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

用于诱导交叉反应抗体的 HIV 疫苗的优化

• 批准号: 7883581
• 负责人: Shan Lu
• 金额: $ 236.62万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-06 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883581
• 关键词: Optimization; HIV; vaccines; induction; cross

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.

描述（由申请人提供）： 该U19应用的目的是进一步推进DNA Prime/蛋白质增强方法，以关注广泛反应性抗体反应的发展。该建议是根据我们最近的第一阶段研究结果开发的，该结果首次有助于候选疫苗在同一人类临床试验中诱导细胞介导的免疫和中和抗体反应。这也是DNA免疫第一次有效地启动人类志愿者的高水平抗体反应。当前的提案代表了我们能够使用高度可重复的疫苗接种技术平台来对实际疫苗配方组成部分进行增量改进的关键进展。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）进行合理的ENV抗原选择，以改善中和中和抗体反应的广度，以及2）优化辅助者的选择，以减少那些protein protein the Protect the One Prote de de de dnna的辅助者，以降低任何潜在的反应性，从而降低了较高的反应性。具体而言，提出了以下目标：目标1：组装和管理高产的研发团队。目标2：通过包括基于良好控制的理性筛选系统选择的ENV抗原来开发下一代多价ENV制剂。目标3：通过测试不同的佐剂并使用替代DNA疫苗递送方法来提高安全性，以降低任何潜在的反应生成性。目标4：进行DNA和蛋白质疫苗成分的GMP制造，确定性毒理学研究以及下一代多价HIV疫苗配方的调节评论。目标5：计划在人类中测试的1阶段安全性和免疫原性临床试验，并转移GMP产品，以便在NIH的HIV疫苗试验网络（HVTN）中进行测试。 相关性：开发进一步改善的候选艾滋病疫苗，以控制世界上的艾滋病毒传播。这种疫苗设计的早期版本在其首次人类研究中显示出令人鼓舞的结果。 项目1 项目名称：优化下一代多价HIV疫苗的免疫原性 配方 项目负责人：医学博士Shan Lu 项目1描述（申请人提供）： 项目1将专注于使用多基因，多价DNA Prime/Protein Boost技术平台的下一代多价ENV HIV疫苗配方的优化。我们的第一个HIV疫苗配方DP6-001是几年前开发的，用于概念证明试验，以证明人类志愿者中DNA Prime/蛋白质增强方法的免疫原性。从1990年代中期从HIV感染患者中分离出的主要ENV抗原根据其遗传进化枝随机选择。现在，HIV疫苗领域的快速进展为我们提供了更多的原代ENV抗原选择，尤其是过去研究较少研究的那些ENV蛋白，以及那些具有对病毒被分离的患者的更详细信息的ENV蛋白。此外，最近开发的假型中和测定法和新建立的靶标HIV-1主要病毒面板（“ The Tiers System”）提供了一个可测量的标准，可指导我们选择更相关的主要初级ENV抗原，以开发针对中和抗体反应诱导的HIV疫苗。通过利用上述进度，我们已经确定了一组主要的ENV抗原，这些抗原能够引起比我们以前的配方DP6-001中包含的抗体更广泛的中和抗体。在该IPCAVD计划的当前项目1中，将进行以下研究：目标1旨在最终选择下一代多价env制剂，以进一步提高中和中和抗体活性的质量。 AIM 2选择免疫原性辅助物作为下一代多价ENV制剂的蛋白质增强的一部分。目标3当通过电穿孔方法传递DNA启动时，下一代多价ENV制剂的免疫原性。 AIM 4以检查由DNA Prime蛋白增强方法引起的免疫血清中的表位谱，并确定负责中和活性的抗体的表位特异性。 相关性：使用多基因，多价DNA Prime-蛋白质增强技术平台优化下一代多价ENV HIV HIV疫苗。