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.
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.
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.
These findings advance our understanding of Long COVID immunology and may help direct future proteomic biomarker endpoints for Long COVID clinical trials.
Pfizer
Computational and Systems Immunology (COMP)
E. Maestri, W. Kwon, Hong Zheng et al.· Journal of Immunology· 0 citations
Summary Background Long COVID is a heterogeneous condition associated with both early immune responses to SARS-CoV-2 and antibody responses to herpesviruses. However, herpesvirus-directed antibody responses during acute SARS-CoV-2 infection and their relationship to subsequent long COVID remain poorly understood. Methods We developed a multiplex bead-based serologic assay using recurrent, public peptide epitopes spanning all eight human herpesviruses. Antibody responses were profiled in longitudinal samples from acute SARS-CoV-2 infection and in early post-infection samples from participants in the NIH RECOVER observational cohort. IgG, IgA, and IgM responses were analysed using peptide-, virus-, and factor-level approaches. Findings During acute SARS-CoV-2 infection, a subset of individuals exhibited increased herpesvirus-directed IgA responses, particularly against beta-herpesviruses, without corresponding increases in IgG or IgM. In RECOVER participants, subsequent long COVID was associated with herpesvirus- and isotype-specific enrichment of high responders, most prominently HHV-6 IgA and HHV-1/HHV-2 IgG. Unsupervised factorisation identified distinct HHV-6 IgG- and IgA-dominant antibody programs with differing clinical and demographic associations. HHV-6 IgG responses were associated with lower symptom burden and relative enrichment among participants without long COVID, whereas HHV-6 IgA responses were associated with greater symptom burden. HHV-6 IgG responses also declined with increasing age, with the association more readily detected among females. Interpretation Early herpesvirus-directed antibody responses following SARS-CoV-2 infection exhibit distinct virus- and isotype-specific patterns associated with long COVID. These findings suggest that heterogeneity in long COVID may be linked to differential herpesvirus-directed humoural immune responses that emerge early after infection. Funding This study was funded by Stanford Post-Acute Recovery Cohort; NIH and RECOVER grants; the Henry Gustav Floren Family Trust; the Stanford Department of Medicine Team Science Program; Stanford Institutes of Medicine Summer Research Program (SIMR); the Doris Duke Charitable Foundation; the SPARK Program; Nucleate Dojo; the Jessica Lynn Saal Memorial Award; the William and Marissa Rastetter Research Scholar Fund through the Robinson Life Sciences, Business, and Entrepreneurship Program; National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health Award.
Ananya Choudhury, M. Burry, W. Kwon et al.· EBioMedicine· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
