The Omicron variant of SARS-CoV-2, which emerged in late 2021, has 37 amino acid substitutions in its spike protein, with 15 in the receptor-binding domain (RBD). These mutations raise concerns about the effectiveness of existing vaccines and antibody-based therapies. The study shows that the Omicron RBD binds to human ACE2 with increased affinity compared to the Wuhan-Hu-1 RBD and also binds to mouse ACE2. Neutralizing activity against Omicron is significantly reduced in plasma from convalescent individuals and vaccinated people, though this loss is less pronounced after a third dose of vaccine. Most monoclonal antibodies targeting the RBD lose neutralizing activity against Omicron, with only three retaining potency. However, some broadly neutralizing antibodies, such as S2K146, S2X259, and S2H97, neutralize Omicron by recognizing antigenic sites outside the RBD. These findings indicate a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize conserved RBD epitopes may be key to controlling the pandemic and future zoonotic spillovers. The evolution of RNA viruses can lead to immune evasion and receptor binding changes through mutations. Previous SARS-CoV-2 variants, such as Beta and Delta, showed resistance to neutralizing antibodies. Omicron, with its high number of mutations, has a significant immune evasion capacity. The study also shows that Omicron can infect mice, suggesting a potential for cross-species transmission. The neutralizing activity of several therapeutic monoclonal antibodies is reduced or abolished against Omicron. The study highlights the importance of developing broadly neutralizing antibodies that target conserved epitopes to counteract antigenic shifts and future viral variants. The findings suggest that the Omicron variant has undergone a significant antigenic shift, which may impact vaccine efficacy and therapeutic strategies. The study provides insights into the mechanisms of immune evasion by Omicron and the potential of broadly neutralizing antibodies in combating the virus.The Omicron variant of SARS-CoV-2, which emerged in late 2021, has 37 amino acid substitutions in its spike protein, with 15 in the receptor-binding domain (RBD). These mutations raise concerns about the effectiveness of existing vaccines and antibody-based therapies. The study shows that the Omicron RBD binds to human ACE2 with increased affinity compared to the Wuhan-Hu-1 RBD and also binds to mouse ACE2. Neutralizing activity against Omicron is significantly reduced in plasma from convalescent individuals and vaccinated people, though this loss is less pronounced after a third dose of vaccine. Most monoclonal antibodies targeting the RBD lose neutralizing activity against Omicron, with only three retaining potency. However, some broadly neutralizing antibodies, such as S2K146, S2X259, and S2H97, neutralize Omicron by recognizing antigenic sites outside the RBD. These findings indicate a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize conserved RBD epitopes may be key to controlling the pandemic and future zoonotic spillovers. The evolution of RNA viruses can lead to immune evasion and receptor binding changes through mutations. Previous SARS-CoV-2 variants, such as Beta and Delta, showed resistance to neutralizing antibodies. Omicron, with its high number of mutations, has a significant immune evasion capacity. The study also shows that Omicron can infect mice, suggesting a potential for cross-species transmission. The neutralizing activity of several therapeutic monoclonal antibodies is reduced or abolished against Omicron. The study highlights the importance of developing broadly neutralizing antibodies that target conserved epitopes to counteract antigenic shifts and future viral variants. The findings suggest that the Omicron variant has undergone a significant antigenic shift, which may impact vaccine efficacy and therapeutic strategies. The study provides insights into the mechanisms of immune evasion by Omicron and the potential of broadly neutralizing antibodies in combating the virus.