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 应用的目标是进一步推进 DNA 引发/蛋白质增强方法，以专注于广泛反应性抗体反应的开发。该提案是根据我们最近的一期研究结果制定的，该研究结果是，候选艾滋病疫苗首次在同一人体临床试验中针对选定的主要 HIV-1 分离株诱导细胞介导的免疫和中和抗体反应。这也是 DNA 免疫首次在人类志愿者中有效引发高水平抗体反应。目前的提案代表了一个关键进展，我们能够利用高度可重复的疫苗接种技术平台对实际疫苗配方的成分进行渐进式改进。通过使用当前的 IPCVD 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) 合理选择 Env 抗原，以提高中和抗体反应的广度，2) 优化佐剂的选择，以减少在我们之前的临床试验中在高剂量 DNA 引发后接受单一蛋白加强的志愿者中任何潜在的高反应原性。具体提出以下目标： 目标1：组建和管理一支高效的研发团队。目标 2：通过包含基于良好控制的合理筛选系统选择的 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 疫苗递送方法来减少任何潜在的反应原性，以提高安全性。目标 4：进行 DNA 和蛋白质疫苗成分的 GMP 生产、明确的毒理学研究以及下一代多价 HIV 疫苗配方的监管审查。目标 5：规划 1 期安全性和免疫原性临床试验，并将用于人体测试的 GMP 产品转移到 NIH 的 HIV 疫苗试验网络 (HVTN)。 相关性：开发进一步改进的候选艾滋病疫苗以控制艾滋病病毒在世界范围内的传播。这种疫苗设计的早期版本在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 配方 项目负责人：卢珊，医学博士、博士 项目 1 描述（由申请人提供）： 项目1将重点利用多基因、多价DNA初免/蛋白质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 疫苗配方 DP6-001 是几年前开发的，用于概念验证试验，以证明 DNA 初免/蛋白质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感染者身上分离出的主要Env抗原是根据他们的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，特别是那些来自过去较少研究的进化枝的Env蛋白，以及那些含有有关分离出病毒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和新建立的目标HIV-1初级病毒组（“Tiers系统”）提供了可测量的标准，以指导我们选择更相关的初级Env抗原来开发HIV疫苗，重点是诱导中和抗体反应。通过利用上述进展，我们鉴定了一组初级 Env 抗原，它们能够引发比我们之前的配方 DP6-001 中包含的抗体更广泛的中和抗体。在该IPCAVD项目当前的项目1中，将进行以下研究： 目标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。目标 2 选择一种免疫原性佐剂作为下一代多价 Env 制剂的蛋白质增强的一部分。目标 3 测试通过电穿孔方法递送 DNA 引发时下一代多价 Env 制剂的免疫原性。目标 4 检查 DNA 初始蛋白增强方法引发的免疫血清中的表位谱，并鉴定负责中和活性的抗体的表位特异性。 相关性：利用多基因、多价 DNA 引发 - 蛋白加强技术平台优化下一代多价 Env HIV 疫苗配方。