Systems immunology reveals the molecular mechanisms of heterogeneous influenza vaccine response in the elderly

Vaccination-induced protection against influenza is greatly diminished and increasingly heterogeneous with age. We investigated longitudinally (up to five timepoints) a cohort of 234 elderly influenza vaccinees across two independent seasons including up to six modalities (multi-omics and immunological parameters). System-level analyses revealed responders exhibited time-dependent changes attributed to a productive vaccine response across all omics layers whereas non-responders did not follow such dynamics, suggestive of systemic dysregulation. Through multi-omics integration, we identified key metabolites and proteins and their likely role in immune response to vaccination. High pre-vaccination IL-15 concentrations negatively associated with antibody production, further supported by experimental validation in mice revealing an IL-15-driven NK-cell axis with a suppressing role on antibody production. Finally, we propose certain long-chain fatty acids as modulators of persistent inflammation in non-responders. Our findings highlight the potential for stratification of vaccinees and open avenues for possible pharmacological interventions to enhance vaccine responses. HIGHLIGHTSO_LIPre-vaccination pro-inflammatory status impedes vaccine responsiveness in the elderly. C_LIO_LIMulti-omics integration reveals key molecules involved in vaccine response. C_LIO_LIHigh pre-vaccination concentrations of IL-15 suppresses vaccine response through NK cell activation. C_LIO_LICertain long-chain fatty acids may act as modulators against chronic inflammation and are potential targets to improve vaccine response. C_LI