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

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疫苗载体在人类中具有复制能力，它应该会推动免疫反应的诱导和扩展，这些免疫反应在数量和效应功能方面都比非复制载体诱导的免疫反应质量更高。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，经过适当的修饰，以诱导对各种HIV毒株的抗体反应；以及2)GB病毒C型E2蛋白，它可能诱导协同抗体反应，从而显著扩大HIV-1的中和作用。在Y1-Y2期间，将评估所有载体在小动物(兔子)中的免疫原性。将确定HIV-1环境特异性抗体，包括中和性和结合性。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。 与公共卫生的相关性：针对导致艾滋病的人类免疫缺陷病毒(HIV)开发安全和保护性疫苗一直非常困难。这项拟议的研究将修改一种现有的腺病毒疫苗，该疫苗曾在1000多万人中安全使用，使其能够表达HIV蛋白，并在动物身上诱导免疫反应。这种疫苗将具有口服的优势和活病毒疫苗的优势，如脊髓灰质炎或麻疹疫苗，但不会有任何导致艾滋病毒感染的风险。

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. PUBLIC HEALTH RELEVANCE: The development of a safe and protective vaccine against the Human Immunodeficiency Virus (HIV) that causes AIDS has been very difficult. The proposed research will modify an existing adenovirus vaccine, which was used safely in more than 10 million people, so that it expresses HIV proteins and induces an immunological response in animals. This vaccine will have the advantage of being taken by mouth and the advantages of a live virus vaccine, such as the polio or measles vaccines but will not have any risk of causing HIV infection.