Abstract
Current mRNA vaccines against SARS-CoV-2 effectively induce systemic and cell-mediated immunity and prevent severe disease. However, they do not induce mucosal immunity that targets the primary route of respiratory infection, and their protective effects wane after a few months. Intranasal vaccines have some advantages, including their non-invasiveness and the additional ability to activate mucosal immunity. In this study, we aimed to explore the effectiveness of an intranasally inoculated spike protein of SARS-CoV-2 mixed with a carboxy-vinyl polymer (S-CVP), a viscous agent. Intranasally inoculated S-CVP strongly induced antigen-specific IgG, including neutralizing antibodies, in the mucosal epithelium and serum and cellular immunity compared to the spike protein mixed with aluminum potassium sulfate. Furthermore, IgA production was detected only with S-CVP vaccination. S-CVP-inoculation in mice significantly suppressed the viral load and inflammation in the lung and protected mice against SARS-CoV-2 challenges, including an early circulating strain and the Omicron BA.1 variant in a manner dependent on CD8+ cells and monocytes/neutrophils. Surprisingly, high antibody responses and protective effects against multiple variants of SARS-CoV-2, including Omicron BA.5, persisted for at least 15 months after the S-CVP immunization. Hence, we propose intranasal inoculation with S-CVP as a promising vaccine strategy against SARS-CoV-2.