Fc-independent SARS-CoV-2 infection-enhancing antibodies decouple N-terminal and receptor-binding domains by cross-linking neighboring spikes

Antibody dependent enhancement (ADE) is a serious concern in vaccine development. The canonical ADE pathways are dependent on the fragment crystallizable (Fc) region of the antibody. In SARS-CoV-2 several antibodies have been discovered that inflict ADE in vitro. These antibodies target the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. We previously proposed that these NTD-targeting infection-enhancing antibodies (NIEAs) cross-link neighboring spike proteins via their NTDs, and that this results in a decoupling between the NTD and receptor binding domain (RBD), facilitating the "RBD down" to "up" transition. In this study we present a combination of molecular dynamics simulations and cryogenic electron microscopy data that, together, demonstrate that NIEAs are indeed able to cross-link neighboring SARS-CoV-2 spike proteins, and that this cross-linking results in a decoupling of the NTD and RBD domains. These findings provide support for an Fc region independent ADE pathway that is not only relevant for SARS-CoV-2 but also for other viruses of which the spike proteins undergo a conformational change upon host cell entry.