Coronavirus nucleocapsid-based vaccine provides partial protection against hetero-species coronavirus in murine models

Most coronavirus vaccines focus on the spike (S) antigen, but the frequent mutations in S raise concerns about the vaccine efficacy against new variants. Although additional antigens with conserved sequences are have been tested, the extent to which these vaccines can provide immunity against different coronavirus species remains unclear. In this study, we assessed the potential of nucleocapsid (N) as a coronavirus vaccine antigen. Immunization with MERS-CoV N induced robust immune responses, providing significant protection against MERS-CoV. Notably, MERS-CoV N elicited cross-reactive T cell responses to SARS-CoV-2 N and significantly reduced lung inflammation following a SARS-CoV-2 challenge in the transient hACE2 mouse model. However, in K18-hACE transgenic mice, the vaccine showed limited protection. Collectively, our findings suggest that coronavirus N can be an effective vaccine antigen against homologous viruses, but its efficacy may vary across different coronaviruses, highlighting the need for further research on pan-coronavirus vaccines using conserved antigens. •DNA vaccines expressing MERS-CoV Nucleocapsid protein induces MERS-CoV-specific antibody and T cell responses.•MERS-CoV N provide protection against lethal MERS-CoV infection.•MERS-CoV N also induces immune responses that cross-react with the other β-coronaviruses such as SARS-CoV and SARS-CoV-2.•MERS-CoV N-based vaccine offers partial or limited protection against SARS-CoV-2 infection depending on host susceptibility.