Development of a Vaccine for HIVAIDS: Translation to the Clinic

一种具有复制能力的Ad4-HIVenv重组病毒已经产生，并在生产前在适当的条件下进行鉴定，用于I期临床试验。另外一种ad4 - hiv - gag重组物也在开发中。对于临床级生产，候选疫苗病毒将在人二倍体细胞中生产。对在这些细胞上生产病毒的最佳方法的探索正在进行中。含有绿色荧光蛋白（GFP）的Ad重组体已经产生，并正在体外研究中用于优化转染程序。此外，在体内使用这些GFP重组体，可以通过几种不同的粘膜途径给药，在恒河猴模型中进行ad重组体的生物分布研究，以确定哪一种途径会导致胃肠道和生殖器/直肠部位的ad复制。这些部位是HIV感染的主要靶点，人们认为疫苗病毒在这些部位复制以引起局部粘膜免疫是可取的。在体内也将探讨ad -重组病毒的持久性。新的ad -重组正在开发中，用于未来的临床应用和恒河猴模型的临床前研究。这些包括含有新型包膜插入的重组，旨在产生广泛、有效的中和抗体。这项工作包括在适当的动物模型中评估新构建的重组疫苗的免疫原性。总体而言，该项目的重点是将具有复制能力的ad -重组疫苗方法推向I期临床试验。这是一种新颖的方法，与非复制性ad -重组疫苗相比，在非人灵长类动物研究中显示出优越的免疫原性。

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.