Development of a Vaccine for HIVAIDS: Translation to the Clinic

编码马赛克Gag基因的可复制Ad4-HIV重组正在cGMP条件下生产，用于I期临床试验。这种临床级别的疫苗将在口服后进行安全性、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艾滋病毒疫苗进行比较免疫原性研究，以促进选择候选疫苗进入第二阶段，并最终进入第三阶段测试。我们还在开发Ad4-HIVenv重组体。这一候选疫苗的最终生产将允许测试具有复制能力的Ad-重组基团/包膜蛋白Boost方法，该方法已在临床前非人类灵长类动物研究中获得了如此强大的保护效果。在更多的临床前研究中，含有绿色荧光蛋白(GFP)的重组体已经产生，并被用于体外研究，以优化转染程序。此外，这些GFP重组体在体内的使用使重组腺病毒在恒河猴模型中的生物分布研究成为可能，这些重组体通过几种不同的粘膜途径给药。结果表明，无论给药途径如何，Ad在外周血、直肠组织和肺组织中的分布相似。直肠组织是HIV感染的主要靶点，人们认为理想的做法是在这个部位复制疫苗载体，以诱导局部粘膜免疫。新的重组子正在开发中，既用于未来的临床应用，也用于恒河猴模型的临床前研究。其中包括含有新的包膜插入的重组体，目的是产生广泛、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，该项目的重点是将复制能力强的Ad-重组疫苗方法转移到I期临床试验中。这是一种新的方法，在非人类灵长类动物研究中显示出比非复制型Ad-重组疫苗更好的免疫原性。

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.