SARS-CoV-2 spike- and nucleoprotein-specific antibodies induced after vaccination or infection promote classical complement activation

Rachel Lamerton; Edith Marcial-Juarez; Sian Faustini; Marisol Perez-Toledo; Margaret Goodall; Sian Jossi; Maddy L Newby; Iain Chapple; Thomas Dietrich; T Veenith; Adrian Shields; Lorraine Harper; Ian Henderson; Julie Rayes; David Wraith; Steve Watson; Max Crispin; Mark Drayson; Alex Richter; Adam Cunningham

doi:10.3389/fimmu.2022.838780

SARS-CoV-2 spike- and nucleoprotein-specific antibodies induced after vaccination or infection promote classical complement activation

Rachel Lamerton, Edith Marcial-Juarez, Sian Faustini, Marisol Perez-Toledo, Margaret Goodall, Sian Jossi, Maddy L Newby, Iain Chapple, Thomas Dietrich, T Veenith, Adrian Shields, Lorraine Harper, Ian Henderson, Julie Rayes, David Wraith, Steve Watson, Max Crispin, Mark Drayson, Alex Richter, Adam Cunningham

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Abstract

Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of antibodies to SARS-CoV-2 from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the subject group from whom the sera were obtained. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending the disease status of the subject and on the specific antigen targeted.

Original language	English
Article number	838780
Number of pages	13
Journal	Frontiers in immunology
Volume	13
DOIs	https://doi.org/10.3389/fimmu.2022.838780
Publication status	Published - 4 Jul 2022

Bibliographical note

Funding Information:
We would like to thank the staff of the Clinical Immunology Service, University of Birmingham for their invaluable work in sample collection and processing. We also gratefully acknowledge the University of Birmingham Protein Expression Facility for the production of nucleoprotein. We thank Jason McLellan for providing the expression plasmid for HexaPro. The content of this manuscript has appeared online as a preprint at https://doi.org/10.1101/2021.11.22.21266681 (61).

This work was supported by the Wellcome Trust Mechanisms of Inflammatory Disease (MIDAS) PhD Programme [grant number 222389/Z/21/Z, part of 108871/B/15/Z] to RL; The Royal Society Newton International Fellowship [grant number NIF\R1\192061] to E.M.J and AC; a British Heart Foundation Intermediate Fellowship [grant number FS/IBSRF/20/25039] to JR; The University of Southampton Coronavirus Response Fund to MC and Medical Research Council [grant number MR/W010011/1] to LH, AR and AC.

Publisher Copyright:
Copyright © 2022 Lamerton, Marcial-Juarez, Faustini, Perez-Toledo, Goodall, Jossi, Newby, Chapple, Dietrich, Veenith, Shields, Harper, Henderson, Rayes, Wraith, Watson, Crispin, Drayson, Richter and Cunningham.

Keywords

vaccine
antibodies
complement
COVID-19
SARS-CoV-2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lamerton, R., Marcial-Juarez, E., Faustini, S., Perez-Toledo, M., Goodall, M., Jossi, S., Newby, M. L., Chapple, I., Dietrich, T., Veenith, T., Shields, A., Harper, L., Henderson, I., Rayes, J., Wraith, D., Watson, S., Crispin, M., Drayson, M., Richter, A., & Cunningham, A. (2022). SARS-CoV-2 spike- and nucleoprotein-specific antibodies induced after vaccination or infection promote classical complement activation. Frontiers in immunology, 13, Article 838780. https://doi.org/10.3389/fimmu.2022.838780

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title = "SARS-CoV-2 spike- and nucleoprotein-specific antibodies induced after vaccination or infection promote classical complement activation",

abstract = "Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of antibodies to SARS-CoV-2 from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the subject group from whom the sera were obtained. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending the disease status of the subject and on the specific antigen targeted.",

keywords = "vaccine, antibodies, complement, COVID-19, SARS-CoV-2",

author = "Rachel Lamerton and Edith Marcial-Juarez and Sian Faustini and Marisol Perez-Toledo and Margaret Goodall and Sian Jossi and Newby, {Maddy L} and Iain Chapple and Thomas Dietrich and T Veenith and Adrian Shields and Lorraine Harper and Ian Henderson and Julie Rayes and David Wraith and Steve Watson and Max Crispin and Mark Drayson and Alex Richter and Adam Cunningham",

note = "Funding Information: We would like to thank the staff of the Clinical Immunology Service, University of Birmingham for their invaluable work in sample collection and processing. We also gratefully acknowledge the University of Birmingham Protein Expression Facility for the production of nucleoprotein. We thank Jason McLellan for providing the expression plasmid for HexaPro. The content of this manuscript has appeared online as a preprint at https://doi.org/10.1101/2021.11.22.21266681 (61). This work was supported by the Wellcome Trust Mechanisms of Inflammatory Disease (MIDAS) PhD Programme [grant number 222389/Z/21/Z, part of 108871/B/15/Z] to RL; The Royal Society Newton International Fellowship [grant number NIF\R1\192061] to E.M.J and AC; a British Heart Foundation Intermediate Fellowship [grant number FS/IBSRF/20/25039] to JR; The University of Southampton Coronavirus Response Fund to MC and Medical Research Council [grant number MR/W010011/1] to LH, AR and AC. Publisher Copyright: Copyright {\textcopyright} 2022 Lamerton, Marcial-Juarez, Faustini, Perez-Toledo, Goodall, Jossi, Newby, Chapple, Dietrich, Veenith, Shields, Harper, Henderson, Rayes, Wraith, Watson, Crispin, Drayson, Richter and Cunningham.",

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Lamerton, R, Marcial-Juarez, E , Faustini, S , Perez-Toledo, M, Goodall, M, Jossi, S, Newby, ML, Chapple, I , Dietrich, T, Veenith, T, Shields, A , Harper, L, Henderson, I, Rayes, J , Wraith, D , Watson, S, Crispin, M, Drayson, M , Richter, A & Cunningham, A 2022, 'SARS-CoV-2 spike- and nucleoprotein-specific antibodies induced after vaccination or infection promote classical complement activation', Frontiers in immunology, vol. 13, 838780. https://doi.org/10.3389/fimmu.2022.838780

TY - JOUR

T1 - SARS-CoV-2 spike- and nucleoprotein-specific antibodies induced after vaccination or infection promote classical complement activation

AU - Lamerton, Rachel

AU - Marcial-Juarez, Edith

AU - Faustini, Sian

AU - Perez-Toledo, Marisol

AU - Goodall, Margaret

AU - Jossi, Sian

AU - Newby, Maddy L

AU - Chapple, Iain

AU - Dietrich, Thomas

AU - Veenith, T

AU - Shields, Adrian

AU - Harper, Lorraine

AU - Henderson, Ian

AU - Rayes, Julie

AU - Wraith, David

AU - Watson, Steve

AU - Crispin, Max

AU - Drayson, Mark

AU - Richter, Alex

AU - Cunningham, Adam

N1 - Funding Information: We would like to thank the staff of the Clinical Immunology Service, University of Birmingham for their invaluable work in sample collection and processing. We also gratefully acknowledge the University of Birmingham Protein Expression Facility for the production of nucleoprotein. We thank Jason McLellan for providing the expression plasmid for HexaPro. The content of this manuscript has appeared online as a preprint at https://doi.org/10.1101/2021.11.22.21266681 (61). This work was supported by the Wellcome Trust Mechanisms of Inflammatory Disease (MIDAS) PhD Programme [grant number 222389/Z/21/Z, part of 108871/B/15/Z] to RL; The Royal Society Newton International Fellowship [grant number NIF\R1\192061] to E.M.J and AC; a British Heart Foundation Intermediate Fellowship [grant number FS/IBSRF/20/25039] to JR; The University of Southampton Coronavirus Response Fund to MC and Medical Research Council [grant number MR/W010011/1] to LH, AR and AC. Publisher Copyright: Copyright © 2022 Lamerton, Marcial-Juarez, Faustini, Perez-Toledo, Goodall, Jossi, Newby, Chapple, Dietrich, Veenith, Shields, Harper, Henderson, Rayes, Wraith, Watson, Crispin, Drayson, Richter and Cunningham.

PY - 2022/7/4

Y1 - 2022/7/4

N2 - Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of antibodies to SARS-CoV-2 from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the subject group from whom the sera were obtained. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending the disease status of the subject and on the specific antigen targeted.

AB - Antibodies specific for the spike glycoprotein (S) and nucleocapsid (N) SARS-CoV-2 proteins are typically present during severe COVID-19, and induced to S after vaccination. The binding of viral antigens by antibody can initiate the classical complement pathway. Since complement could play pathological or protective roles at distinct times during SARS-CoV-2 infection we determined levels of antibody-dependent complement activation along the complement cascade. Here, we used an ELISA assay to assess complement protein binding (C1q) and the deposition of C4b, C3b, and C5b to S and N antigens in the presence of antibodies to SARS-CoV-2 from different test groups: non-infected, single and double vaccinees, non-hospitalised convalescent (NHC) COVID-19 patients and convalescent hospitalised (ITU-CONV) COVID-19 patients. C1q binding correlates strongly with antibody responses, especially IgG1 levels. However, detection of downstream complement components, C4b, C3b and C5b shows some variability associated with the subject group from whom the sera were obtained. In the ITU-CONV, detection of C3b-C5b to S was observed consistently, but this was not the case in the NHC group. This is in contrast to responses to N, where median levels of complement deposition did not differ between the NHC and ITU-CONV groups. Moreover, for S but not N, downstream complement components were only detected in sera with higher IgG1 levels. Therefore, the classical pathway is activated by antibodies to multiple SARS-CoV-2 antigens, but the downstream effects of this activation may differ depending the disease status of the subject and on the specific antigen targeted.

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JO - Frontiers in immunology

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SARS-CoV-2 spike- and nucleoprotein-specific antibodies induced after vaccination or infection promote classical complement activation

Abstract

Bibliographical note

Keywords

UN SDGs

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Cite this