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.
Plain language summary
Long COVID is a condition in which people continue to have symptoms for more than three months after SARS-CoV-2 infection. Ongoing inflammation is thought to contribute to long COVID, but it is unclear whether COVID-19 vaccination or re-infection with SARS-CoV-2 lead to similar, worse or different inflammatory responses compared with the initial infection in people with this condition. We examined blood proteins linked to inflammation and the nervous system to better understand these responses in people with long COVID, individuals that had completely recovered from the first infection and healthy controls. We found that in both long COVID individuals and completely recovered people there were different changes in the level of some immune-related proteins after vaccination or re-infection compared with the response after the original infection suggesting a different immune response from the initial infection upon re-exposure.
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Data availability
To protect patient privacy, this study uses anonymised data from the COVID PROFILE study. Data have been deposited into Zenodo https://doi.org/10.5281/zenodo.15237087 and are available as Supplementary Data 2 and 3. The source data for Figs. 2, 3 and 4 is in Supplementary Data 2. The source data for Figs. 4 and 5 is in Supplementary Data 3.
Code availability
R code has been deposited into Zenodo https://doi.org/10.5281/zenodo.15237087. This paper does not report original code. This project leverages open-source R code. We have documented the specific R packages and functions used in relevant sections.
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Acknowledgements
We wish to thank Anne Hart, Maureen Ford and all members of the COVID PROFILE consortium and the study participants in the COVID PROFILE study. We also wish to thank Dr. Lauren Smith for her valuable discussion and input around data analysis. Dr. Bansal received funding from the University of Bergen, The National Graduate School in Infection Biology and Antimicrobials (or IBA) and Pasteur legatet & Thjøtta’s legat, University of Oslo, Norway [101563]. The COVID PROFILE study was supported by WHO Unity funds (2020/1085469-0), and WEHI philanthropic funds. I.M. is supported by an NHMRC Senior Research Fellowship (#1043345). This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.
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S.W.Z.O and E.M.E. conceptualised the study. A.B., S.W.Z.O., J.C., I.A. and E.M.E. performed the data analysis. S.W.Z.O., N.W.K. and R.M. generated the data. A.B., S.W.Z.O., N.W.K., R.B. and E.M.E. designed experimental work; A.B., S.W.Z.O. and E.M.E. wrote the first draft of the manuscript. R.B., I.M., I.A. and R.J.C. provided guidance and discussion and edited the manuscript.
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Communications Medicine thanks Ruth Drury, Gerald Mboowa, Lalit Batra, Guo-Lin Wang, Andreza Lemos Salvio and the other, anonymous, reviewer for their contribution to the peer review of this work. Peer review reports are available.
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Bansal, A., Olechnowicz, S.W.Z., Kiernan-Walker, N. et al. Divergent inflammatory and neurology-related protein levels in long COVID following primary and breakthrough SARS-CoV-2 infections. Commun Med (2026). https://doi.org/10.1038/s43856-026-01541-6
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DOI: https://doi.org/10.1038/s43856-026-01541-6
