In vitro, classical complement activation differs by disease severity and between SARS-CoV-2 antigens

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 anti-SARS-CoV-2 antibodies 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 antigen and subjects studied. 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 on the specific antigen targeted and the disease status of the subject.

SARS-CoV-2 Spike- and Nucleoprotein-Specific Antibodies Induced After Vaccination or Infection Promote Classical Complement Activation

“…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).…”

Immunogenicity and safety of a RBD vaccine against SARS-CoV-2 in a murine model

“…With ACE-2 receptors and thus blocking the infection of cells in these hosts [ 5 , 16 ]. In addition, these antibodies could also mediate the destruction of the virus through the balanced activation of other immunological mechanisms such as antibody-mediated cell cytotoxicity and the activation of the membrane attack complex and opsonization processes mediated by the classical pathway of complement [ 17 ]. The present study has limitations, such as the non-evaluation of a cellular immune response towards the Th1 pattern.…”