Intranasal peptide- and siRNA- based dendritic cell-targeted nano-vaccine against SARS-CoV-2

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to tremendously affect all life aspects. Unfortunately, we still experience waves of increased morbidity of COVID-19 due to highly infectious SARS-CoV-2 variants that have evaded the neutralizing antibodies generated by the current vaccines. In addition, the low vaccination rate in developing countries, partially attributed to the immunization supply cold-chain of the current vaccines, contributes to the evolution of novel vaccines1. These hurdles point to the global demand for novel vaccines based on technologies with long shelf-life at room temperature (RT), such as lyophilized vaccines. Here, we report the development of a specific, stable, safe, and immunogenic next-generation peptide- and siRNA- based nano-vaccine (NV) against COVID-19 that can be administered intranasally. To develop this NV, we selected two immunogenic SARS-CoV-2 peptide antigens by bioinformatics approaches. The chosen combination was proven to efficiently upregulate DC activation and expansion, which resulted in strong induction of antigen-specific T-and B-cell immunities against SARS-CoV-2, including neutralizing antibodies that blocked viral infection against all five variants. Moreover, our NV generated immunological memory and secreted anti-SARS-CoV-2 antibodies upon re-challenge with SARS-CoV-2 proteins. In addition, the coordinated regulation of the PD-L1/PD-1 pathway by siRNA, and the multivalent peptide presentation by DC were enabled by this NV. The long-term stability at RT and the needle-free administration of our NV make it a relevant candidate for increasing global vaccination in low-income countries, a crucial step to contain the current SARS-CoV-2 virus and thereby prevent the development of new variants.