Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston, MA 02139, USA.
Sci Transl Med. 2014 Mar 19;6(228):228ra38. doi: 10.1126/scitranslmed.3007736.
The human phase 2B RV144 ALVAC-HIV vCP1521/AIDSVAX B/E vaccine trial, held in Thailand, resulted in an estimated 31.2% efficacy against HIV infection. By contrast, vaccination with VAX003 (consisting of only AIDSVAX B/E) was not protective. Because protection within RV144 was observed in the absence of neutralizing antibody activity or cytotoxic T cell responses, we speculated that the specificity or qualitative differences in Fc-effector profiles of nonneutralizing antibodies may have accounted for the efficacy differences observed between the two trials. We show that the RV144 regimen elicited nonneutralizing antibodies with highly coordinated Fc-mediated effector responses through the selective induction of highly functional immunoglobulin G3 (IgG3). By contrast, VAX003 elicited monofunctional antibody responses influenced by IgG4 selection, which was promoted by repeated AIDSVAX B/E protein boosts. Moreover, only RV144 induced IgG1 and IgG3 antibodies targeting the crown of the HIV envelope V2 loop, albeit with limited coverage of breakthrough viral sequences. These data suggest that subclass selection differences associated with coordinated humoral functional responses targeting strain-specific protective V2 loop epitopes may underlie differences in vaccine efficacy observed between these two vaccine trials.
人类 2B 期 RV144 ALVAC-HIV vCP1521/AIDSVAX B/E 疫苗试验在泰国进行，结果表明该疫苗对 HIV 感染的有效率约为 31.2%。相比之下，接种 VAX003（仅由 AIDSVAX B/E 组成）并没有起到保护作用。由于在 RV144 中观察到的保护作用与中和抗体活性或细胞毒性 T 细胞反应无关，我们推测非中和抗体的 Fc 效应子谱的特异性或定性差异可能导致了这两项试验之间观察到的疗效差异。我们表明，RV144 方案通过选择性诱导高功能免疫球蛋白 G3（IgG3），引发了具有高度协调的 Fc 介导效应子反应的非中和抗体。相比之下，VAX003 引发了单功能抗体反应，受 IgG4 选择的影响，而 AIDSVAX B/E 蛋白加强针的重复接种促进了 IgG4 的选择。此外，只有 RV144 诱导了针对 HIV 包膜 V2 环冠的 IgG1 和 IgG3 抗体，尽管对突破性病毒序列的覆盖有限。这些数据表明，与针对特定保护性 V2 环表位的协调体液功能反应相关的亚类选择差异可能是这两项疫苗试验之间观察到的疫苗疗效差异的基础。
