗接种技术平台对实际疫苗制剂的组分进行渐进式改进。通过使用当前的IPCAVD计划，我们建议进行先进的疫苗优化研究，以解决两个关键问题：1）进行Env抗原的合理选择以提高中和抗体应答的广度，和2）为了优化佐剂的选择，以减少在我们的研究中在高剂量DNA初免后接受一种蛋白质加强的志愿者中任何潜在的高反应原性，以前的临床试验。具体而言，提出了以下目标：目标1：组装和管理一个高生产力的研究和开发团队。目标二：通过纳入基于良好受控的合理筛选系统选择的Env抗原，开发下一代多价Env制剂。目标三：通过测试不同的佐剂和使用替代DNA疫苗递送方法来降低任何潜在的反应原性，以提高安全性。目标4：进行DNA和蛋白质疫苗组分的GMP生产、确定性毒理学研究以及下一代多价HIV疫苗制剂的监管审查。目标5：计划1期安全性和免疫原性临床试验，并将GMP产品转移到NIH的HIV疫苗试验网络（HVTN）进行人体试验。 相关性：开发进一步改进的候选艾滋病疫苗，以控制艾滋病毒在世界范围内的传播。这种疫苗设计的早期版本在其首次人体研究中显示出有希望的结果。 项目1 项目名称：优化下一代多价HIV疫苗的免疫原性 制剂 项目负责人：Shan Lu，MD，PhD 项目1描述（由申请人提供）： 项目1将专注于使用多基因、多价DNA初免/蛋白加强技术平台优化下一代多价Env HIV疫苗配方。我们的第一个HIV疫苗制剂DP 6 -001是几年前开发的，用于概念验证试验，以证明DNA初免/蛋白加强方法在人类志愿者中的免疫原性。20世纪90年代中期从HIV感染者中分离的主要Env抗原是基于其遗传进化枝随机选择的。HIV疫苗领域的快速进展现在为我们提供了更多的主要Env抗原选择，特别是过去研究较少的进化枝中的Env蛋白，以及具有关于病毒分离患者的更详细信息的Env蛋白。此外，最近开发的假型中和试验和新建立的靶HIV-1原代病毒组（“Tiers系统”）提供了可测量的标准，以指导我们选择更相关的原代Env抗原，用于开发专注于诱导中和抗体应答的HIV疫苗。通过利用上述进展，我们已经鉴定了一组初级Env抗原，其能够引发比我们先前制剂DP 6 -001中包含的中和抗体更广泛的中和抗体。在该IPCAVD项目的当前项目1中，将进行以下研究：目的1最终确定下一代多价Env制剂的选择，以进一步提高中和抗体活性的质量。目的2选择免疫原性佐剂作为下一代多价Env制剂的蛋白加强的一部分。目的3检测新一代多价Env制剂在电穿孔法DNA引发时的免疫原性。目的4检测DNA引物-蛋白加强免疫法诱导的免疫血清中抗原表位谱，并鉴定中和抗体的抗原表位特异性。 相关性：使用多基因、多价DNA初免-蛋白加强技术平台优化下一代多价Env HIV疫苗制剂。

DESCRIPTION (provided by applicant): The goal of this U19 application is to further advance the DNA prime/protein boost approach to focus on the development of broadly reactive antibody responses. This proposal is developed based on our recent phase 1 study result that, for the first time, a candidate AIDS vaccine induced both cell-mediated immunity and neutralizing antibody responses against selected primary HIV-1 isolates in the same human clinical trial. It was also the first time that DNA immunization was effective in priming high level antibody responses in human volunteers. The current proposal represents a key progress that we are able to use a highly reproducible vaccination technology platform to conduct incremental improvements on the components of actual vaccine formulations. By using the current IPCAVD program, we propose to conduct advanced vaccine optimization studies in order to address two key issues: 1) to conduct a rational selection of Env antigens in order to improve the breadth of neutralizing antibody responses, and 2) to optimize the selection of adjuvants to reduce any potential high reactogenicity in those volunteers who received the one protein boost after the high dose DNA prime in our previous clinical trial. Specifically, the following aims are proposed: Objective 1: To assemble and manage a highly productive research and development team. Objective 2: To develop the next generation polyvalent Env formulation by including Env antigens that were selected based on a well controlled rational screening system. Objective 3: To improve the safety profile by testing different adjuvants and using alternative DNA vaccine delivery method to reduce any potential reactogenicity. Objective 4: To conduct GMP manufacturing of DNA and protein vaccine components, definitive toxicology studies, and regulatory reviews of the next generation polyvalent HIV vaccine formulation. Objective 5: To plan for a Phase 1 safety and immunogenicity clinical trial and transfer GMP products to be tested in humans to NIH's HIV Vaccine Trial Network (HVTN). RELEVANCE: Developing a further improved candidate AIDS vaccine to control HIV virus transmission in the world. An early version of this vaccine design showed promising results in its first human study. PROJECT 1 Project Title: Optimizing the Immunogenicity of Next Generation Polyvalent HIV Vaccine Formulations Project Leader: Shan Lu, MD, PhD PROJECT 1 DESCRIPTION (provided by applicant): Project 1 will focus on the optimization of the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime/protein boost technology platform. Our first HIV vaccine formulation, DP6-001, was developed several years ago for a proof-of-concept trial to demonstrate the immunogenicity of the DNA prime/protein boost approach in human volunteers. The primary Env antigens isolated from HIV infected patients in mid-1990s were selected randomly based on their genetic clades. Rapid progress in the HIV vaccine field now provides us with a much larger selection of primary Env antigens, especially those Env proteins from clades less studied in the past and those Env proteins with more detailed information about the patients from whom the viruses were isolated. In addition, the recently developed pseudotyped neutralization assay and newly established target HIV-1 primary virus panel ("the Tiers System") provides a measurable standard to guide our selection of more relevant primary Env antigens for the development of HIV vaccines focusing on the induction of neutralizing antibody responses. By taking advantage of the above progress, we have identified a group of primary Env antigens that were able to elicit much broader neutralizing antibodies than those included in our previous formulation DP6-001. In the current Project 1 of this IPCAVD program, the following studies will be conducted: Aim 1 To finalize the selection of next generation polyvalent Env formulation to further improve the quality of neutralizing antibody activities. Aim 2 To select an immunogenic adjuvant to be used as part of the protein boost for the next generation polyvalent Env formulation. Aim 3 To test the immunogenicity of next generation polyvalent Env formulation when the DNA priming is delivered by the electroporation method. Aim 4 To examine the epitope profiles in immune sera elicited by DNA prime-protein boost approach and identify the epitope specificities of antibodies responsible for the neutralizing activities. RELEVANCE: To optimize the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime - protein boost technology platform.