Divergent inflammatory and neurology-related protein levels in long COVID following primary and breakthrough SARS-CoV-2 infections

BACKGROUND: 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 persistent inflammation has emerged as an important feature of this condition, it is unclear if immune responses from COVID-19 vaccination or SARS-CoV-2 re-infection exacerbate or mirror the initial inflammatory responses. METHODS: We quantified 182 inflammatory and neurology-related proteins in plasma using multiplexed affinity proteomics. Plasma samples from the COVID PROFILE cohort conducted in Victoria, Australia, 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). To establish baseline plasma profiles, protein levels were benchmarked against unvaccinated, SARS-CoV-2 naive individuals (n = 24). In addition, 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 to assess inflammatory and neurology protein plasma levels after antigen exposure in these contexts. RESULTS: In this cohort Boruta feature selection and lasso regression models identified IL-20, HAGH, NAAA, CLEC10A, LXN, and MCP-1, TRAIL, G-CSF, NBL1, and CCL23 as best discriminating proteins when comparing the long COVID group to groups of either healthy or COVID-19 recovered. Notably, longitudinal analysis indicated differences in the levels of a subset of plasma proteins following primary infection compared to after COVID-19 booster vaccination and breakthrough infection within the groups. CONCLUSIONS: These findings suggest that there is an altered immune response outcome primarily observed in individuals with long COVID upon re-exposure.

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Publication Details

Journal
Communications Medicine
Published
2026-04-13
DOI
https://doi.org/10.1038/s43856-026-01541-6
Primary Topic
Long-Term Effects of COVID-19
Type
article
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article

Divergent inflammatory and neurology-related protein levels in long COVID following primary and breakthrough SARS-CoV-2 infections

I. A. Azeez, Rachel Evans, Jason A. Tye–Din, Ryan Munnings et al.
Communications Medicine
Long-Term Effects of COVID-19
article

Divergent inflammatory and neurology-related protein levels in long COVID following primary and breakthrough SARS-CoV-2 infections

I. A. Azeez, Rachel Evans, Jason A. Tye–Din, Ryan Munnings, Maureen Forde, Erin D. Lucas, Lisa J. Ioannidis, Joanna R. Groom, Sam W.Z. Olechnowicz, Ramin Mazhari, Nicholas Kiernan‐Walker, Ivo Müeller, Siavash Foroughi, Anne C. Hart, Dylan Sheerin, Anna K. Coussens, Marilou Barrios, Eamon Conway, Vanessa L. Bryant, Diana S. Hansen, Maria Edmonds, Amit Bansal, Anthony J. Farchione, Rory Bowden, Mai B. Margetts, Emily M. Eriksson, Jasper Cornish, Rebecca Jane Cox, George W. Ashdown, Shazia Ruybal‐Pesántez, Lee Henneken, J. B. Cumming, Catherine Chen
article en

Abstract

BACKGROUND: 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 persistent inflammation has emerged as an important feature of this condition, it is unclear if immune responses from COVID-19 vaccination or SARS-CoV-2 re-infection exacerbate or mirror the initial inflammatory responses. METHODS: We quantified 182 inflammatory and neurology-related proteins in plasma using multiplexed affinity proteomics. Plasma samples from the COVID PROFILE cohort conducted in Victoria, Australia, 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). To establish baseline plasma profiles, protein levels were benchmarked against unvaccinated, SARS-CoV-2 naive individuals (n = 24). In addition, 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 to assess inflammatory and neurology protein plasma levels after antigen exposure in these contexts. RESULTS: In this cohort Boruta feature selection and lasso regression models identified IL-20, HAGH, NAAA, CLEC10A, LXN, and MCP-1, TRAIL, G-CSF, NBL1, and CCL23 as best discriminating proteins when comparing the long COVID group to groups of either healthy or COVID-19 recovered. Notably, longitudinal analysis indicated differences in the levels of a subset of plasma proteins following primary infection compared to after COVID-19 booster vaccination and breakthrough infection within the groups. CONCLUSIONS: These findings suggest that there is an altered immune response outcome primarily observed in individuals with long COVID upon re-exposure.

Communications Medicine
Burnet Institute (AU), The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), Haukeland University Hospital (NO), Peter Doherty Institute (AU), University of Bergen (NO)
Reduced inequalities
Openalex Percentile: Top 15%
Long-Term Effects of COVID-19
DOIOpen Access PDFOpenAlex
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