Contributing to research themes:
The SARS-CoV-2 spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogate whether nucleocapsid-specific antibodies can improve protection against SARSCoV-2. We first immunized mice with a nucleocapsid-based vaccine, and then transferred sera from these mice into naïve mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific monoclonal antibody (mAb) exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated antibodydependent cellular cytotoxicity (ADCC) against infected cells. These findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based monoclonal antibody therapies to treat COVID-19.