GSK, Rixensart, 1330, Belgium.
Institute for Medical Immunology and ULB Center for Research in Immunology (U-CRI), Faculty of Medicine, Université libre de Bruxelles (ULB), Brussels, 1070, Belgium.
Sci Transl Med. 2024 Jul 31;16(758):eadl3381. doi: 10.1126/scitranslmed.adl3381.
The adjuvant AS01 plays a key role in the immunogenicity of several approved human vaccines with demonstrated high efficacy. Its adjuvant effect relies on activation of the innate immune system. However, specific effects of AS01-adjuvanted vaccines on innate cell function and epigenetic remodeling, as described for Bacille Calmette-Guérin (BCG) and influenza vaccines, are still unknown. We assessed the long-term functional and epigenetic changes in circulating monocytes and dendritic cells induced by a model vaccine containing hepatitis B surface antigen and AS01 in healthy adults (NCT01777295). The AS01-adjuvanted vaccine, but not an Alum-adjuvanted vaccine, increased the number of circulating monocytes and their expression of human leukocyte antigen (HLA)-DR, which correlated with the magnitude of the memory CD4 T cell response. Single-cell analyses revealed epigenetic alterations in monocyte and dendritic cell subsets, affecting accessibility of transcription factors involved in cell functions including activator protein-1 (), , , and interferon regulatory factor. The functional changes were characterized by a reduced proinflammatory response to Toll-like receptor activation and an improved response to interferon-γ, a cytokine critical for the adjuvant's mode of action. Epigenetic changes were most evident shortly after the second vaccine dose in CD14 monocytes, for which accessibility differences of some transcription factors could persist for up to 6 months postvaccination. Together, we show that reprogramming of monocyte subsets occurs after vaccination with an AS01-adjuvanted vaccine, an effect that may contribute to the impact of vaccination beyond antigen-specific protection.
佐剂 AS01 在几种已批准的具有高功效的人类疫苗的免疫原性中发挥着关键作用。其佐剂作用依赖于固有免疫系统的激活。然而，AS01 佐剂疫苗对固有细胞功能和表观遗传重塑的具体影响，如卡介苗和流感疫苗所描述的，尚不清楚。我们评估了含有乙型肝炎表面抗原和 AS01 的模型疫苗在健康成年人中诱导的循环单核细胞和树突状细胞的长期功能和表观遗传变化（NCT01777295）。AS01 佐剂疫苗，但不是 Alum 佐剂疫苗，增加了循环单核细胞的数量及其人类白细胞抗原 (HLA)-DR 的表达，这与记忆 CD4 T 细胞反应的幅度相关。单细胞分析显示单核细胞和树突状细胞亚群的表观遗传改变，影响参与细胞功能的转录因子的可及性，包括激活蛋白-1 (),,, 和干扰素调节因子。功能变化的特征是对 Toll 样受体激活的促炎反应降低，对干扰素-γ的反应增强，干扰素-γ是佐剂作用模式的关键细胞因子。在第二次疫苗接种后不久，CD14 单核细胞中最明显的是表观遗传变化，其中一些转录因子的可及性差异在接种疫苗后长达 6 个月内持续存在。总之，我们表明，接种 AS01 佐剂疫苗后会发生单核细胞亚群的重编程，这种效应可能有助于疫苗接种除抗原特异性保护之外的影响。
