Multi-omic Signatures of Vaccine Responses in Healthy Early Adolescents 2308797

Abstract Introduction Early adolescence represents a distinct phase of immune maturation between childhood and adulthood, yet this age window has rarely been profiled in depth at a systems level. This study examines how vaccine-induced immune responses are shaped during this critical developmental window. Methods We followed 11—13-year-olds for up to two years with repeated PBMC collection, including visits before and after combination (Tdap/MCV4/HPV/influenza), stand-alone influenza, and COVID-19 (prime/booster) vaccination. We generated scRNA-seq, Olink plasma proteomics, flow cytometry, influenza-specific IgG, and HAI titers. These readouts were analyzed across adolescent vaccine exposures, and influenza responses were compared to young and older adult influenza vaccine cohorts. Results Adolescents mounted distinct humoral and transcriptional responses to influenza vaccination versus adults. At the humoral level, adolescents displayed an age-associated pattern of strain-specific influenza IgG and HAI titers, with less cross-reactive memory IgG than adults. At the transcriptional level, adolescents showed strong activation of naïve T cells, NK cells, and monocytes, whereas adults had greater vaccine-responsive changes in the B cell compartment. Across four adolescent visits, we observed naïve T cell activation with minor variation in magnitude and distribution of responding cell types. We searched for non-naïve, clonally expanded cells within phenotypically naïve T cells and found no TCR clonotype expansion across vaccination visits, suggesting that activation signaling in this population is not primarily driven by TCR-specific responses. Conclusion Early adolescent immune responses demonstrate non-specific transcriptional activation across lineages and across vaccine visits - highlighting early adolescence as a unique period of immunity with distinct vaccine-mediated responses compared to adults. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)