A SARS-CoV-2 variant-induced NTD-targeting antibody enhances viral infection via a distinctive binding mode

SARS-CoV-2 infection elicits both neutralizing and non-neutralizing monoclonal antibodies (mAbs), primarily targeting to the N-terminal domain (NTD), receptor-binding domain (RBD), and S2 subunit of the spike protein. Notably, a unique subset of NTD-targeting mAbs isolated from prototype Wuhan-Hu-1 strain infected donors displayed a capacity of facilitating the viral infection independent of the fragment crystallizable (Fc) region in vitro. However, the rapid evolution of SARS-CoV-2 variants, particularly with NTD mutations, has led to widespread immune evasion. Whether SARS-CoV-2 variants could still induce NTD-targeting infection-enhancing antibodies (NIEAs) remains unclear. Here, we identified a distinctive NIEA, ConD-854, from a Delta variant primarily infected donor, with broad infection-enhancing activities against most pre-Omicron variants but not against post-Omicron variants. Structural and functional analysis revealed that ConD-854 enhanced the viral infection through an Fc-independent bivalent binding mechanism with a largely shared recognition epitope, but its heavy-light chain orientation was nearly perpendicular relative to the reported prototype strain-induced NIEAs. Collectively, our findings demonstrated that the primary infection of Delta variant could still induce the NIEAs targeting the similar epitope as those elicited by prototype strain infection. Mutations in Delta NTD were located outside the infection-enhancing epitope and did not affect the induction of NIEAs. Remarkably, we defined a distinctive structural paradigm for an NIEA to recognize the viral epitope. These results enriched our understanding of antiviral antibodies and provided insights for future vaccine design.