Ad4 vectored HIV-Env vaccines with improved immunogenicity

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）作为疫苗递送载体。Ad4病毒是美国军用腺病毒疫苗的一个组成部分，该疫苗是为口服剂型配制的。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疫苗载体具有复制能力，应能诱导和扩大在大小和效应功能方面不同于非复制载体诱导的反应。在本提案中，我们概述了一项为期一年的计划，以构建和测试实验性Ad4载体活疫苗。多达六种Ad4载体疫苗将被设计用于编码HIV env蛋白，以诱导针对多种HIV毒株广泛有效的抗体反应。然后将在兔子身上测试载体疫苗，以评估对一系列HIV分离株有效的中和抗体反应，以及抗体依赖细胞介导的HIV病毒抑制。粘膜疫苗递送也将通过口服给药进行评估。按照设计，这个SBIR项目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，并有可能产生一种适合在非人灵长类动物中进一步测试和潜在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) 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.