Rodrigues Kristen A, Zhang Yiming J, Lam Jonathan, Aung Aereas, Morgan Duncan M, Romanov Anna, Maiorino Laura, Yousefpour Parisa, Gibson Grace, Ozorowski Gabriel, Gregory Justin R, Amlashi Parastoo, Van Richard, Buckley Maureen, Ward Andrew B, Schief William R, Love J Christopher, Irvine Darrell J
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Harvard-MIT Health Sciences and Technology Program, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Sci Transl Med. 2025 Jun 18;17(803):eadw7499. doi: 10.1126/scitranslmed.adw7499.
Vaccine adjuvants play important roles in shaping the humoral response to immunization. Here, we analyzed mechanisms of action of a clinically relevant combination adjuvant strategy, where phosphoserine (pSer)-tagged immunogens bound to aluminum hydroxide (alum) adjuvant, promoting prolonged antigen release to draining lymph nodes, are combined with a saponin nanoparticle adjuvant termed SMNP, which alters lymph flow and antigen entry into lymph nodes. When used with a stabilized HIV envelope trimer antigen in mice, this combined adjuvant approach promoted substantial enhancements in germinal center and antibody responses relative to either adjuvant alone. Using single-cell RNA and B cell receptor sequencing, we found that the alum-pSer/SMNP combination augmented the clonal expansion and diversity of the germinal center B cell repertoire, coincident with an increased proportion of S-phase germinal center B cells and expression of positive selection markers. Moreover, we found that the combination adjuvant approach, but not alum-pSer delivery or SMNP alone, promoted accumulation of intact antigen on follicular dendritic cells, reflecting integrated effects of slow antigen delivery and altered lymph node uptake. Genetic ablation of expression by follicular dendritic cells eliminated antigen accumulation and hampered the antigen-specific germinal center response, supporting antigen delivery to these cells as a key mechanism of the improved response elicited by this combination adjuvant. These results demonstrate how adjuvants with complementary mechanisms of action affecting vaccine biodistribution and kinetics can enhance humoral immunity.
疫苗佐剂在塑造免疫接种的体液反应中发挥着重要作用。在此，我们分析了一种临床相关联合佐剂策略的作用机制，即与氢氧化铝（明矾）佐剂结合的磷酸丝氨酸（pSer）标记免疫原，可促进抗原向引流淋巴结的持续释放，并与一种称为SMNP的皂苷纳米颗粒佐剂联合使用，后者可改变淋巴流动以及抗原进入淋巴结的过程。在小鼠中与稳定化的HIV包膜三聚体抗原联合使用时，这种联合佐剂方法相对于单独使用任何一种佐剂，均能显著增强生发中心反应和抗体反应。通过单细胞RNA和B细胞受体测序，我们发现明矾-pSer/SMNP组合增加了生发中心B细胞库的克隆扩增和多样性，同时S期生发中心B细胞的比例增加以及阳性选择标志物的表达增加。此外，我们发现联合佐剂方法，而非单独的明矾-pSer递送或SMNP，可促进完整抗原在滤泡树突状细胞上的积累，这反映了缓慢抗原递送和改变的淋巴结摄取的综合作用。滤泡树突状细胞表达的基因缺失消除了抗原积累并阻碍了抗原特异性生发中心反应，支持向这些细胞递送抗原是这种联合佐剂引发改善反应的关键机制。这些结果证明了具有影响疫苗生物分布和动力学的互补作用机制的佐剂如何增强体液免疫。
