Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses
Anna L. McNaughton, … , Sunetra Gupta, Craig P. Thompson
Anna L. McNaughton, … , Sunetra Gupta, Craig P. Thompson
Published May 24, 2022
Citation Information: JCI Insight. 2022;7(13):e156372. https://doi.org/10.1172/jci.insight.156372.
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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.

Authors

Anna L. McNaughton, Robert S. Paton, Matthew Edmans, Jonathan Youngs, Judith Wellens, Prabhjeet Phalora, Alex Fyfe, Sandra Belij-Rammerstorfer, Jai S. Bolton, Jonathan Ball, George W. Carnell, Wanwisa Dejnirattisai, Christina Dold, David W. Eyre, Philip Hopkins, Alison Howarth, Kreepa Kooblall, Hannah Klim, Susannah Leaver, Lian Ni Lee, César López-Camacho, Sheila F. Lumley, Derek C. Macallan, Alexander J. Mentzer, Nicholas M. Provine, Jeremy Ratcliff, Jose Slon-Compos, Donal Skelly, Lucas Stolle, Piyada Supasa, Nigel Temperton, Chris Walker, Beibei Wang, Duncan Wyncoll, Oxford Protective T Cell Immunology for COVID-19 (OPTIC) consortium, Scottish National Blood Transfusion Service (SNBTS) consortium, Peter Simmonds, Teresa Lambe, John Kenneth Baillie, Malcolm G. Semple, Peter J.M. Openshaw, International Severe Acute Respiratory and emerging Infection Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) investigators, Uri Obolski, Marc Turner, Miles Carroll, Juthathip Mongkolsapaya, Gavin Screaton, Stephen H. Kennedy, Lisa Jarvis, Eleanor Barnes, Susanna Dunachie, José Lourenço, Philippa C. Matthews, Tihana Bicanic, Paul Klenerman, Sunetra Gupta, Craig P. Thompson

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Figure 5

Antibody responses are directed against the S2 subunit of the HCoV-OC43 spike protein.

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Antibody responses are directed against the S2 subunit of the HCoV-OC43 ...
(A) Fold change in responses to various domains/subunits in the HCoV-OC43 spike protein and nucleocapsid. Indirect ELISAs were used to analyze responses to the NTD, S1 subunit and S2 subunit of the HCoV-OC43 spike protein, in addition to the HCoV-OC43 nucleocapsid. Fold change via ELISA was determined relative to the average value in the SARS-CoV-2 antibody-negative blood donor cohort as indicated by the gray division in the figure. Antibody levels are increased against all antigens apart from the nucleocapsid, with the largest increase in antibody response to the S2 subunit of the spike protein. (B) Correlation in responses between SARS-CoV-2 antigens and HCoV-OC43 spike protein domains and nucleocapsid. The log-scale OD405 values from the HCoV-OC43 spike and nucleocapsid ELISAs (along the rows) is compared to the MSD V-PLEX SARS-CoV-2 results (columns). A linear model fit on the log-scale is annotated with the associated 95% confidence intervals and R2 and P values. Values and model fits for the nonfatal COVID-19 outcomes group are given in purple, while red is used for the fatal outcome group. The HCoV-OC43 S2 subunit ELISA result is only correlated with the concentration of SARS-CoV-2 antibodies in the fatal group. (C) Correlations between ELISA and MSD V-PLEX SARS-CoV-2 assay responses. Responses to the S2 subunit of HCoV-OC43 are strongly correlated with the MSD concentration of SARS-CoV-2 antibodies in those who died from COVID-19 but not those who survived. Notably, there is a positive correlation between the S2 subunit response and the HCoV-OC43 and HCoV-HKU1 spike responses in the fatal COVID-19 outcome group. t tests were used to assess significance, and the reported P values were adjusted for multiple comparisons using the Holm-Bonferroni method, in A. Spearman’s rank correlations (ρ) are shown for each pair of antigens in B and C.