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. 2025 Jul 30;232(1):50-59.
doi: 10.1093/infdis/jiaf211.

Systemic and SARS-CoV-2 specific Immune Disturbances in Individuals With Post-COVID Syndrome

Veronica Ober  1   2 , Felix Völk  1 , Julia Sbierski-Kind  3   4   5 , Eva Grüner  1 , Renate Stirner  1 , Gabriele Reiling  1 , Svenja Feldmann  1 , Gerardo Ibarra  6 , Ulrich Seybold  1 , Hans Stubbe  6   7 , Kristina Adorjan  8   9 , Johannes R Bogner  1 , Julia Roider  1   2
Affiliations

Systemic and SARS-CoV-2 specific Immune Disturbances in Individuals With Post-COVID Syndrome

Veronica Ober et al. J Infect Dis. .

Abstract

Background: Post-coronavirus disease 2019 syndrome (PCS) is characterized by persistent symptoms lasting >12 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The underlying pathological mechanisms remain poorly understood.

Methods: We conducted detailed immunological analyses in 47 individuals with PCS, assessed >12 weeks after acute SARS-CoV-2 infection, and we compared them with 25 convalescent controls without symptoms. We performed immune phenotyping of T- and B-cell subsets, assessed SARS-CoV-2-specific responses using activation-induced marker (AIM) flow cytometry for T cells, and tetramer staining of spike-specific B cells. Cytokine levels in peptide-stimulated cell supernatants and plasma were quantified using a Luminex platform.

Results: Individuals with PCS exhibited reduced frequencies of AIM-positive SARS-CoV-2-specific T cells (OX40+PDL1+) and CD8 T cells (CD137+CD69+) following peptide stimulation with spike or nucleocapsid antigen, accompanied by diminished interferon γ and interleukin 2, as measured in the cell culture supernatants. In contrast, non-virus-specific T-cell populations, including memory differentiation, activation and helper cell differentiation status, did not differ between the groups. Individuals with PCS showed a significant increase in total (CD19+) and activated (CD86+HLA-DR+) B cells but not in SARS-CoV-2 spike-specific B cells (approximately 0.2% of total B cells). Plasma cytokine analysis revealed elevated markers associated with vascular damage and inflammation in those with PCS.

Conclusions: Persistent immune disturbances in individuals with PCS are characterized by reduced SARS-CoV-2-specific T-cell responses, increased B-cell activation, and altered inflammatory and vascular biomarkers. These findings provide insights into the underlying mechanisms of PCS and may contribute to biomarker discovery and therapeutic development.

Trial no: DRKS00030974 (registry: https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/_node.html).

Keywords: Post–COVID-19 syndrome; SARS-CoV-2–specific immunity; inflammation; long COVID.

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Conflict of interest statement

Potential conflicts of interest. V. O. received financial support from MSD as participant in the Expert Input Forum (EIF) Rising Stars 2024. F. V. has received speaker fees from RG Gesellschaft für Information und Organisation for a presentation at the “4. Tag der Arbeitsmedizin” in Munich. J. R. received research project funding and financial support to attend scientific meetings, as well as speaker fees from Pfizer, BioNTech, ViiV Healthcare, and Gilead Sciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.