Abstract The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has led to concerns that ancestral SARS-CoV-2-based vaccines may not be effective against newly emerging Omicron subvariants. The concept of “imprinted immunity” suggests that individuals vaccinated with ancestral virus-based vaccines may not develop effective immunity against newly emerging Omicron subvariants, such as BQ.1.1 and XBB.1. In this study, we investigated this possibility using hamsters. Although natural infection induced effective antiviral immunity, breakthrough infections in hamsters with BQ.1.1 and XBB.1 Omicron subvariants after receiving the 3-dose mRNA-lipid nanoparticle vaccine resulted in only faintly induced humoral immunity, supporting the possibility of imprinted immunity. The emergence of SARS-CoV-2 Omicron XBB subvariants raises vaccine effectiveness concerns. Our hamster model demonstrated that ancestral virus-based vaccines failed to produce effective neutralizing antibodies against Omicron subvariants (eg, BQ.1.1, XBB.1) during breakthrough infections, supporting the concept of imprinted immunity.