Systems Immunology of Long Covid: Insights from the STOP-PASC Clinical Trial 2265936

Evan Maestri; Woo Joo Kwon; Hong Zheng; Tyler Prestwood; Haley Hedlin; Jane Liang; Holly McCann; Ben Jones; Rufei Lu; Graham Wiley; Emily Haraguchi; Oliver Wirz; Jumana Afaghani; Brandon Lam; Jeremy Wood; Scott Boyd; Joel Guthridge; Upinder Singh; Hector Bonilla; Prasanna Jagannathan; P J Utz; Linda Geng; Purvesh Khatri

doi:10.1093/jimmun/vkag141.1084

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Systems Immunology of Long Covid: Insights from the STOP-PASC Clinical Trial 2265936

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Systems Immunology of Long Covid: Insights from the STOP-PASC Clinical Trial 2265936

Evan Maestri, Woo Joo Kwon, Hong Zheng, Tyler Prestwood, Haley Hedlin, Jane Liang, Holly McCann, Ben Jones, Rufei Lu, Graham Wiley, …

The Journal of immunology (1950), Vol.215(Supplement_1), vkag1411084

07/28/2026

DOI: 10.1093/jimmun/vkag141.1084

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Abstract

Introduction Post Acute Sequelae of COVID-19 (PASC), also called Long COVID, is an infection-associated chronic syndrome. Despite proposed viral persistence mechanisms, no therapeutic benefit was observed in randomized placebo-controlled trials of nirmatrelvir/ritonavir (NMV/r) in adults with Long COVID, including the Selective Trial of Paxlovid for PASC (STOP-PASC). 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. Conclusion These findings advance our understanding of Long COVID immunology and may help direct future proteomic biomarker endpoints for Long COVID clinical trials. Funding Source Pfizer Topic Categories Computational and Systems Immunology (COMP)

Infections — Viral

Molecules - ChemokinesMolecules — Complement

Molecules — Autoantibodies

Processes — Inflammation

Animals — Human

Details

Title: Subtitle: Systems Immunology of Long Covid: Insights from the STOP-PASC Clinical Trial 2265936
Creators: Evan Maestri - Stanford Medicine
Woo Joo Kwon - Stanford University
Hong Zheng - Stanford University
Tyler Prestwood - Stanford University
Haley Hedlin - Stanford University
Jane Liang - Kaiser Permanente
Holly McCann - Stanford University
Ben Jones - Oklahoma Medical Research Foundation
Rufei Lu - Oklahoma Medical Research Foundation
Graham Wiley - Oklahoma Medical Research Foundation
Emily Haraguchi - Stanford University
Oliver Wirz - Stanford University
Jumana Afaghani - Stanford University
Brandon Lam - Stanford University
Jeremy Wood - University of Kentucky
Scott Boyd - Stanford University
Joel Guthridge - Oklahoma Medical Research Foundation
Upinder Singh - University of Iowa
Hector Bonilla - Stanford University
Prasanna Jagannathan - Stanford University
P J Utz - Stanford University
Linda Geng - Stanford University
Purvesh Khatri - Stanford University
Resource Type: Abstract
Publication Details: The Journal of immunology (1950), Vol.215(Supplement_1), vkag1411084
DOI: 10.1093/jimmun/vkag141.1084
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: Oxford University Press
Grant note: Pfizer
Pfizer
Alternative title: IMMUNOLOGY2026™ Abstracts
Language: English
Date published: 07/28/2026
Academic Unit: Internal Medicine
Record Identifier: 9985244536302771

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