Replicating Ad4-HIV vaccine development based on improved HIV Env and GBV-C E2

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疫苗载体在人体中是可复制的，其应驱动免疫应答的诱导和扩增，所述免疫应答在量级和效应器功能方面比由非复制载体诱导的免疫应答质量更高。在Y1中，将对多种Ad 4载体进行工程改造以表达独特的抗原，包括：1）具有适当修饰的HIV-1 Env进化枝C蛋白，目的是诱导广泛有效的针对各种HIV毒株的抗体应答;和2）GB病毒C型E2蛋白，其可诱导协同抗体应答，这将显著扩大HIV-1中和。在Y1-Y2中，将评估所有载体在小动物（兔）中的免疫原性。将测定HIV-1 Env特异性抗体（中和和结合）。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 higher in quality, 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 with the appropriate modifications for the purpose of inducing antibody responses broadly effective against a variety of HIV strains; and 2) GB virus type C E2 protein, which may induce synergistic antibody responses which would significantly broaden HIV-1 neutralization. In Y1-Y2, all vectors will be assessed for immunogenicity in small animals (rabbits). HIV-1 Env-specific antibody, both neutralizing and binding, 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.