Postdoctoral Associate The Jackson laboratory for Genomic Medicine Farmington, Connecticut, United States
Introduction/Rationale: Seasonal influenza remains a major burden in older adults, with up to one-third failing to mount protective responses. This non-responsiveness often persists across vaccine platforms and seasons, and the immune mechanisms underlying this variability, particularly within the innate compartment, remain poorly understood.
Methods: To address this, we recruited 60 older adults (≥65 years) and administered Fluzone High-Dose during the 2022-2023 season. We quantified antibody titers using Hemagglutination-inhibition assay at baseline, Day7, Day35, and Day180, and found heterogeneity in antibody responses. To identify cellular and molecular features associated with this variation, we applied a multivariate ranking approach and selected the top 10 responders and 10 non-responders for single-cell (scRNASeq and DOGMA-seq) profiling of peripheral blood mononuclear cells (PBMCs) at baseline, Day1, and Day7.
Results: Fluzone responders exhibited a significant reduction in circulating cDC2 and monoDC frequencies at Day 1, consistent with migration to secondary lymphoid tissues. Transcriptionally, these subsets showed robust induction of interferon-stimulated genes (ISGs) and upregulation of CD40, a co-stimulatory molecule which correlated with antibody response. Epigenetically, responder cDC2s demonstrated increased chromatin accessibility at interferon-regulated loci (GBP5, IRF1) and enhanced IRF/JUN motif activity, supporting transcriptional reprogramming of antiviral pathways at Day1. These early transcriptional (ISGs, CD40) changes significantly correlated with IgG1⁺ plasmablast expansion at Day 7 in responders, linking innate activation of cDC2 and monoDCs to humoral outcomes.
Conclusion: These findings identify Day1 immune remodeling of cDC2 and monoDCs as a factor for effective influenza vaccine responses among older adults, offering mechanistic insights for precision influenza vaccine strategies.
