Membrane-targeted immunogenic compositions using exosome mimetic approach for vaccine development against SARS-CoV-2...

The COVID-19 pandemic has underscored the urgent need for a vaccine strategy that is safe, effective, rapid, cost-efficient, and scalable for large-scale deployment during widespread infectious outbreaks. Here, we present a new vaccination strategy that meets these critical requirements. The SARS-CoV-2 S protein consists of the S1 and S2 subunits. The S2 subunit acts as the viral cell membrane fusion protein, and mutations in its C-terminal region facilitate the transport of the entire S protein to the cell membrane. When we expressed the SARS-CoV-2 S protein with a deletion of 21 amino acids from its C-terminal region in various cell types, we observed a dense presence of the protein in the cell membrane, as determined by IHC, dot blot, and ELISA. In the cell membrane-SARS-CoV-2 S protein complex, the cell membrane functions as an exosome mimic, carrying protein antigens (S protein) in their most natural form, as no further protocols are used to attach antigens to the membrane. We demonstrate that using the membrane-S protein component as a vaccine yields a more robust and protective immune response, with enhanced safety compared to mRNA-based or inactivated virus-based vaccines against SARS-CoV-2. Additionally, we show that fusing the transmembrane domain of the Vesicular Stomatitis Virus (VSV) G protein with the SARS-CoV-2 S1 protein effectively transports the S1 protein to the cell membrane, similar to SARS-CoV-2 S Δ21. We propose that designing the S2 subunit of the SARS-CoV-2 S protein, or its analogues such as the VSV-G protein, as carriers for fusing bacterial, viral, or tumor proteins with antigenic properties-and transporting them to the cell membrane-could result in a comprehensive vaccination protocol applicable to all bacteria, viruses, and even tumors.