Combining spike- and nucleocapsid-based vaccines improves distal control of SARS-CoV-2

SARS-CoV-2 infection causes respiratory insufficiency and neurological manifestations, including loss of smell and psychiatric disorders, and can be fatal. Most vaccines are based on the spike antigen alone, and although they have shown efficacy at preventing severe disease and death, they do not always confer sterilizing immunity. Here, we interrogate whether SARS-CoV-2 vaccines could be improved by incorporating nucleocapsid as an antigen. We show that, after 72 h of challenge, a spike-based vaccine confers acute protection in the lung, but not in the brain. However, combining a spike-based vaccine with a nucleocapsid-based vaccine confers acute protection in both the lung and brain. These findings suggest that nucleocapsid-specific immunity can improve the distal control of SARS-CoV-2, warranting the inclusion of nucleocapsid in next-generation COVID-19 vaccines. [Display omitted] •SARS-CoV-2 vaccines do not prevent breakthrough infection in K18-ACE2 mice•A spike vaccine confers better protection than a nucleocapsid vaccine•A spike vaccine confers acute protection in lung, but not in brain•Combining spike and nucleocapsid vaccines improves distal protection in brain Most SARS-CoV-2 vaccines are based on the spike antigen alone, and it is unknown whether including other viral antigens improves protection. Dangi et al. show that combining a spike vaccine with a nucleocapsid vaccine improves the control of a SARS-CoV-2 infection, warranting the inclusion of nucleocapsid in next-generation SARS-CoV-2 vaccines.