Durable Interferon‐Linked Blood Signatures During COVID‐19 Convalescence

Thrombotic risk in COVID‐19 extends beyond acute illness, including in nonhospitalized individuals, suggesting that thrombo‐inflammatory biology may persist during recovery. Longitudinal sampling with pre‐infection baselines is needed to distinguish infection‐associated signals from inter‐individual variability and time‐related drift in blood gene expression. To define coordinated, time‐resolved whole‐blood transcriptomic programs during SARS‐CoV‐2 convalescence using longitudinal within‐person comparisons before and after infection, alongside COVID‐19–naïve controls. Adults were sampled longitudinally with specimens collected before SARS‐CoV‐2 infection (T0) and at ~3 months (T1) and ~6 months (T2) post‐infection; COVID‐19–naïve controls were sampled across matched timepoints. COVID‐19–naïve status was confirmed using a multiplex anti‐nucleocapsid IgG assay spanning multiple variant antigens. Whole‐blood RNA‐seq (PAXgene) was analyzed with DESeq. 2 using models that incorporated time point and participant. To prioritize infection‐linked changes, genes differentially expressed over time in controls were identified and excluded from comparisons between COVID‐19 time points. Pathways were assessed by pre‐ranked GSEA (MSigDB) and clustered with aPEAR. After excluding control‐associated genes, COVID‐19 convalescence remained associated with marked transcriptional remodeling (T1 vs. T0: 782 genes; T2 vs. T0: 655 genes; p < 0.05) and persistent pathway‐level changes. Interferon‐α and interferon‐γ signatures were enriched at both T1 and T2, and a core set of interferon‐associated genes remained elevated across convalescence. SARS‐CoV‐2 infection is followed by durable whole‐blood immune‐defense programs, including persistent interferon signaling, detectable up to 6 months post‐infection. These sustained signatures support a model of prolonged post‐infectious immune activation that may contribute to extended thromboinflammatory risk.