Abstract
Severe COVID-19 associates with humoral immune response dysregulation. While antibodies confer protection against SARS-CoV-2, evidence also support their putative contribution to disease severity. Our study demonstrates that higher levels of S2-IgG, and S2-, RBD-, and Nucleocapsid-IgA differentiate severe and non-severe cases. However, no major antibody functional differences are found between both COVID-19 manifestations. Enhanced Fc-dependent functions in severe cases are primarily driven by increased antibody titers. No differences in antibody avidity are found between severe and non-severe cases, but a gradation in binding strength across specificities suggests that early anti-RBD, -S2, and -Nucleocapsid antibodies may originate from different pathways. In golden Syrian hamsters, S2 immunization or transfer of RBD-depleted antibodies isolated from severe and non-severe cases promote a faster clinical recovery after SARS-CoV-2 challenge, despite a transient initial weight loss. These findings indicate that antibodies are not major determinants of COVID-19 severity and suggest additional factors influencing disease outcomes.