The Omicron variant of SARS-CoV-2, first detected in southern Africa, has rapidly spread globally and is expected to become dominant due to its high transmissibility. A key feature of Omicron is its numerous spike mutations, which significantly reduce the effectiveness of current COVID-19 vaccines and antibody therapies. This study demonstrates that Omicron is highly resistant to neutralization by sera from both convalescent patients and vaccinated individuals, including those who received booster doses of mRNA-based vaccines. The study also shows that 17 out of 19 tested monoclonal antibodies, including those approved for clinical use, lose their neutralizing activity against Omicron. Four new spike mutations (S371L, N440K, G446S, and Q493R) contribute to Omicron's resistance to antibodies. The Omicron variant poses a serious threat to existing vaccines and therapies, necessitating the development of new interventions to counter its evolutionary trajectory. The study highlights the urgent need for updated vaccines and treatments as Omicron's mutations continue to challenge current immune responses.The Omicron variant of SARS-CoV-2, first detected in southern Africa, has rapidly spread globally and is expected to become dominant due to its high transmissibility. A key feature of Omicron is its numerous spike mutations, which significantly reduce the effectiveness of current COVID-19 vaccines and antibody therapies. This study demonstrates that Omicron is highly resistant to neutralization by sera from both convalescent patients and vaccinated individuals, including those who received booster doses of mRNA-based vaccines. The study also shows that 17 out of 19 tested monoclonal antibodies, including those approved for clinical use, lose their neutralizing activity against Omicron. Four new spike mutations (S371L, N440K, G446S, and Q493R) contribute to Omicron's resistance to antibodies. The Omicron variant poses a serious threat to existing vaccines and therapies, necessitating the development of new interventions to counter its evolutionary trajectory. The study highlights the urgent need for updated vaccines and treatments as Omicron's mutations continue to challenge current immune responses.