Proteomic signatures of COVID-19 Post-Vaccination/Post-Infection Syndrome (PV/PIS): insights into immune dysregulation and coagulopathy

During the global rollout of COVID-19 vaccines, a subset of individuals reported persistent symptoms following vaccination, with clinical presentations overlapping those of Long COVID and requiring individualised treatment strategies. Distinguishing between vaccine-related adverse events and post-infectious sequelae is challenging, particularly given the potential for unrecognised asymptomatic or mild SARS-CoV-2 infection before or after vaccination. To address this complexity, we defined our disease cohort as individuals experiencing persistent symptoms ( ≥ 12 weeks) following SARS-CoV-2 vaccination, without a confirmed history of prolonged symptoms after acute infection; for clarity, we refer to this group as presenting with Post-Vaccination/Post-Infection Syndrome (PV/PIS). In this study, we conducted a plasma proteomic analysis of digested microclot deposits isolated from platelet-poor plasma samples of 14 individuals with PV/PIS compared to 16 healthy controls, using liquid-chromatography-mass spectrometry. We identified significant alterations in coagulation factors, acute phase proteins, and immune response modulators in the PV/PIS group compared to controls. Notably, elevated levels of serum amyloid A1 and A2, attractin, and coagulation factors X and XI were observed, alongside downregulation of immune-regulatory proteins. These findings suggest that PV/PIS is characterised by persistent immune dysregulation and coagulopathy. This proteomic signature was found to only partially overlap with that previously reported in a proteomics analysis on Long COVID samples, collected prior to vaccination availability. Our results highlight the complex interplay between immune activation, endothelial dysfunction, and coagulation pathologies in PV/PIS, with distinct differences detected between these systems in Long COVID and PV/PIS, paving the way for more targeted protein research in these conditions.