Ad4 vectored HIV-Env vaccines with improved immunogenicity

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)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，该疫苗是以口服形式配制的。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疫苗载体是具有复制能力的载体，它应该驱动在大小和效应功能方面与非复制载体所诱导的不同的反应的诱导和扩展。在这项提案中，我们概述了构建和测试实验性Ad4载体活疫苗的一年计划。将对多达6种Ad4载体疫苗进行改造，以编码HIV env蛋白，以诱导对各种HIV毒株广泛有效的抗体反应。然后，这些载体疫苗将在兔子身上进行测试，以评估对一系列艾滋病毒分离株有效的中和抗体反应，以及抗体依赖的细胞介导的病毒对艾滋病毒的抑制。黏膜疫苗的投放也将通过口服进行评估。按照设计，SBIR计划的初始阶段将提供足够的数据来确定Ad4载体系统在诱导有效抗体反应方面的效用，并有可能生产出适合于在非人类灵长类动物身上进一步测试和潜在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。这种疫苗将具有作为活病毒疫苗的优势，例如脊髓灰质炎或麻疹疫苗，可以口服，而不会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) as a vaccine delivery vehicle. The Ad4 virus was 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 which should drive the induction and expansion of responses that are different, in terms of magnitude and effector functions, than those induced by non-replicating vectors. In this proposal we outline a one year plan to construct and test experimental live Ad4 vectored vaccines. Up to six Ad4 vectored vaccines will be engineered to encode HIV env proteins for the purpose of inducing antibody responses broadly effective against a variety of HIV strains. The vectored vaccines will then be tested in rabbits to assess neutralizing antibody responses that are effective against a range of HIV isolates, and antibody-dependent cell-mediated virus inhibition of HIV. Mucosal vaccine delivery will also be assessed using oral administration. As designed the initial phase of this SBIR program will provide sufficient data to determine the utility of this Ad4 vector system for inducing effective antibody responses and potentially could yield an experimental vaccine suitable for further testing in nonhuman primates and potentially 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 advantages of being live virus vaccine, such as the polio or measles vaccines, which can be taken by mouth without risk of causing HIV infection.