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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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 languageEnglish
Article number838780
Number of pages13
JournalFrontiers in immunology
Publication statusPublished - 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 (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.


  • vaccine
  • antibodies
  • complement
  • COVID-19
  • SARS-CoV-2


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