Chimeric adenoviruses for an improved HIV vaccine

描述（由申请人提供）：我们的提案将解决使用下一代基于腺病毒（Ad）的载体开发安全有效的艾滋病毒疫苗的需求。已经采用多种病毒载体来实现基于基因的疫苗接种。一种特别有前途的方法是基于通过无复制能力的腺病毒载体（Ad）的遗传转导。这种效用已经预测了基于Ad的载体在广泛的疫苗方法中的应用，包括最近的研究证明了对疟疾、埃博拉、SARS、假单胞菌和HIV的效用。 然而，STEP HIV疫苗临床试验的最新结果未能重现在动物模型系统中看到的有希望的结果。在这方面，该试验使用了基于Ad 5的疫苗，未能保护Ad 5血清阴性个体免受感染，甚至可能在先前对腺病毒具有免疫力的疫苗接种者中增强感染。总的来说，普遍同意的是，需要努力降低载体相对于预先存在的Ad 5免疫的免疫原性，以产生更安全和有效的基于Ad的载体作为HIV疫苗。因此，我们的建议将通过如下工程化多个遗传改变来解决这些关键点：（1）为了逃避对Ad 5载体的体液应答，将主要衣壳蛋白六邻体交换为Ad 3的六邻体，Ad 3是一种不太流行的血清型。人类免疫应答主要集中在Ad衣壳六邻体的高变区（HVR）中存在的表位;因此，嵌合的Ad 5 H3衣壳将逃避免疫前Ab对Ad 5六邻体的识别（2）为了诱导HIV特异性免疫应答，我们将采用抗原的HIV衣壳掺入。 我们假设这些Ad载体可以绕过Ad 5免疫并提供HIV特异性免疫。基于腺病毒的疫苗接种方法的全部优点目前受到宿主对载体的相关免疫力的限制。实现该提案的目标将扩大我们目前对宿主-载体相互作用的理解，这对于推进Ad载体平台作为开发有效HIV疫苗的可行方法至关重要。. 公共卫生相关性：在这项提案中，我们寻求解决安全和有效的艾滋病毒疫苗使用下一代腺病毒为基础的载体的需求。这些研究将在体外环境以及完善的啮齿动物模型系统中进行。这些发现有可能转化为人类/临床环境。

DESCRIPTION (provided by applicant): Our proposal will address the need for a safe and effective HIV vaccine using next generation adenovirus (Ad) - based vectors. A variety of viral vectors have been employed to accomplish gene-based vaccination. One particularly promising approach is based upon genetic transduction via replication-incompetent adenoviral vectors (Ad). This utility has predicated the application of Ad-based vectors for a wide range of vaccine approaches, including recent studies demonstrating utility for Malaria, Ebola, SARS, Pseudomonas, and HIV. However, the recent findings of the STEP HIV vaccine clinical trial failed to reproduce promising findings seen in animal model systems. In this regard, this trial, which used a Ad5-based vaccine, failed to protect Ad5-seronegative individuals against infection and may even have enhanced infection in vaccinees with prior immunity to adenoviruses. In the aggregate, the general agreement is that efforts to reduce vector immunogenicity with respect to pre-existing Ad5 immunity will be required to generate a safer and effective Ad- based vector as an HIV vaccine. Therefore, our proposal will address these key points by engineering multiple genetic alterations as follows: (1) To evade humoral responses to the Ad5 vector, the major capsid protein hexon will be exchanged for the hexon of Ad3, a less prevalent serotype. Human immune responses largely focus on epitopes present in the hypervariable regions (HVR) of the Ad capsid hexon; therefore, a chimeric Ad5H3 capsid will evade recognition by preimmune Abs to Ad5 hexon (2) To induce HIV specific immune responses we will employ HIV capsid incorporation of antigen. We hypothesize that these Ad vectors can circumvent Ad5 immunity and provide HIV-specific immunity. The full merit of the promising adenovirus-based approach for vaccination is currently limited by host related immunity toward the vector. Accomplishing the goals of this proposal will expand our current understanding of host-vector interactions that will be critical for advancing the Ad vector platform as a viable approach for developing effective HIV vaccines. . PUBLIC HEALTH RELEVANCE: In this proposal, we seek to address the need for a safe and effective HIV vaccine using next generation adenovirus-based vectors. These studies will be carried out in an in vitro context as well as a well-established rodent model system. These findings have the potential for translation into a human/clinical setting.