Single-cell-resolved dynamic immune remodeling following Omicron infection and recovery in vaccinated individuals

Breakthrough SARS-CoV-2 Omicron infections occur despite vaccination, yet post-infection immune recovery remains incompletely understood. Here, we performed longitudinal single-cell transcriptomic and targeted proteomic profiling of peripheral blood mononuclear cells (PBMCs) from healthy individuals and vaccinated patients during infection, early recovery, and 3-month post-recovery. Omicron infection induced coordinated immune remodeling with contraction of T and B cell compartments; expansion of plasma, regulatory T, and dendritic cells; and suppression of inflammatory and metabolic pathways, including TNFα-NF-κB and mTORC1 signaling. Innate populations rebounded rapidly, whereas adaptive compartments recovered slowly with sustained suppression of IL-2, IL-12, and IL-15 modules. Chemokine surges (CXCL1, CXCL5, and CXCL8) resolved during convalescence, whereas selective cytokines (CCL5 and CCL8) and interleukins (IL-6, IL-18, and IL-24) persisted. Trajectory analysis revealed non-uniform remodeling of T cell states with persistent differentiation signatures across naive, effector, and memory compartments. Overall, vaccination tempered early immune collapse and accelerated innate rebound, highlighting interleukin-linked checkpoints and metabolic regulation underlying post-vaccination immune resilience.