Development of a Vaccine for HIVAIDS: Translation to the Clinic

在cGMP条件下，一种具有复制能力的Ad4-HIV重组蛋白编码了一种镶嵌gag基因，将用于I期临床试验。这种临床级疫苗将在口服给药后进行安全性、初始免疫原性和剂量水平的评估。此外，该产品将能够与其他载体HIV疫苗进行比较免疫原性研究，以促进候选疫苗的选择，进而进入II期和最终的III期测试。我们也在开发一种Ad4-HIVenv重组病毒。该候选疫苗的最终生产将允许测试具有复制能力的ad -重组引物/包膜蛋白增强方法，该方法已在临床前非人灵长类动物研究中引起了如此强大的保护效果。在其他临床前研究中，已经产生了含有绿色荧光蛋白（GFP）的Ad重组体，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。结果表明，无论给药途径如何，Ad在外周血、直肠组织和肺中的分布是相似的。直肠组织是HIV感染的主要目标，人们认为疫苗载体在该部位复制以引起局部粘膜免疫是可取的。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-HIV recombinant encoding a mosaic gag gene is being produced under cGMP conditions for use in a phase I clinical trial. This clinical grade vaccine will be evaluated following oral administration for safety, initial immunogenicity, and dose level. Additionally, this product will enable comparative immunognicity studies with other vectored HIV vaccines to facilitate selection of candidate vaccines to move forward to phase II and eventually phase III testing. We are also developing an Ad4-HIVenv recombinant. Eventual production of this candidate vaccine will allow testing of the replication-competent Ad-recombinant prime/envelope protein boost approach which has elicited such potent protective efficacy in pre-clinical non-human primate studies. In additional pre-clinical studies, 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. Results have shown that Ad distribution in peripheral blood, rectal tissue and in the lung is similar regardless of the route of administration. Rectal tissue is a principal target of HIV infection, and it is believed desirable that a vaccine vector replicate at this site in order to elicit local mucosal immunity. 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.