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

描述（由申请人提供）：尽管最近在该领域遇到挫折，但开发疫苗以预防或降低艾滋病毒感染率仍然是一个高度优先事项。从失败和成功的实验项目中吸取的教训表明，需要将新的方法应用于艾滋病毒疫苗设计，目的是诱导在体内适当部位具有适当类型、质量、强度和活性的免疫应答。一种有前途的方法是使用腺病毒血清型4（Ad 4）作为疫苗递送载体。Ad 4病毒是美国军用腺病毒疫苗中的一种组分，其被配制用于以口服剂型施用。口服给药对于HIV疫苗应该是有利的，因为这种给药途径比肠胃外注射更可能诱导粘膜免疫应答，并且将特别靶向肠粘膜组织。Ad 4疫苗载体在人中是可复制的，其应驱动免疫应答的诱导和扩增，所述免疫应答在幅度和效应子功能方面不同于由非复制载体诱导的免疫应答。在Y1中，多个Ad 4载体将被工程化以表达独特的抗原，包括：1）HIV-1 Env进化枝C蛋白，目的是诱导广泛有效的针对多种HIV毒株的抗体应答; 2）GBV-C E2糖蛋白，其可以诱导阻断HIV-1细胞附着的抗体;和3）Gag蛋白，其可以诱导T细胞应答，所述T细胞应答促进杀死HIV-1病毒感染的细胞。由于人腺病毒如Ad 4不在非人动物（包括NHP）中复制，我们还将构建类似的复制型猿猴腺病毒（SAd 7）载体以允许直接比较Ad 4（NHP中的非复制型载体）与类似的复制型载体SAd 7的功效。在Y2进行NHP研究之前，将在小动物（小鼠/兔）中评估所有载体的免疫原性。一旦在NHP中确认免疫原性，我们将在NHP R5 SHIV C进化枝攻毒研究中评价其疗效。将测定抗体（中和和ADCVI）和T细胞免疫应答（IFN-）。该SBIR计划的完成将提供足够的数据来确定该Ad 4载体系统用于诱导有效抗体和T细胞应答的效用，并且可能产生适合于临床开发的实验疫苗。

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.