Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4⁺ T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.

开发有效的人类免疫缺陷病毒 1 (HIV-1) 疫苗需要先天免疫细胞和适应性免疫细胞之间的协同作用。在这里，我们表明，重组金丝雀痘载体 ALVAC + Alum 对转录因子 CREB1 及其靶基因的诱导增强了非人灵长类动物 (NHP) 的免疫原性，并预测 RV144 试验中 HIV-1 获得性减少。这些靶基因包括那些编码与 NHP 中针对猿猴免疫缺陷病毒攻击的增强保护相关的细胞因子/趋化因子的基因。 CREB1 靶基因的表达可能是由 cGAMP（STING 激动剂）直接调节的 p-CREB1 活性引起的，该活性驱动 CD4 ⁺ T 细胞和 B 细胞募集到抗原呈递位点。重要的是，与用 ALVAC + Alum 免疫的 NHP 不同，用 ALVAC + MF59 免疫的 NHP（HVTN702 试验中的方案没有显示出对 HIV 感染的保护作用）表现出 CREB1 靶基因表达显着降低。我们的综合系统生物学方法已验证 CREB1 是疫苗功效的关键驱动因素，并强调触发 CREB1 信号传导的佐剂可能对有效的 HIV-1 疫苗至关重要。