Persistent IP-10/CXCL10 dysregulation following mild Omicron breakthrough infection: Immune network signatures across COVID-19 waves and implications for mRNA vaccine outcomes

Abstract

This study explores immune responses in mild Omicron-era COVID-19 breakthrough cases, focusing on cytokine dysregulation, antibody dynamics, and Long COVID. We analyzed samples from 114 mild symptomatic COVID-19 patients across multiple pandemic waves, each dominated by different SARS-CoV-2 variants, at three timepoints: (T1: 2–4 weeks, T2: 3–4 months, T3: 6–8 months post-infection). Persistent IP-10 elevation up to 8 months post–Omicron breakthrough infection suggests sustained low-grade immune activation that appears unique to this wave. Hybrid immunity from Omicron breakthrough infections elicited broad cross-variant antibody recognition but showed declining neutralization over time. Among vaccination regimens, mRNA-inclusive combinations were associated with lower Long COVID scores. CoV-229E antibody levels correlated with Long COVID scores. These findings underscore the need for extended monitoring of even mild COVID-19 cases and highlight the potential of mRNA vaccines in reducing post-COVID-19 complications. Insights into post-infection immune alterations and vaccine effects can inform the development of future vaccination strategies and approaches for managing post-COVID-19 conditions.