Development of a Vaccine for HIVAIDS: Translation to the Clinic

编码嵌合gag基因的复制型Ad 4-HIV重组体正在cGMP条件下生产，用于I期临床试验。将在口服和/或鼻内给药后的I期试验中评价该临床级疫苗的安全性、免疫原性和剂量水平。该产品将能够与其他载体HIV疫苗进行比较免疫原性研究，以促进候选疫苗的选择，从而进入II期和最终的III期测试。Ad 4-HIVenv重组体也正在生产中。该候选疫苗的生产将允许测试复制能力的Ad-重组初免/包膜蛋白加强方法，该方法在我们的临床前非人灵长类动物研究中引起了有效的保护功效。含有绿色荧光蛋白的Ad重组体已用于通过几种不同粘膜途径给药后恒河猴模型中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感染的主要靶点，并且认为疫苗载体在该位点复制以引发局部粘膜免疫是理想的。 新的Ad重组体正在开发中，用于未来的临床应用和恒河猴模型的临床前研究。这些包括含有旨在产生广泛的、有效的中和抗体的新型包膜插入物的重组体。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，一项非复制型Ad 5-HIV疫苗的III期临床试验显示，在人群中缺乏保护效力，并暗示在对Ad 5具有预先存在的免疫力的个体中，感染可能会增强。这所谓的？STEP？在SIV恒河猴系统中模拟试验，结果概括为没有功效。然而，阴茎刺激后SIV感染的增强并未得到证实。需要进一步研究来评估这一问题。总的来说，我们的项目集中在移动复制能力的广告重组疫苗的方法进入I期临床试验。这是一种新的方法，与非复制型Ad重组疫苗相比，其在非人灵长类动物研究中显示出上级免疫原性。

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.