Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

Abstract

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an “original antigenic sin” type response.

SARS-CoV-2 infections elicit higher levels of original antigenic sin antibodies compared with SARS-CoV-2 mRNA vaccinations

“…We previously found that antibodies against the FL-S of the common OC43 β-hCoV are boosted upon SARS-CoV-2 infection in hospitalized patients with severe disease ( Anderson et al., 2021 ). Other studies have also shown that levels of antibodies against β-hCoVs including both OC43 and HKU1 are higher in COVID-19 patients compared with healthy donors ( Aydillo et al., 2021 ; Bangaru et al., 2022 ; Grobben et al., 2021 ; McNaughton et al., 2022 ; Roltgen et al., 2022 ; Shrock et al., 2020 ; Song et al., 2021 ). Consistent with these findings, we found that antibodies reactive to the FL-S of the common OC43 and HKU1 β-hCoVs increased upon SARS-CoV-2 infections in health care workers, while antibodies to the FL-S of the common 229E α-hCoV did not ( Figure 2 A).…”

“…Francis found that antibodies elicited by influenza vaccines often bound strongly to influenza virus strains that an individual was exposed to in childhood, although it is not apparent if these recalled influenza virus antibody responses typically occur at the expense of producing de novo antibodies (as we reviewed here [ Cobey and Hensley, 2017 ]) The functional consequences of eliciting low-affinity S2-reactive antibodies following SARS-CoV-2 infections are unclear. Our previous studies found no correlation between OC43-reactive antibody induction and disease outcome following SARS-CoV-2 infection ( Anderson et al., 2021 ), but recent studies have suggested that the recall of OC43-reactive antibodies is associated with a compromised de novo SARS-CoV-2 response in individuals with fatal COVID-19 ( McNaughton et al., 2022 ) and that recalled β-hCoV-specific immunoglobulin G (IgG) antibodies are unable to neutralize SARS-CoV-2 ( Aguilar-Bretones et al., 2021 ). Further studies are required to determine how the induction of different types of hCoV and SARS-CoV-2 antibodies affect disease outcome following SARS-CoV-2 infections.…”

“…It is unknown if the recall of β-hCoV antibodies upon SARS-CoV-2 infections impacts disease outcome. A recent study suggests that the recall of OC43 β-hCoV antibodies is associated with a compromised de novo SARS-CoV-2 response in individuals with fatal COVID-19 ( McNaughton et al., 2022 ).…”

Vaccine-associated enhanced disease in humans and animal models: Lessons and challenges for vaccine development

“…T-cell-mediated recall of primary responses to the detriment of de novo responses to a new antigen has been described for other viruses (Klenerman and Zinkernagel, 1998). Although initial observations were not confirmed in subsequent studies, in the context of coronaviruses, it was suggested that previous exposure to non-pandemic seasonal coronaviruses (HKU1, NL63, OC43, and 229E) that cause common coldlike symptoms or other pandemic coronaviruses (SARS-CoV-1, MERS-CoV) may lead to the exacerbation of COVID-19 upon subsequent exposure to SARS-CoV-2 (Focosi et al, 2021;McNaughton et al, 2022). Extension of this notion led to the early presupposed idea that COVID-19 disease might be more severe in adults than in children due to magnified exposure to coronaviruses throughout their lifespan and associated preexisting cross-reactive non-neutralizing antibodies (Fierz and Walz, 2020).…”

Combination therapy of infliximab and thiopurines, but not monotherapy with infliximab or vedolizumab, is associated with attenuated IgA and neutralisation responses to SARS-CoV-2 in inflammatory bowel disease

“…IgG responses to whole spike, receptor binding domain and nucleocapsid following SARS-CoV-2 detection in patients with IBD and healthy controls. (A) IgG SARS-CoV-2 spike responses measured by high-throughput V-PLEX MSD ELISA 8. (B) IgG SARS-CoV-2 receptor binding domain (RBD) of the spike responses measured by V-PLEX MSD.…”