By the end of 2021, the Omicron mutant of SARS-CoV-2 rapidly replaced the Delta mutant and became widely prevalent worldwide. Its S protein was mutated at 36 sites, resulting in significant changes in virulence and transmissibility, and was capable of immune escape. Both human and animal studies showed that the Omicron mutant was less virulent than the previous circulating strains. Vaccination is currently the most common means of epidemic prevention and control. Studies have found that the protection of vaccines against Omicron mutant strains has significantly decreased. Therefore, animal models are needed to evaluate the effectiveness of new immunization strategies or specific/polyvalent vaccines against Omicron. Animal experiments showed that booster immunization can prevent Omicron infection to a certain extent, which is one of the important directions to explore the immunization strategy against Omicron mutant. Besides, protective effects of specific and polyvalent vaccines have also been preliminarily confirmed, and subsequent preclinical trials are progressing. The development of polyvalent vaccines against existing and potential mutant strains is of great significance for epidemic prevention and control. In laboratory conditions, using animal model to carry out live virus attack experiment is a key technical means to verify the effectiveness of protective neutralizing antibody and vaccine in vivo. This article will review the research progress of vaccine against Omicron variant strain from the direction of animal model.