Dysregulated inflammation in solid tumor malignancy patients shapes polyfunctional antibody responses to COVID-19 vaccination

Ruth A. Purcell; Marios Koutsakos; Lukasz Kedzierski; Lilith F. Allen; Oscar H. Lloyd Williams; Jo-Wai Douglas Wang; George Cavic; Adam K. Wheatley; Wen Shi Lee; Bruce D. Wines; P. Mark Hogarth; Emily M. Eriksson; Ivo Mueller; Katherine A. Bond; Deborah A. Williamson; Janine M. Trevillyan; Jason A. Trubiano; Thi H. O. Nguyen; Pradhipa Ramanathan; Stephen J. Rogerson; Kelly B. Arnold; Kanta Subbarao; Adrian Lee; Amanda L. Hudson; Alexander Yuile; Helen R. Wheeler; Stephen J. Kent; Kevin John Selva; Siddhartha Mahanty; Katherine Kedzierska; Aude M. Fahrer; Yada Kanjanapan; Amy W. Chung

doi:10.1038/s41541-025-01268-w

Dysregulated inflammation in solid tumor malignancy patients shapes polyfunctional antibody responses to COVID-19 vaccination

Ruth A. Purcell^*, Marios Koutsakos, Lukasz Kedzierski, Lilith F. Allen, Oscar H. Lloyd Williams, Jo-Wai Douglas Wang, George Cavic, Adam K. Wheatley, Wen Shi Lee, Bruce D. Wines, P. Mark Hogarth, Emily M. Eriksson, Ivo Mueller, Katherine A. Bond, Deborah A. Williamson, Janine M. Trevillyan, Jason A. Trubiano, Thi H. O. Nguyen, Pradhipa Ramanathan, Stephen J. RogersonKelly B. Arnold, Kanta Subbarao, Adrian Lee, Amanda L. Hudson, Alexander Yuile, Helen R. Wheeler, Stephen J. Kent, Kevin John Selva, Siddhartha Mahanty, Katherine Kedzierska, Aude M. Fahrer, Yada Kanjanapan, Amy W. Chung

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Solid tumor malignancy (STM) patients experience increased risk of breakthrough SARS-CoV-2 infection owing to reduced COVID-19 vaccine immunogenicity. However, the underlying immunological causes of impaired neutralization remain poorly characterized. Furthermore, non-neutralizing antibody functions can contribute to reduced disease severity but remain understudied within high-risk populations. We dissected polyfunctional antibody responses in STM patients and age-matched controls who received adenoviral vector- or mRNA-based COVID-19 vaccine regimens. Elevated inflammatory biomarkers, including agalactosylated IgG, interleukin (IL)-6, IL-18, and an expanded population of CD11c⁻CD21⁻ double negative 3 (DN3) B cells were observed in STM patients and were associated with impaired neutralization. In contrast, mRNA vaccination induced Fc effector functions that were comparable in patients and controls and were cross-reactive against SARS-CoV-2 variants. These data highlight the resilience of Fc functional antibodies and identify systemic inflammatory biomarkers that may underpin impaired neutralizing antibody responses, suggesting potential avenues for immunomodulation via rational vaccine design.

Original language	English
Article number	217
Pages (from-to)	1-15
Number of pages	15
Journal	npj Vaccines
Volume	10
DOIs	https://doi.org/10.1038/s41541-025-01268-w
Publication status	Published - 6 Oct 2025

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Purcell, R. A., Koutsakos, M., Kedzierski, L., Allen, L. F., Lloyd Williams, O. H., Wang, J.-W. D., Cavic, G., Wheatley, A. K., Lee, W. S., Wines, B. D., Mark Hogarth, P., Eriksson, E. M., Mueller, I., Bond, K. A., Williamson, D. A., Trevillyan, J. M., Trubiano, J. A., Nguyen, T. H. O., Ramanathan, P., ... Chung, A. W. (2025). Dysregulated inflammation in solid tumor malignancy patients shapes polyfunctional antibody responses to COVID-19 vaccination. npj Vaccines, 10, 1-15. Article 217. https://doi.org/10.1038/s41541-025-01268-w

@article{8ea88ef961fe4dfabfdd808d7812c606,

title = "Dysregulated inflammation in solid tumor malignancy patients shapes polyfunctional antibody responses to COVID-19 vaccination",

abstract = "Solid tumor malignancy (STM) patients experience increased risk of breakthrough SARS-CoV-2 infection owing to reduced COVID-19 vaccine immunogenicity. However, the underlying immunological causes of impaired neutralization remain poorly characterized. Furthermore, non-neutralizing antibody functions can contribute to reduced disease severity but remain understudied within high-risk populations. We dissected polyfunctional antibody responses in STM patients and age-matched controls who received adenoviral vector- or mRNA-based COVID-19 vaccine regimens. Elevated inflammatory biomarkers, including agalactosylated IgG, interleukin (IL)-6, IL-18, and an expanded population of CD11c−CD21− double negative 3 (DN3) B cells were observed in STM patients and were associated with impaired neutralization. In contrast, mRNA vaccination induced Fc effector functions that were comparable in patients and controls and were cross-reactive against SARS-CoV-2 variants. These data highlight the resilience of Fc functional antibodies and identify systemic inflammatory biomarkers that may underpin impaired neutralizing antibody responses, suggesting potential avenues for immunomodulation via rational vaccine design.",

author = "Purcell, \{Ruth A.\} and Marios Koutsakos and Lukasz Kedzierski and Allen, \{Lilith F.\} and \{Lloyd Williams\}, \{Oscar H.\} and Wang, \{Jo-Wai Douglas\} and George Cavic and Wheatley, \{Adam K.\} and Lee, \{Wen Shi\} and Wines, \{Bruce D.\} and \{Mark Hogarth\}, P. and Eriksson, \{Emily M.\} and Ivo Mueller and Bond, \{Katherine A.\} and Williamson, \{Deborah A.\} and Trevillyan, \{Janine M.\} and Trubiano, \{Jason A.\} and Nguyen, \{Thi H. O.\} and Pradhipa Ramanathan and Rogerson, \{Stephen J.\} and Arnold, \{Kelly B.\} and Kanta Subbarao and Adrian Lee and Hudson, \{Amanda L.\} and Alexander Yuile and Wheeler, \{Helen R.\} and Kent, \{Stephen J.\} and Selva, \{Kevin John\} and Siddhartha Mahanty and Katherine Kedzierska and Fahrer, \{Aude M.\} and Yada Kanjanapan and Chung, \{Amy W.\}",

note = "Funding: This research was funded in whole or part by the National Health and Medical Research Council (NHMRC). NHMRC EL2 Investigator grant \#2008092 was awarded to A.W.C. and NHMRC L2 Investigator grant \#2033783 was awarded to K.K. A.K.W., W.S.L., T.H.O.N., K.S., S.J.K., and K.J.S. are also supported by NHMRC Investigator grants. O.H.L.W. is supported by an NHMRC Ideas grant \#2029642 to S.J.R. This study was further supported by a Medical Research Future Fund (MRFF) grant \#2016062 to J.A.T., A.K.W., T.H.O.N., K.K., S.J.K., and A.W.C. The COVID PROFILE study was supported by WHO Unity funds (2020/1085469-0), and WEHI philanthropic funds. The DISCOVER-HCP study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Centers of Excellence for Influenza Research and Response (CEIRR) grant \#HHSN272201400005C to the University of Rochester and a subcontract to KS. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.",

year = "2025",

month = oct,

day = "6",

doi = "10.1038/s41541-025-01268-w",

language = "English",

volume = "10",

pages = "1--15",

journal = "npj Vaccines",

issn = "2059-0105",

publisher = "Nature Research",

}

Purcell, RA, Koutsakos, M, Kedzierski, L, Allen, LF, Lloyd Williams, OH, Wang, J-WD, Cavic, G, Wheatley, AK, Lee, WS, Wines, BD, Mark Hogarth, P, Eriksson, EM, Mueller, I, Bond, KA, Williamson, DA, Trevillyan, JM, Trubiano, JA, Nguyen, THO, Ramanathan, P, Rogerson, SJ, Arnold, KB, Subbarao, K, Lee, A, Hudson, AL, Yuile, A, Wheeler, HR, Kent, SJ, Selva, KJ, Mahanty, S, Kedzierska, K, Fahrer, AM, Kanjanapan, Y & Chung, AW 2025, 'Dysregulated inflammation in solid tumor malignancy patients shapes polyfunctional antibody responses to COVID-19 vaccination', npj Vaccines, vol. 10, 217, pp. 1-15. https://doi.org/10.1038/s41541-025-01268-w

TY - JOUR

T1 - Dysregulated inflammation in solid tumor malignancy patients shapes polyfunctional antibody responses to COVID-19 vaccination

AU - Purcell, Ruth A.

AU - Koutsakos, Marios

AU - Kedzierski, Lukasz

AU - Allen, Lilith F.

AU - Lloyd Williams, Oscar H.

AU - Wang, Jo-Wai Douglas

AU - Cavic, George

AU - Wheatley, Adam K.

AU - Lee, Wen Shi

AU - Wines, Bruce D.

AU - Mark Hogarth, P.

AU - Eriksson, Emily M.

AU - Mueller, Ivo

AU - Bond, Katherine A.

AU - Williamson, Deborah A.

AU - Trevillyan, Janine M.

AU - Trubiano, Jason A.

AU - Nguyen, Thi H. O.

AU - Ramanathan, Pradhipa

AU - Rogerson, Stephen J.

AU - Arnold, Kelly B.

AU - Subbarao, Kanta

AU - Lee, Adrian

AU - Hudson, Amanda L.

AU - Yuile, Alexander

AU - Wheeler, Helen R.

AU - Kent, Stephen J.

AU - Selva, Kevin John

AU - Mahanty, Siddhartha

AU - Kedzierska, Katherine

AU - Fahrer, Aude M.

AU - Kanjanapan, Yada

AU - Chung, Amy W.

N1 - Funding: This research was funded in whole or part by the National Health and Medical Research Council (NHMRC). NHMRC EL2 Investigator grant #2008092 was awarded to A.W.C. and NHMRC L2 Investigator grant #2033783 was awarded to K.K. A.K.W., W.S.L., T.H.O.N., K.S., S.J.K., and K.J.S. are also supported by NHMRC Investigator grants. O.H.L.W. is supported by an NHMRC Ideas grant #2029642 to S.J.R. This study was further supported by a Medical Research Future Fund (MRFF) grant #2016062 to J.A.T., A.K.W., T.H.O.N., K.K., S.J.K., and A.W.C. The COVID PROFILE study was supported by WHO Unity funds (2020/1085469-0), and WEHI philanthropic funds. The DISCOVER-HCP study was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Centers of Excellence for Influenza Research and Response (CEIRR) grant #HHSN272201400005C to the University of Rochester and a subcontract to KS. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.

PY - 2025/10/6

Y1 - 2025/10/6

N2 - Solid tumor malignancy (STM) patients experience increased risk of breakthrough SARS-CoV-2 infection owing to reduced COVID-19 vaccine immunogenicity. However, the underlying immunological causes of impaired neutralization remain poorly characterized. Furthermore, non-neutralizing antibody functions can contribute to reduced disease severity but remain understudied within high-risk populations. We dissected polyfunctional antibody responses in STM patients and age-matched controls who received adenoviral vector- or mRNA-based COVID-19 vaccine regimens. Elevated inflammatory biomarkers, including agalactosylated IgG, interleukin (IL)-6, IL-18, and an expanded population of CD11c−CD21− double negative 3 (DN3) B cells were observed in STM patients and were associated with impaired neutralization. In contrast, mRNA vaccination induced Fc effector functions that were comparable in patients and controls and were cross-reactive against SARS-CoV-2 variants. These data highlight the resilience of Fc functional antibodies and identify systemic inflammatory biomarkers that may underpin impaired neutralizing antibody responses, suggesting potential avenues for immunomodulation via rational vaccine design.

AB - Solid tumor malignancy (STM) patients experience increased risk of breakthrough SARS-CoV-2 infection owing to reduced COVID-19 vaccine immunogenicity. However, the underlying immunological causes of impaired neutralization remain poorly characterized. Furthermore, non-neutralizing antibody functions can contribute to reduced disease severity but remain understudied within high-risk populations. We dissected polyfunctional antibody responses in STM patients and age-matched controls who received adenoviral vector- or mRNA-based COVID-19 vaccine regimens. Elevated inflammatory biomarkers, including agalactosylated IgG, interleukin (IL)-6, IL-18, and an expanded population of CD11c−CD21− double negative 3 (DN3) B cells were observed in STM patients and were associated with impaired neutralization. In contrast, mRNA vaccination induced Fc effector functions that were comparable in patients and controls and were cross-reactive against SARS-CoV-2 variants. These data highlight the resilience of Fc functional antibodies and identify systemic inflammatory biomarkers that may underpin impaired neutralizing antibody responses, suggesting potential avenues for immunomodulation via rational vaccine design.

UR - https://www.scopus.com/pages/publications/105018194713

U2 - 10.1038/s41541-025-01268-w

DO - 10.1038/s41541-025-01268-w

M3 - Article

SN - 2059-0105

VL - 10

SP - 1

EP - 15

JO - npj Vaccines

JF - npj Vaccines

M1 - 217

ER -

Dysregulated inflammation in solid tumor malignancy patients shapes polyfunctional antibody responses to COVID-19 vaccination

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