Girard M P, Verrier B
Professeur honoraire à l'Université Paris 7-Denis Diderot, 39 rue Seignemartin, 69008 Lyon.
DR2 CNRS, Unité Inserm U503, IFR 128, CERVI, 21 av. Tony-Garnier, 69007 Lyon.
Virologie (Montrouge). 2006 Jun 1;10(3):193-206. doi: 10.1684/vir.2011.4836.
Some 50 phase I clinical trials of candidate vaccines against HIV/AIDS, 2 phase II trials and 2 phase III trials have been completed since the 1980s, altogether involving more than 16,000 volunteers. Although several neutralization epitopes have been identified on the surface of the virus glycoprotein spikes, the design of an envelope-based HIV vaccine capable of eliciting broadly reactive neutralizing antibodies remains as an elusive goal. A gp120- based vaccine, which was tested in two phase III trials, one in the USA and the other in Thailand, was found to be devoid of protective efficacy. The observation was made in the monkey model, using the simian immunodeficiency virus (SIV), that both virus loads and the clinical evolution of the disease were controlled by the CD8+ T-cell response (CTL) of the animals. This has prompted the development of vaccine candidates capable of inducing HIV-specific T-cell responses. A series of HIV vaccines based on live virus vectors already are in clinical studies, including a live recombinant canarypox virus vaccine (ALVAC), which is in phase III in Thailand, a non-replicative adenovirus type 5 (Ad5) vaccine, which has entered phase II clinical trials in the USA and The Caribbeans, and live recombinant vaccines based on the attenuated vaccinia virus MVA vector, which already have been through several phase I/II studies. These live recombinant vaccines have been evaluated either alone or as booster immunizations after priming with DNA vaccines. A whole array of other vaccines based on live vector vaccines, pseudoviral particles, peptides and other designs, have been tested in nonhuman primate models. So far, using the macaque/SIV model, none of the available vaccine candidates has been able to prevent infection following experimental challenge of the animals, but the vaccinated animals showed significant reduction of viral loads as compared to controls and were able to maintain their CD4+ T-cell count. T-cell stimulating vaccines thus illustrate a new paradigm in vaccinology, that of vaccines which are unable to prevent infection, but can prevent the occurrence of disease or at least slow down its evolution through continuous control of virus replication in the vaccinated host. The efficacy of these vaccines in humans now remains to be established.
自20世纪80年代以来，已经完成了约50项针对艾滋病毒/艾滋病候选疫苗的I期临床试验、2项II期试验和2项III期试验，总共涉及16000多名志愿者。尽管在病毒糖蛋白刺突表面已鉴定出几个中和表位，但设计一种能够引发广泛反应性中和抗体的基于包膜的艾滋病毒疫苗仍然是一个难以实现的目标。一种基于gp120的疫苗在美国和泰国进行了两项III期试验，结果发现该疫苗没有保护效力。在猴子模型中使用猴免疫缺陷病毒（SIV）进行观察发现，动物的病毒载量和疾病的临床进展均受其CD8 + T细胞应答（CTL）的控制。这促使了能够诱导艾滋病毒特异性T细胞应答的候选疫苗的研发。一系列基于活病毒载体的艾滋病毒疫苗已进入临床研究，包括在泰国进行III期试验的重组金丝雀痘病毒活疫苗（ALVAC）、在美国和加勒比地区进入II期临床试验的非复制型5型腺病毒（Ad5）疫苗，以及基于减毒痘苗病毒MVA载体的重组活疫苗，该疫苗已完成多项I/II期研究。这些重组活疫苗已单独进行评估，或在DNA疫苗初免后作为加强免疫进行评估。基于活载体疫苗、假病毒颗粒、肽和其他设计的一系列其他疫苗已在非人灵长类动物模型中进行了测试。到目前为止，在猕猴/SIV模型中，现有的候选疫苗均无法在动物经实验性攻击后预防感染，但与对照组相比，接种疫苗的动物病毒载量显著降低，并且能够维持其CD4 + T细胞计数。因此，T细胞刺激疫苗阐明了疫苗学中的一种新范式，即这类疫苗无法预防感染，但可以通过持续控制接种宿主中的病毒复制来预防疾病的发生或至少减缓其进展。这些疫苗在人体中的疗效目前仍有待确定。
