Gurunathan S, Habib R El, Baglyos L, Meric C, Plotkin S, Dodet B, Corey L, Tartaglia J
Sanofi Pasteur, R&D, Swiftwater, PA 18370-0187, USA.
Vaccine. 2009 Mar 23;27(14):1997-2015. doi: 10.1016/j.vaccine.2009.01.039. Epub 2009 Feb 4.
Generating broadly neutralizing antibodies with candidate vaccines has remained an elusive goal. Consequently, vaccine candidates developed have aimed at eliciting cell-mediated immune effector activities (CMI) that could delay disease progression, and maybe also limit secondary transmission, by controlling virus replication. There is considerable discussion about what types of endpoints would constitute definable standardized clinical benefit to the individual that would result in licensure of these candidate vaccines. Identifying biomarkers that can be used as surrogates for clinical endpoints in randomized clinical trials would be useful, because it would shorten studies and reduce costs. Biological markers associated with disease progression and secondary transmission and that may be used as prognosis markers and surrogate endpoints in HIV vaccine trials have emerged from analyses of data from studies on natural history of HIV infection. Extensive literature is cited to support the use of plasma viral load as a primary endpoint for supporting licensure decisions. Overall, a significant result on viral load in a vaccine trial should be considered as a significant breakthrough for vaccines and be aggressively pursued with the caveat that such a result should rapidly be followed by well-defined studies to verify durable virological and immunological vaccine benefit, as well as ultimate clinical benefit. The review also provides perspectives on magnitude of viral load reduction, durability of viral load reduction for reduced progression of HIV disease.
利用候选疫苗产生广泛中和抗体一直是一个难以实现的目标。因此，已开发的候选疫苗旨在引发细胞介导的免疫效应活动（CMI），通过控制病毒复制来延缓疾病进展，或许还能限制二次传播。关于何种类型的终点能够构成对个体可明确界定的标准化临床益处从而使这些候选疫苗获得许可，存在大量讨论。识别可在随机临床试验中用作临床终点替代指标的生物标志物将很有用，因为这将缩短研究时间并降低成本。通过对HIV感染自然史研究数据的分析，已出现了与疾病进展和二次传播相关且可在HIV疫苗试验中用作预后标志物和替代终点的生物标志物。大量文献被引用来支持将血浆病毒载量用作支持许可决定的主要终点。总体而言，疫苗试验中病毒载量方面的显著结果应被视为疫苗的重大突破并积极追求，但需注意的是，这一结果应迅速跟进明确的研究，以验证持久的病毒学和免疫学疫苗益处以及最终的临床益处。该综述还提供了关于病毒载量降低幅度、病毒载量降低的持久性以减缓HIV疾病进展的观点。
