In the past few years, the continuous pandemic of COVID-19 caused by SARS-CoV-2 has placed a huge burden on public health. In order to effectively deal with the emergence of new SARS-CoV-2 variants, it becomes meaningful to further enhance the immune responses of individuals who have completed the first-generation vaccination. To understand whether sequential administration using different variant sequence-based inactivated vaccines could induce better immunity against the forthcoming variants, we tried five inactivated vaccine combinations in a mouse model and compared their immune responses. Our results showed that the sequential strategies have a significant advantage over homologous immunization by inducing robust antigen-specific T cell immune responses in the early stages of immunization. Furthermore, the three-dose vaccination strategies in our research elicited better neutralizing antibody responses against the BA.2 Omicron strain. These data provide scientific clues for finding the optimal strategy within the existing vaccine platform in generating cross-immunity against multiple variants including previously unexposed strains.