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.

Fc-dependent functional activity of ChAdOx1-S and CoronaVac vaccine-induced antibodies to the SARS-CoV-2 spike protein

“…IgG and IgM strongly fix complement component C1q, and our analyses suggest that IgM played a more substantial role in mediating C1q-fixation amongst naturally infected individuals. Conversely, IgG was the main determinant in vaccinated individuals, as previously shown in vaccinees with low IgM (55). However, C1q-fixation responses were modest in our study, which influence the strength and significance of these associations.…”

Complement dysregulation is a predictive and therapeutically amenable feature of long COVID

“…10,[14][15][16][17]19 In mechanistic terms, complement activation under these circumstances has been variously attributed to direct virus-mediated triggering of the classical, lectin, and/or alternative pathways, activation of the classical pathway via antiviral antibodies, and/or indirect activation via contact with infected cells and/or damaged tissue. [20][21][22][23][24] These observations have been used to rationalize interventions with complement blocking drugs to mitigate the hyperinflammatory state that characterizes severe COVID-19. Early pilot studies reported positive effects using repurposed existing drugs to inhibit complement activation or the terminal pathway.…”

“…10,14–17,19 In mechanistic terms, complement activation under these circumstances has been variously attributed to direct virus-mediated triggering of the classical, lectin, and/or alternative pathways, activation of the classical pathway via antiviral antibodies, and/or indirect activation via contact with infected cells and/or damaged tissue. 20–24…”

Short-Term Effect of SARS-CoV-2 Spike Protein Receptor-Binding Domain-Specific Antibody Induction on Neutrophil-Mediated Immune Response in Mice

“…Taking this into account, we can suggest that the interaction of IgG-opsonized virus particles with FcγRIIB, which expression was enhanced by vaccination, could prevent neutrophil activation and subsequent NET formation that we observed in the present study. Additionally, IgG-opsonized virus particles can activate the classical complement pathway [ 29 ]. Both the lectin and classical pathways of complement activation play pathogenic role during COVID-19 and can induce platelet activation, netosis, and thrombosis [ 30 , 31 , 32 ].…”