Systems Immunology of Long Covid: Insights from the STOP-PASC Clinical Trial

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Abstract
Background: Post Acute Sequelae of COVID-19 (PASC), also referred to as Long COVID, is an infection-associated chronic syndrome with heterogenous symptom profiles that occurs in a subset of people following SARS-CoV-2 infection. Despite proposed viral persistence mechanisms, no therapeutic benefit was observed in two randomized placebo-controlled trials of nirmatrelvir/ritonavir (NMV/r) in adults with Long COVID, including the Selective Trial of Paxlovid for PASC (STOP-PASC) and PAX LC. This systems immunology analysis aimed to characterize immune profiles of participants during clinical trial intervention, identify biomarkers associated with patient-reported outcomes, and investigate potential mechanisms underlying Long COVID. Methods: We performed comprehensive immunological profiling of 152 STOP-PASC trial participants using plasma proteomics (Olink® Explore HT 5400 panel), autoantigen arrays, viral serology, and microclot assays at baseline, day 15, and week 10. We assessed associations between immune features and patient-reported outcomes. We also conducted meta-analysis of nine independent Long COVID proteomics cohorts (n=590 total samples) to identify conserved inflammatory signatures. Results: NMV/r treatment at day 15 compared with baseline induced transient changes in plasma proteins that normalized by week 10, primarily impacting myeloid cell/monocyte, lysosome, and complement activation pathways. Cardiovascular symptoms were negatively associated with SARS-CoV-2 antibody levels at baseline. No widespread differences in autoantibody profiles, Epstein-Barr virus (EBV) reactivation, or microclotting were observed between STOP-PASC Long COVID participants, pre-pandemic controls, and individuals without Long COVID. Meta-analysis of publicly available Olink® data from Long COVID cohorts identified a conserved 60-protein Long COVID Signature (LCS) score revealing multi-compartment immune activation involving monocyte, neutrophil, and T/NK cell modules. Conclusions: These findings advance our understanding of Long COVID immunology and may help direct future proteomic biomarker endpoints for Long COVID clinical trials.

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