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和/或鼻内给药后的I期试验中评估安全性、免疫原性和剂量水平。该产品将能够与其他载体HIV疫苗进行免疫原性比较研究，以促进候选疫苗的选择，进而进入II期和最终的III期测试。一种Ad4-HIVenv重组病毒也正在生产中。该候选疫苗的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，该方法在我们的临床前非人灵长类动物研究中引起了强有力的保护效果。含有绿色荧光蛋白的Ad重组体已通过几种不同的粘膜途径给药，用于恒河猴模型中Ad重组体的临床前生物分布研究。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。此前，一种非复制性Ad5- hiv疫苗的III期临床试验显示，在人群中缺乏保护功效，同时表明，在预先对Ad5免疫的个体中，感染可能会增强。这就是所谓的？一步?试验在SIV恒河猴系统中建模，结果显示无效。然而，阴茎攻击后SIV感染的增强尚未得到证实。需要进一步的研究来评价这个问题。总的来说，我们的项目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 in a phase I trial following oral and/or intranasal administration for safety, immunogenicity, and dose level. This product will enable comparative immunogenicity studies with other vectored HIV vaccines to facilitate selection of candidate vaccines to move forward to phase II and eventually phase III testing. An Ad4-HIVenv recombinant is also being produced. Production of this candidate vaccine will allow testing of the replication-competent Ad-recombinant prime/envelope protein boost approach which has elicited potent protective efficacy in our pre-clinical non-human primate studies. Ad recombinants containing the green fluorescent protein have been used in pre-clinical 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. Previously, a phase III clinical trial of a non-replicating Ad5-HIV vaccine showed lack of protective efficacy in people together with a suggestion that infection might have been enhanced in individuals with pre-existing immunity to Ad5. This so-called ?STEP? trial was modeled in the SIV rhesus macaque system and results were recapitulated in showing no efficacy. However, enhancement of SIV infection following a penile challenge was not confirmed. Further studies will be needed to evaluate this issue. Overall, our 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.