LAUSR

Global coronavirus disease 2019 (COVID‐19) pandemics highlight the need of developing vaccines with universal and durable protection against emerging SARS‐CoV‐2 variants. Here we developed an extended‐release vaccine delivery system (GP‐diABZI‐RBD), consisting the original SARS‐CoV‐2 WA1 strain receptor‐binding domain (RBD) as the antigen and diABZI stimulator of interferon genes (STING) agonist in conjunction with yeast β‐glucan particles (GP‐diABZI) as the platform. GP‐diABZI‐RBD could activate STING pathway and inhibit SARS‐CoV‐2 replication. Compared to diABZI‐RBD, intraperitoneal injection of GP‐diABZI‐RBD elicited robust cellular and humoral immune responses in mice. Using SARS‐CoV‐2 GFP/ΔN transcription and replication‐competent virus‐like particle system (trVLP), we demonstrated that GP‐diABZI‐RBD‐prototype vaccine exhibited the strongest and durable humoral immune responses and antiviral protection; whereas GP‐diABZI‐RBD‐Omicron displayed minimum neutralization responses against trVLP. By using pseudotype virus (PsVs) neutralization assay, we found that GP‐diABZI‐RBD‐Prototype, GP‐diABZI‐RBD‐Delta, and GP‐diABZI‐RBD‐Gamma immunized mice sera could efficiently neutralize Delta and Gamma PsVs, but had weak protection against Omicron PsVs. In contrast, GP‐diABZI‐RBD‐Omicron immunized mice sera displayed the strongest neutralization response to Omicron PsVs. Taken together, the results suggest that GP‐diABZI can serve as a promising vaccine delivery system for enhancing durable humoral and cellular immunity against broad SARS‐CoV‐2 variants. Our study provides important scientific basis for developing SARS‐CoV‐2 VOC‐specific vaccines.