Serological Analysis Reveals an Imbalanced IgG Subclass Composition Associated with COVID-19 Disease Severity

Abstract

COVID-19 is associated with a wide spectrum of disease severity, ranging from asymptomatic to acute respiratory distress syndrome (ARDS). Paradoxically, a direct relationship has been suggested between COVID-19 disease severity, and the levels of circulating SARS-CoV-2-specific antibodies, including virus neutralizing titers. Through a serological analysis of serum samples from 536 convalescent healthcare workers, we found that SARS-CoV-2-specific and virus-neutralizing antibody levels were indeed elevated in individuals that experienced severe disease. The severity-associated increase in SARS-CoV-2-specific antibody was dominated by IgG, with an IgG subclass ratio skewed towards elevated receptor binding domain (RBD)- and S1-specific IgG3. However, RBD- and S1-specific IgG1, rather than IgG3 were best correlated with virus-neutralizing titers. We propose that Spike-specific IgG3 subclass utilization contributes to COVID-19 disease severity through potent Fc-mediated effector functions. These results have significant implications for SARS-CoV-2 vaccine design, and convalescent plasma therapy.

Dynamics of antibodies to SARS-CoV-2 in convalescent plasma donors

“…We also quantitatively examined the IgG1 and IgG3 subclass response and found that in our study population IgG1 appeared to be by far the dominant IgG subtype. This is in contrast to previous studies that suggest an IgG subclass ratio skewed towards IgG3 during SARS-CoV-2 infection [33,39]. A possible explanation for this discrepancy is that in these studies the plasma samples were collected shortly after COVID-19 disease recovery, while in our study samples were collected up to 22 weeks after onset of All rights reserved.…”

“…We observed that IgG anti-RBD consisted mainly of IgG1, median for IgG3 is 2.5% (IQR 1.5 – 5.1%; Figure S2A). Since higher subclass ratios were reported for antibodies against the S2 vs S1 domain of the S protein [32, 33], we also tested IgG1 and IgG3 in a subset of samples against the full S protein, but we obtained very similar results (Figure S2B).…”

“…perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 6, 2021. ; https://doi.org/10.1101/2021.01.06.20249035 doi: medRxiv preprint 7 reported for antibodies against the S2 vs S1 domain of the S protein [32,33], we also tested IgG1 and IgG3 in a subset of samples against the full S protein, but we obtained very similar results (Figure S2B).…”

Antibody (IgA, IgG, and IgG Subtype) Responses to SARS-CoV-2 in Severe and Nonsevere COVID-19 Patients

“…More importantly, Yates et. al demonstrated spike-specific IgG1, and not IgG3 was closely correlated with in vitro viral neutralization, and greater proportion of S1 or RBD-specific IgG3 was associated with COVID-19 disease severity (32). The dynamics of IgG1 and IgG3 was similar to IgG when duration or severity was considered, with IgG1 showing no difference in the third week.…”

Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19

“…Alveolar capillary microthrombi are nine times more prevalent in COVID-19 than in influenza autopsies (Lax et al, 2020). Patients exhibit elevated D-dimer levels and widespread thrombotic microvascular injury (De Voeght et al, 2020;Rapkiewicz et al, 2020). Several studies suggest altered platelet immune cell interactions (Leppkes et al, 2020, Manne et al, 2020 and the presence of megakaryocytes (MKs) in affected lungs (Meyerholz and McCray, 2020).…”