ABSTRACT Elucidating the detailed features of emerging SARS‐CoV‐2 strains both in vitro and in vivo is indispensable for the development of effective vaccines or drugs against viral infection. We thoroughly characterized the virological and pathogenic features of eight different pandemic SARS‐CoV‐2 strains, from the WT strain to current circulating sublineage EG.5.1, both in vitro and in vivo. Besides detailed virological features observed in Vero E6 cells, the Omicron variants, from BA.1 to EG.5.1, exhibited enhanced infectious effects to upper respiratory tract in K18 human angiotensin‐converting enzyme (ACE2) (K18 hACE2) transgenic mice. Both XBB.1.9.1 and EG.5.1 presented stronger tropism to brain, which could be the main reason for the increased lethal effects on mice. In addition, the pathogenesis comparisons among all these viruses in C57BL/6JGpt mice indicated that Omicron variant BA.1 and two new sublineages XBB.1.9.1 and EG.5.1 possessed dual tropisms to both human and mice, which were further confirmed by subsequent bioinformatic analyses and actual affinity comparison between viral RBDs and mouse or human receptor ACE2. Furthermore, the immunocompromised BKS‐db mice were found to be more susceptible to Omicron strains compared to C57BL/6JGpt mice, which revealed that viral infectivity was determined by both its affinity to the host receptor and host immunocompetence. Thus, this study not only contributes to a systematic understanding of the pathogenic features of SARS‐CoV‐2 in mice, but also provides new insights to combat potential future surges of new SARS‐CoV‐2 variants.

Characterization of the Pathogenic Features of Multiple SARS‐CoV‐2 Pandemic Strains in Different Mouse Models