Oral, replicating Ad4-HIV vaccine development & evaluation in NHP challenge model

描述(由申请人提供)：尽管该领域最近出现了挫折，但开发预防或降低艾滋病毒感染率的疫苗仍然是一项高度优先的任务。失败和成功的实验项目的教训表明，需要将新的方法应用于艾滋病毒疫苗设计，目标是诱导适当类型、质量、大小和在人体适当部位活跃的免疫反应。一种有希望的方法是使用腺病毒血清4型(Ad4)作为疫苗递送载体。Ad4病毒是美国军用腺病毒疫苗的一种成分，该疫苗是以口服剂型配制的。口服给药对HIV疫苗来说应该是有利的，因为这种给药途径比非肠道注射更有可能诱导粘膜免疫反应，并将特别针对肠道粘膜组织。Ad4疫苗载体在人类体内具有复制能力，应该可以驱动免疫反应的诱导和扩展，这些免疫反应在大小和效应功能方面与非复制载体诱导的免疫反应不同。在Y1，将设计多个Ad4载体来表达独特的抗原，包括：1)HIV-1包膜C蛋白，用于诱导对多种HIV毒株的广泛有效的抗体反应；2)GBV-C E2糖蛋白，可能诱导阻断HIV-1细胞附着的抗体；以及3)Gag蛋白，可能诱导T细胞反应，促进对HIV-1病毒感染细胞的杀伤。由于Ad4等人腺病毒不能在包括NHP在内的非人类动物中复制，我们还将构建类似的复制型猿腺病毒(SAd7)载体，以便直接比较Ad4(NHP中的非复制型载体)和类似的复制型载体SAd7的效果。在Y2进行NHP研究之前，将评估所有载体在小动物(小鼠/兔子)中的免疫原性。一旦NHP的免疫原性被确认，我们将在NHP R5SHV分支C挑战研究中评估它们的有效性。抗体(中和性和ADCVI)和T细胞免疫反应(干扰素-)都将被检测。这项SBIR计划的完成将提供足够的数据来确定这种Ad4载体系统在诱导有效抗体和T细胞反应方面的效用，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 vaccine to prevent, or reduce the rate of, HIV infections remains a high priority despite recent setbacks in the field. The lessons from failed and successful experimental programs indicate the need to apply new approaches to HIV 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. A promising approach is the use of the Adenovirus serotype 4 (Ad4) as a vaccine delivery vehicle. The Ad4 virus is a component in the US Military adenovirus vaccine which was formulated for administration in an oral dosage form. Oral delivery should be advantageous for HIV vaccines because this route of administration is more likely to induce mucosal immune responses than parenteral injection and would target the gut mucosal tissues in particular. The Ad4 vaccine vector is replication-competent in humans which should drive the induction and expansion of immune responses that are different, in terms of magnitude and effector functions, than those induced by non- replicating vectors. In Y1, multiple Ad4 vectors will be engineered to express unique antigens including: 1) HIV-1 Env clade C protein for the purpose of inducing antibody responses broadly effective against a variety of HIV strains; 2) GBV-C E2 glycoprotein, which may induce antibodies that block HIV-1 cellular attachment; and 3) Gag protein, which may induce T cell responses which promote killing of HIV-1 virus infected cells. Since human adenoviruses such as Ad4 do not replicate in non-human animals, including NHPs, we will also construct analogous replicating Simian adenovirus (SAd7) vectors to allow a direct comparison of the efficacy of Ad4 (non-replicating vector in NHPs) with an analogous replicating vector, SAd7. All vectors will be assessed for immunogenicity in small animals (mice /rabbits) before proceeding to NHP studies in Y2. Once immunogenicity is confirmed in NHPs, we will evaluate their efficacy in an NHP R5 SHIV clade C challenge study. Both antibody (neutralizing and ADCVI) and T cell immune responses (IFN- ) will be determined. Completion of this SBIR program will provide sufficient data to determine the utility of this Ad4 vector system for inducing effective antibody and T cell responses and potentially could yield an experimental vaccine suitable for clinical development.