HIV B-Cell Lineage Vaccine Design Based on Replicating SAd and Env Protein in NHP

基于 NHP 中 SAd 和 Env 蛋白复制的 HIV B 细胞谱系疫苗设计

• 批准号: 8846707
• 负责人: Jeffery Alexander
• 金额: $ 80.15万
• 依托单位: PAXVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846707
• 关键词: Acquired Immunodeficiency Syndrome; Adenovirus Vector; Adenoviruses; Animal Testing; Animals; Antibodies; Antigens; B-Cell Development; B-Lymphocytes; Binding; Binding Sites; Canarypox Vectors; Cell Lineage; Cells; Characteristics; Clinical; Cloning; DNA Sequence; Data; Development; Dose; Evaluation; Evolution; Exposure to; Glycoproteins; Goals; HIV; HIV-1; Human; Human Adenoviruses; Immune response; Immunization; In Vitro; Individual; Infection; Influenza; Lead; Life; Measles Vaccine; Modeling; Natural Immunity; Oral cavity; Oryctolagus cuniculus; Patients; Phase; Phase I Clinical Trials; Plasma; Poliomyelitis; Process; Production; Proteins; Receptors, Antigen, B-Cell; Recombinants; Research; Risk; Simian Adenoviruses; Site; Small Business Innovation Research Grant; Somatic Mutation; Staging; Surface; System; T memory cell; T-Lymphocyte; Testing; Transgenes; Translating; Vaccination; Vaccine Design; Vaccines; Viral Antibodies; Viral Vector; Virus; Western Blotting; base; design; design and construction; env Gene Products; immunogenicity; insight; neutralizing antibody; nonhuman primate; novel strategies; phase 1 study; prevent; programs; protein expression; public health relevance; recombinant virus; response; transgene expression; vaccination strategy; vaccine development; vector

 DESCRIPTION (provided by applicant): Development of a HIV-1 vaccine to prevent, or reduce, the rate of infection remains a high priority. The lessons from numerous failed and the recent modestly successful RV144 Thai trial indicate the need to advance new approaches to HIV-1 vaccine design with the goal of inducing immune responses that are the appropriate type, quality, magnitude and active in the appropriate sites in the body. Our strategy is to build upon the RV144 study which implemented a canarypox vector prime (T and B cell immunogens) followed by a recombinant envelope (Env) protein boost immunization. The primary objective of this project is to assess an immunization strategy to induce broadly neutralizing antibodies (BnAbs) in nonhuman primates based on vaccines containing recombinant simian adenovirus (SAd) viral vectors and HIV-1 Env glycoproteins selected from sequential isolates of an HIV-1-infected individual that ultimately developed CD4-binding site BnAbs. The premise of this approach is to engage naive B-cell receptors of BnAbs, and continue to immunize with select immunogens to stimulate somatic mutation that leads to induction of BnAbs. Our central hypothesis is that the combination of replicating adenovirus persistently expressing Envs selected at critical junctions during development of BnAbs will be efficient vaccine immunogens for inducing protective antibodies against HIV-1 infection. It will be evaluated whether serial or swarm immunization with SAds expressing Envs delivered with matching Env glycoprotein immunogens can induce BnAbs. The recombinant SAdEnv vectors will be assessed for immunogenicity in rabbits before proceeding to NHP studies in Year 2. Both antibody (binding, neutralizing, and ADCVI) and Env-specific T cell immune responses will be evaluated. Completion of this SBIR II program may provide sufficient data to determine the utility of the replicating adenovirus vector system for expressing B cell lineage Envs and potentially could yield an experimental vaccine suitable for clinical development.

 描述（由申请人提供）：开发HIV-1疫苗以预防或降低感染率仍然是一个高度优先事项。从许多失败的经验教训和最近适度成功的RV 144泰国试验表明，需要推进新的方法来设计HIV-1疫苗，目的是诱导免疫反应，是适当的类型，质量，规模和活跃在适当的网站在身体。我们的策略是建立在RV 144研究的基础上，该研究实施了金丝雀痘载体初免（T和B细胞免疫原），然后是重组包膜（Env）蛋白加强免疫。该项目的主要目的是评估一种免疫策略，以诱导非人灵长类动物产生广泛中和抗体（BnAbs），该策略基于含有重组猿猴腺病毒（SAd）病毒载体和HIV-1 Env糖蛋白的疫苗，这些糖蛋白选自最终产生CD 4结合位点BnAbs的HIV-1感染个体的连续分离株。这种方法的前提是接合BnAb的幼稚B细胞受体，并继续用选择的免疫原免疫以刺激导致BnAb诱导的体细胞突变。我们的中心假设是，在BnAb的开发过程中，在关键连接处选择的持续表达Env的复制腺病毒的组合将是用于诱导针对HIV-1感染的保护性抗体的有效疫苗免疫原。将评价用表达与匹配的Env糖蛋白免疫原一起递送的Env的SAd进行连续或群体免疫是否可以诱导BnAb。在第2年进行NHP研究之前，将评估重组SAdEnv载体在兔子中的免疫原性。将评价抗体（结合、中和和ADCVI）和Env特异性T细胞免疫应答。该SBIR II计划的完成可以提供足够的数据来确定用于表达B细胞谱系Env的复制型腺病毒载体系统的效用，并且可能产生适合于临床开发的实验疫苗。