LAUSR

SARS‐CoV‐2 has evolved into a panel of variants of concern (VOCs) and constituted a sustained threat to global health. The wildtype (WT) SARS‐CoV‐2 isolates fail to infect mice, while the Beta variant, one of the VOCs, has acquired the capability to infect standard laboratory mice, raising a spreading risk of SARS‐CoV‐2 from humans to mice. However, the infectivity and pathogenicity of other VOCs in mice remain not fully understood. In this study, we systematically investigated the infectivity and pathogenicity of three VOCs, Alpha, Beta, and Delta, in mice in comparison with two well‐understood SARS‐CoV‐2 mouse‐adapted strains, MASCp6 and MASCp36, sharing key mutations in the receptor‐binding domain (RBD) with Alpha or Beta, respectively. Our results showed that the Beta variant had the strongest infectivity and pathogenicity among the three VOCs, while the Delta variant only caused limited replication and mild pathogenic changes in the mouse lung, which is much weaker than what the Alpha variant did. Meanwhile, Alpha showed comparable infectivity in lungs in comparison with MASCp6, and Beta only showed slightly lower infectivity in lungs when compared with MASCp36. These results indicated that all three VOCs have acquired the capability to infect mice, highlighting the ongoing spillover risk of SARS‐CoV‐2 from humans to mice during the continued evolution of SARS‐CoV‐2, and that the key amino acid mutations in the RBD of mouse‐adapted strains may be referenced as an early‐warning indicator for predicting the spillover risk of newly emerging SARS‐CoV‐2 variants.