Dynamic Covalent Hydrogel as a Single‐Dose Vaccine Adjuvant for Sustained Antigen Release and Significantly Elevated Humoral Immunity

Abstract Vaccine is the most important way for fighting against infection diseases. However, multiple injections and unsatisfied immune responses are the main obstacles for current vaccine application. Herein, a dynamic covalent hydrogel (DCH) is used as a single‐dose vaccine adjuvant for eliciting robust and sustained humoral immunity. By adjusting the mass ratio of the DCH gel, 10–30 d constant release of the loaded recombinant protein antigens is successfully realized, and it is proved that sustained release of antigens can significantly improve the vaccine efficacy. When loading SARS‐CoV‐2 RBD (Wuhan and Omicron BA.1 strains) antigens into this DCH gel, an over 32 000 times and 8000 times improvement is observed in antigen‐specific antibody titers compared to conventional Aluminum adjuvanted vaccines. The universality of this DCH gel adjuvant is confirmed in a Nipah G antigen test as well as a H1N1 influenza virus antigen test, with much improved protection of C57BL/6 mice against H1N1 virus infection than conventional Aluminum adjuvanted vaccines. This sustainably released, single‐dose DCH gel adjuvant provides a new promising option for designing next‐generation infection vaccines.