Severe COVID-19 patients display a back boost of seasonal coronavirus-specific antibodies

Abstract

Severe acquired respiratory syndrome coronavirus-2 (SARS-CoV-2) is the cause of coronavirus disease (COVID-19). In severe COVID-19 cases, higher antibody titers against seasonal coronaviruses have been observed than in mild cases. To investigate antibody cross-reactivity as potential explanation for severe disease, we determined the kinetics, breadth, magnitude and level of cross-reactivity of IgG against SARS-CoV-2 and seasonal CoV nucleocapsid and spike from 17 severe COVID-19 cases at the clonal level. Although patients mounted a mostly type-specific SARS-CoV-2 response, B-cell clones directed against seasonal CoV dominated and strongly increased over time. Seasonal CoV IgG responses that did not neutralize SARS-CoV-2 were boosted well beyond detectable cross-reactivity, particularly for HCoV-OC43 spike. These findings support a back-boost of poorly protective coronavirus-specific antibodies in severe COVID-19 patients that may negatively impact de novo SARS-CoV-2 immunity, reminiscent of original antigenic sin.

Humoral Responses and Serological Assays in SARS-CoV-2 Infections

“…Such responses have been shown for influenza and dengue virus and are associated with poor virus neutralization and can have profound consequences on vaccine efficacy (190)(191)(192)(193). For SARS-CoV-2 infections, a number of studies have now reported back-boosting of non-neutralizing sCoV antibody production (116,118,167,194,195). These antibodies appear to be most prominently targeted against conserved epitopes in OC43 and HKU1, both betacoronaviruses (194,195).…”

“…For SARS-CoV-2 infections, a number of studies have now reported back-boosting of non-neutralizing sCoV antibody production (116,118,167,194,195). These antibodies appear to be most prominently targeted against conserved epitopes in OC43 and HKU1, both betacoronaviruses (194,195). Interestingly, none of these studies presented evidence that a sCoV antibody boost was associated with either protection against SARS-CoV-2 infection or COVID-19 severity.…”

“…Interestingly, none of these studies presented evidence that a sCoV antibody boost was associated with either protection against SARS-CoV-2 infection or COVID-19 severity. In fact, a negative correlation was observed in some studies, providing additional support to a disfavorable consequence of immunological imprinting (194,195). Given that most of the leading SARS-CoV-2 vaccine candidates being currently developed use the full (S1-S2) spike protein as the primary viral antigen, special consideration needs to be given as to whether inclusion of the S2 domain will be a factor that that impedes vaccine efficacy.…”

Immunogenicity and crossreactivity of antibodies to the nucleocapsid protein of SARS-CoV-2: utility and limitations in seroprevalence and immunity studies

“…[40][41][42] Alternatively, these preexisting crossreactive antibodies could interfere with the development and/or maintenance of effective levels of anti-SARS-CoV-2 antibodies 43,44 and, even worse, they could have a negative impact by mediating antibody-dependent disease enhancement (ADE), 45,46 which could be associated with severe prognosis. 47,48 Our study aimed to better characterize the immunogenicity, specificity and crossreactivity of anti-N antibodies from SARS-CoV-2 and 229E, HKU1, NL63, and OC43 HCoV, measured simultaneously. To this end, we tested several antigenic fragments in multiplex to measure different immunoglobulin (Ig) isotypes, and compared their relative immunogenicity in prepandemic and pandemic samples, including SARS-CoV-2 positive cases.…”

Decay of Fc-dependent antibody functions after mild to moderate COVID-19

“…Cross-reactive antibodies between endemic human coronaviruses (HCoV) and SARS-CoV-2 have been widely reported ( 27, 28 ), suggesting past exposure to HCoVs may prime ADCC and ADP immunity against SARS-CoV-2. In addition, several studies have shown back-boosting of antibodies against endemic human coronaviruses (HCoV) following infection with SARS-CoV-2 ( 29, 30 ), likely due to the recall of pre-existing B cell responses against conserved regions of S. We thus determined whether IgG antibodies against S from four HCoV strains (OC43, HKU1, 229E and NL63) (Table S2) were boosted in COVID-19 convalescent subjects compared to uninfected healthy controls. We found that COVID-19 convalescent subjects had increased IgG antibodies against S from the betacoronaviruses OC43 and HKU1 (that are more closely related to SARS-CoV-2) at the first timepoint sampled compared to uninfected controls (Fig S7), while there was no difference in IgG levels against S from the alphacoronaviruses 229E and NL63.…”