Constructing the cGAMP‐Aluminum Nanoparticles as a Vaccine Adjuvant‐Delivery System (VADS) for Developing the Efficient Pulmonary COVID‐19 Subunit Vaccines

Abstract The cGAMP‐aluminum nanoparticles (CAN) are engineered as a vaccine adjuvant‐delivery system to carry mixed RBD (receptor‐binding domain) of the original severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its new variant for developing bivalent pulmonary coronavirus disease 2019 (COVID‐19) vaccines (biRBD‐CAN). High phosphophilicity/adsorptivity made intrapulmonary CAN instantly form the pulmonary ingredient‐coated CAN (piCAN) to possess biomimetic features enhancing biocompatibility. In vitro biRBD‐CAN sparked APCs (antigen‐presenting cells) to mature and make extra reactive oxygen species, engendered lysosome escape effects and enhanced proteasome activities. Through activating the intracellular stimulator of interferon genes (STING) and nucleotide‐binding domain and leucine‐rich repeat and pyrin domain containing proteins 3 (NALP3) inflammasome pathways to exert synergy between cGAMP and AN, biRBD‐CAN stimulated APCs to secret cytokines favoring mixed Th1/Th2 immunoresponses. Mice bearing twice intrapulmonary biRBD‐CAN produced high levels of mucosal antibodies, the long‐lasting systemic antibodies, and potent cytotoxic T lymphocytes which efficiently erased cells displaying cognate epitopes. Notably, biRBD‐CAN existed in mouse lungs and different lymph nodes for at least 48 h, unveiling their sustained immunostimulatory activity as the main mechanism underlying the long‐lasting immunity and memory. Hamsters bearing twice intrapulmonary biRBD‐CAN developed high resistance to pseudoviral challenges performed using different recombinant strains including the ones with distinct SARS‐CoV‐2‐spike mutations. Thus, biRBD‐CAN as a broad‐spectrum pulmonary COVID‐19 vaccine candidate may provide a tool for controlling the emerging SARS‐CoV‐2 variants.