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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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Research Article Immunology Infectious disease

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

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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 3

Neutralizing antibody levels correlate with disease severity.

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Neutralizing antibody levels correlate with disease severity.
(A) Neutra...
(A) Neutralizing antibody levels. Neutralization titers were higher in the individuals admitted to the ICU with COVID-19. There was no significant difference between individuals admitted to an ICU with fatal or nonfatal COVID-19 outcomes (t test: P = 0.99). (B) ACE2 inhibition assay results. Samples were also analyzed with an MSD R-PLEX ACE2 inhibition assay. The level of ACE2-binding inhibition was not statistically significant for the full-length spike protein, but the individuals admitted to an ICU with fatal COVID-19 outcomes showed statistically lower ACE2-RBD binding inhibition in comparison with the nonfatal ICU cohort (t test: P = 0.02). (C) Neutralizing antibody levels as a proportion of total spike antibody response. There was no statistically significant difference between any of the groups. (D) ACE2-binding inhibition as a proportion of total spike antibody response. ACE2-binding inhibition responses were significantly lower in individuals with fatal COVID-19 outcomes in comparison with those with nonfatal COVID-19 outcomes when measured by the R-PLEX full-length spike but not the RBD inhibition assays (t test: RBD; P = 0.25, spike; P = 0.018). t tests were used to assess significance, and the reported P values were adjusted for multiple comparisons using the Holm-Bonferroni method. *P < 0.05, ****P < 0.0001.

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