Optimizing the immunogenicity of next generation polyvalent HIV vaccine formulati

优化下一代多价 HIV 疫苗配方的免疫原性

• 批准号: 8499206
• 负责人: Shan Lu
• 金额: $ 234.3万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499206
• 关键词: Adjuvant; Antibodies; Antibody Binding Sites; Antibody Formation; Antibody Specificity; Biological Assay; Biological Markers; Cellular Immunity; Clinical Research; Clinical Trials; DNA; DNA Vaccines; Data; Development; Drug Formulations; Electroporation; Epitopes; Equilibrium; Future; Genes; Genetic; HIV; HIV vaccine; HIV-1; Human; Human Volunteers; Immune Sera; Immune response; Immunization; Injection of therapeutic agent; Intramuscular; Manuscripts; Measurable; Methods; Monitor; Needles; Oryctolagus cuniculus; Patients; Phase; Proteins; Publishing; QS21; Safety; Serum; System; Technology; Testing; Vaccines; Viral; Virus; Work; base; design; env Gene Products; immunogenic; immunogenicity; improved; neutralizing antibody; next generation; pre-clinical; preclinical study; programs; screening; vaccine development

Project 1 will focus on the optimization of the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DMA 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 DMA 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 DMA priming is delivered by the electroporation method. Aim 4 To examine the epitope profiles in immune sera elicited by DMA prime-protein boost approach and identify the epitope specificities of antibodies responsible for the neutralizing activities.

项目1将侧重于优化下一代多价Env HIV疫苗制剂， 多基因、多价DNA引物-蛋白质增强技术平台。 我们的第一个艾滋病毒疫苗制剂DP6 - 001是几年前开发的，用于概念验证试验， 证明了DMA初免-蛋白加强方法在人类志愿者中的免疫原性。的 20世纪90年代中期从HIV感染患者中分离的主要Env抗原是基于以下随机选择的： 他们的基因分支艾滋病毒疫苗领域的快速进展现在为我们提供了更多的选择， 一级Env抗原，特别是来自过去研究较少的进化枝的那些Env蛋白和来自进化枝的那些Env蛋白， 这些蛋白质具有关于分离出病毒的患者的更详细的信息。此外，本发明还提供了一种方法， 最近开发假型中和试验和新建立的靶向HIV-1原代病毒 小组（“等级系统”）提供了一个可衡量的标准，以指导我们选择更相关的主要 以中和抗体诱导为重点的HIV疫苗开发用Env抗原 应答利用上述进展，我们鉴定了一组Env的主要抗原 能够引发比我们先前配方中包含的更广泛的中和抗体， DP6 - 001。在本IPCAVD项目的当前项目1中，将进行以下研究： 目的1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。 目的2选择免疫原性佐剂作为下一代蛋白加强免疫的一部分 多价Env制剂。 目的3检测下一代多价Env制剂在DMA引发时的免疫原性。 通过电穿孔方法递送。 目的4检测DMA引物-蛋白加强免疫法诱导的免疫血清表位谱， 鉴定负责中和活性的抗体的表位特异性。