AbstractVarious vaccines have been challenged by SARS‐CoV‐2 variants. Here, we reported a yeast‐derived recombinant bivalent vaccine (Bivalent wild‐type [Wt]+De) based on the wt and Delta receptor‐binding domain (RBD). Yeast derived RBD proteins based on the wt and Delta mutant were used as the prime vaccine. It was found that, in the presence of aluminium hydroxide (Alum) and unmethylated CpG‐oligodeoxynucleotides (CpG) adjuvants, more cross‐protective immunity against SARS‐CoV‐2 prototype and variants were elicited by bivalent vaccine than monovalent wtRBD or Delta RBD. Furthermore, a heterologous boosting strategy consisting of two doses of bivalent vaccines followed by one dose adenovirus vectored vaccine exhibited cross‐neutralization capacity and specific T cell responses against Delta and Omicron (BA.1 and BA.4/5) variants in mice, superior to a homologous vaccination strategy. This study suggested that heterologous prime‐boost vaccination with yeast‐derived bivalent protein vaccine could be a potential approach to address the challenge of emerging variants.