Chimeric adenoviruses for an improved HIV vaccine

描述(由申请者提供)：我们的建议将解决使用基于下一代腺病毒(Ad)的载体的安全和有效的HIV疫苗的需求。各种病毒载体已被用于实现基于基因的疫苗接种。一种特别有希望的方法是基于复制能力不强的腺病毒载体(Ad)的基因转导。这一效用预测了基于Ad的载体在广泛的疫苗方法中的应用，包括最近展示了对疟疾、埃博拉、SARS、假单胞菌和艾滋病毒的效用的研究。 然而，STEP HIV疫苗临床试验的最新发现未能重现在动物模型系统中看到的有希望的发现。在这方面，这项使用了基于Ad5的疫苗的试验，未能保护Ad5血清阴性的人免受感染，甚至可能增加了先前对腺病毒免疫的接种者的感染。总的来说，普遍的共识是，需要努力降低相对于先前存在的Ad5免疫的载体的免疫原性，以产生更安全和有效的基于Ad的载体作为HIV疫苗。因此，我们的建议将通过设计多个基因改变来解决这些关键点，如下所示：(1)为了避免对Ad5载体的体液反应，主要衣壳蛋白六邻体将被交换为AD3的六外显子，AD3是一种不太流行的血清型。人类的免疫反应主要集中在AdCapsid Hexon高变区(HVR)的表位上，因此，嵌合的Ad5H3衣壳将逃避Ad5 Hexon前免疫抗体的识别(2)为了诱导HIV特异性免疫反应，我们将使用HIV衣壳掺入抗原。 我们推测这些Ad载体可以规避Ad5免疫，并提供HIV特异性免疫。以腺病毒为基础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的限制。实现这一建议的目标将扩大我们目前对宿主-载体相互作用的理解，这对于推动Ad载体平台成为开发有效艾滋病毒疫苗的可行方法至关重要。。

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. .