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，但开发预防或降低艾滋病毒感染率的疫苗仍然是一个高度优先事项。从失败和成功的实验方案中吸取的教训表明，需要在艾滋病毒疫苗设计中应用新的方法，目的是诱导在体内适当部位具有适当类型、质量、强度和活性的免疫反应。一种有希望的方法是使用腺病毒血清型4 （Ad4）作为疫苗递送载体。Ad4病毒是美国军用腺病毒疫苗中的一种成分，该疫苗是为口服剂型而配制的。口服给药对于HIV疫苗是有利的，因为这种给药途径比肠外注射更有可能诱导粘膜免疫反应，特别是针对肠道粘膜组织。Ad4疫苗载体在人体内具有复制能力，这应该会促使免疫反应的诱导和扩大，这种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中，多个Ad4载体将被改造以表达独特的抗原，包括：1)HIV-1 Env clade C蛋白，目的是诱导广泛有效地对抗各种HIV毒株的抗体反应；2) GBV-C E2糖蛋白，可诱导阻断HIV-1细胞附着的抗体；3) Gag蛋白，可诱导T细胞反应，促进HIV-1病毒感染细胞的杀伤。由于人类腺病毒（如Ad4）不能在包括NHPs在内的非人类动物中复制，我们还将构建类似的复制猿猴腺病毒（SAd7）载体，以便直接比较Ad4 （NHPs中的非复制载体）与类似的复制载体SAd7的效果。所有载体将在小动物（小鼠/兔子）中进行免疫原性评估，然后在二年级进行NHP研究。一旦确认了NHP的免疫原性，我们将在NHP R5 SHIV clade C攻击研究中评估其有效性。抗体（中和和ADCVI）和T细胞免疫反应（IFN-）将被确定。SBIR项目的完成将提供足够的数据来确定Ad4载体系统在诱导有效抗体和T细胞反应方面的效用，并可能产生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.