Divergent inflammatory and neurology-related plasma protein profiles in individuals with long COVID following primary and breakthrough SARS-CoV-2 infections

Long COVID is a complex condition where symptoms persist for more than 3 months after SARS-CoV-2 infection and affects an estimated 5-30% of individuals. While the pathobiology of long COVID is still evolving, persistent inflammation has emerged as an important feature of this condition. However, it is unclear if immune responses from COVID-19 vaccination or SARS-CoV-2 re-infection exacerbate or mirror the initial inflammatory responses. To address this question, we quantified 182 inflammatory and neurology-related proteins in plasma using multiplexed affinity proteomics. Plasma samples were collected 6-9 months after first infection, but before COVID-19 vaccination from individuals who had recovered from COVID-19 (n=21) or from individuals with long COVID (n=12). This was benchmarked against plasma from unvaccinated, SARS-CoV-2 naive individuals (n=24). In addition to this cross-sectional analysis, we performed longitudinal analysis in a subset of individuals (n=34), where paired samples collected 2-4 weeks after a third COVID-19 vaccine dose and after SARS-CoV-2 breakthrough infection were available. Boruta feature selection and lasso regression models identified a distinct plasma profile in long COVID individuals, characterised by elevated IL-20, HAGH, NAAA, CLEC10A, LXN, and MCP-1 and reduced TRAIL, G-CSF, NBL1, and CCL23 protein concentrations. Notably, longitudinal analysis demonstrated that neither COVID-19 booster vaccination nor breakthrough infection replicated inflammatory and neurology-related plasma protein profiles observed after primary infection suggesting an altered immune response outcome in individuals with long COVID upon re-exposure.