ABSTRACT
Prevention and intervention methods are urgently needed to curb the global pandemic of coronavirus disease-19 caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Herein, a general pro-antigen strategy for subunit vaccine development based on the reversibly formulated receptor binding domain of SARS-CoV-2 spike protein (S-RBD) is reported. Since the poor lymph node targeting and uptake of S-RBD by antigen-presenting cells prevent effective immune responses, S-RBD protein is formulated into a reversible nanogel (S-RBD-NG), which serves as a pro-antigen with enhanced lymph node targeting and dendritic cell and macrophage accumulation. Synchronized release of S-RBD monomers from the internalized S-RBD-NG pro-antigen triggers more potent immune responses in vivo. In addition, by optimizing the adjuvant used, the potency of S-RBD-NG is further improved, which may provide a generally applicable, safer, and more effective strategy for subunit vaccine development against SARS-CoV-2 as well as other viruses.
Subject(s)
Antigens, Viral/immunology , COVID-19/immunology , COVID-19/prevention & control , Immunity , Nanogels/chemistry , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/metabolism , Animals , COVID-19/virology , Cell Line , Dendritic Cells/metabolism , Immunization , Lymph Nodes/immunology , Macrophages/metabolism , Mice , Nanogels/ultrastructure , Neutralization Tests , Protein Domains , Spike Glycoprotein, Coronavirus/chemistryABSTRACT
Flexible multivalent 3D nanosystems that can deform and adapt onto the virus surface via specific ligand-receptor multivalent interactions can efficiently block virus adhesion onto the cell. We here report on the synthesis of a 250â nm sized flexible sialylated nanogel that adapts onto the influenza A virus (IAV) surface via multivalent binding of its sialic acid (SA) residues with hemagglutinin spike proteins on the virus surface. We could demonstrate that the high flexibility of sialylated nanogel improves IAV inhibition by 400 times as compared to a rigid sialylated nanogel in the hemagglutination inhibition assay. The flexible sialylated nanogel efficiently inhibits the influenza A/X31 (H3N2) infection with IC50 values in low picomolar concentrations and also blocks the virus entry into MDCK-II cells.