Development of a Vaccine for HIVAIDS: Translation to the Clinic

已经产生了具有复制能力的Ad 4-HIVenv重组病毒，并且正在进行 在生产前在适当条件下进行表征，用于I期临床试验 审判另一种Ad 4-HIVgag重组体也正在开发中。临床级 候选疫苗病毒将在人二倍体细胞中产生。探索 在这些细胞上生产病毒的最佳方法正在进行中。Ad重组体， 已经产生了绿色荧光蛋白（GFP），并将其用于体外研究 用于优化转染程序。此外，这些GFP重组体在 体内已经允许在恒河猴模型中进行Ad-重组体的生物分布研究 在通过几种不同的粘膜途径给药后， 一种导致在胃肠道和生殖器/直肠部位的Ad复制。这些网站是 艾滋病毒感染的主要目标，并认为希望疫苗病毒 在这些位点复制以引起局部粘膜免疫。持续存在 还将在体内探索Ad-重组病毒。新的Ad重组体正在开发中 既用于将来的临床应用，也用于恒河猴模型的临床前研究。这些 包括含有新包膜插入物的重组体，所述插入物旨在产生广泛的、有效的 中和抗体这项工作包括评估免疫原性的新的 在适当的动物模型中构建重组疫苗。总的来说，这个项目是 专注于将可复制的Ad重组疫苗方法进入I期 临床试验这是一种新的方法，在免疫原性方面显示出上级免疫原性。 非人灵长类动物研究与非复制型Ad-重组疫苗的比较。

A replication-competent Ad4-HIVenv recombinant virus has been generated and is being characterized prior to production under appropriate conditions for use in a phase I clinical trial. An additional Ad4-HIVgag recombinant is also under development. For clinical grade production the candidate vaccine virus will be produced in human diploid cells. Exploration of the optimal method for virus production on these cells is on-going. Ad recombinants containing the green fluorescent protein (GFP) have been generated and are being used in studies in vitro for optimization of transfection procedures. In addition, use of these GFP recombinants in vivo has allowed biodistribution studies of the Ad-recombinant in the rhesus macaque model following administration by several different mucosal routes in order to determine which one(s) results in Ad-replication at gastrointestinal and genital/rectal sites. These sites are principal targets of HIV infection, and it is believed desirable that the vaccine virus replicate at these sites in order to elicit local mucosal immunity. Persistence of the Ad-recombinant virus will also be explored in vivo. New Ad-recombinants are under development both for future clinical use and for pre-clinical studies in the rhesus macaque model. These include recombinants containing novel envelope inserts intended to generate broad, potent neutralizing antibodies. This work includes assessment of immunogenicity of the newly constructed recombinant vaccines in appropriate animal models. Overall, this project is focused on moving the replication-competent Ad-recombinant vaccine approach into phase I clinical trials. This is a novel approach, which has shown superior immunogenicity in non-human primate studies in comparison to non-replicating Ad-recombinant vaccines.