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

 描述(由申请人提供)：开发艾滋病毒-1疫苗以预防或降低感染率仍然是一个高度优先的任务。从多次失败和最近在泰国进行的RV144试验的经验教训表明，需要推进艾滋病毒-1疫苗设计的新方法，目的是诱导适当类型、质量、大小和在人体适当部位活跃的免疫反应。我们的策略是建立在RV144研究的基础上，该研究实施了金丝雀痘载体Prime(T和B细胞免疫原)，然后是重组包膜(Env)蛋白增强免疫。本项目的主要目标是评估一种免疫策略，以在非人类灵长类动物中诱导广谱中和抗体(BNAbs)，该疫苗包含重组猿腺病毒(SAD)病毒载体和从HIV-1感染者的序列分离株中选择的HIV-1包膜糖蛋白，该病毒最终产生了CD4结合位点bNAbs。这种方法的前提是激活幼稚的bNAbs的B细胞受体，并继续用精选的免疫原免疫以刺激体细胞突变，从而诱导bNAbs的产生。我们的中心假设是，在bNAbs发育的关键时刻选择持续表达env的复制腺病毒组合将是有效的疫苗免疫原，用于诱导针对HIV-1感染的保护性抗体。用SADS表达的env表达的env与匹配的env糖蛋白免疫原串联免疫或群体免疫是否能诱导bNAb，这将被评估。在第二年进行NHP研究之前，将评估重组SAdEnv载体在兔身上的免疫原性。将评估抗体(结合、中和和ADCVI)和环境特异性T细胞免疫反应。该SBIR II计划的完成可能会提供足够的数据来确定复制型腺病毒载体系统表达B细胞系env的实用性，并有可能生产出适合临床开发的实验性疫苗。

 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.