Revealing immune signatures of lasting vaccine-induced immunity through systems immunology 2693

Description Vaccination saves millions of lives annually, yet infectious diseases remain a leading cause of death due to variability in vaccine-induced immune responses from genetic, environmental, and immunological factors. To address this challenge, we compared vaccines inducing durable immunity (e.g., Yellow Fever vaccine) with those needing annual administration due to transient immunity (e.g., seasonal influenza vaccine). We aimed to understand pre-vaccination immune profiles associated with establishing durable, protective immunity. Leveraging datasets from the Human Immunology Project Consortium (24 studies, six pathogens, 1,405 individuals), we analyzed immune signatures at cellular and molecular levels. Predictive modeling of early gene expression (7,262 genes) identified unique immunological pathways and pre-vaccination profiles differentiating durable from transient responses. Individuals with durable immunity exhibited higher baseline adaptive immune component activities: CD8 T cells, T helper cells, and B cells. The IL-2, Wnt, and Notch signaling pathways were more active at baseline, suggesting a predisposition to long-lasting immunity. These pathways promote immune cell survival, differentiation, and immune memory maintenance, sustaining protective immunity beyond initial antigen exposure. Our findings reveal novel molecular drivers of durable immunity, paving the way for targeted vaccine designs that optimize long-term protection across diverse populations and pathogens.