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

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 coronavirus disease (COVID-19) outcomes 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 intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal 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 ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response

DIII vaccination induces DENV-specific neutralising antibodies.

<p>A) Neutralisation and ADE of all four DENV serotypes, ZIKV, WNV and YFV, with DENV anti-DIII sera. To prove anti-DIII reactivity, DENV viruses were tested using pooled sera against the homologous serotypes, while non-DENV viruses were tested against all four anti-DIII sera (in all cases, n = 3 for each virus-sera combination). B) FRNT₅₀ titres, as determined in (A), * indicates FRNT₅₀ titres below detection limit of the assay (≥25).</p

Reactivity profiles of anti-DENV sera in DENV-infected cells.

<p>Immunofluorescence of Vero cells infected with all four DENV serotypes and reacted with antibodies elicited with 3sE and 4sE or the corresponding 3DI/DII and 4DI/DII. mAb 4G2, the homologous anti-DIII and the tetravalent anti-DIII sera were included as controls to show reactivity towards each serotype. N.I., non-infected cells; P.I., pre-immune serum. Bar, 30 μm. Representative images from independent experiments are shown.</p

DENV-DIII tetravalent vaccine formulation elicits DENV-specific neutralising antibodies.

<p>A) Neutralisation and ADE of all four DENV serotypes, ZIKV, WNV and YFV, with pooled sera from mice vaccinated with the Tetra-DIII formulation (in all cases, for each virus-sera combination n = 3). B) FRNT₅₀, as determined in (A), * indicates FRNT₅₀ titres below detection limit of the assay (≥25).</p

DENV DI/DII induces poorly-neutralising, highly-enhancing cross-reactive antibodies.

<p>A) Neutralisation and ADE of all four DENV serotypes, ZIKV, WNV and YFV, with DENV anti-3DI/DII and anti-4DI/DII pooled sera (in all cases, n = 3 for each virus-sera combination). B) FRNT₅₀ titres, as determined in (A), * indicates FRNT₅₀ titres below detection limit of the assay (≥25).</p

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

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 coronavirus disease (COVID-19) outcomes 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 intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal 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 ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response