COVID-19 pandemic caused by SARS-CoV-2 infection has an impact on global public health and social economy. The emerging immune escape of SARS-CoV-2 variants pose great challenges to the development of vaccines based on original strains. The development of second-generation COVID-19 vaccines to induce immune responses with broad-spectrum protective effects is a matter of great urgency. Here, a prefusion-stabilized spike (S) trimer protein based on B.1.351 variant was expressed and prepared with CpG7909/aluminum hydroxide dual adjuvant to investigate the immunogenicity in mice. The results showed that the candidate vaccine could induce a significant receptor binding domain-specific antibody response and a substantial interferon-γ-mediated immune response. Furthermore, the candidate vaccine also elicited robust cross-neutralization against the pseudoviruses of the original strain, Beta variant, Delta variant and Omicron variant. The vaccine strategy of S-trimer protein formulated with CpG7909/aluminum hydroxide dual adjuvant may be considered a means to increase vaccine effectiveness against future variants.