The study investigates the immune evasion, infectivity, and fusogenicity of the SARS-CoV-2 BA.2.86 and FLip variants. BA.2.86 is less resistant to neutralization by bivalent vaccine-induced antibodies compared to FLip and other XBB variants but more resistant to mAb S309. BA.2.86 shows higher fusogenicity and infectivity in CaLu-3 cells compared to 293T-ACE2 cells. The study highlights the importance of ongoing variant surveillance and the need for updated COVID-19 vaccines. Key findings include: 1. **Immune Evasion**: BA.2.86 is less immune evasive compared to FLip and other XBB variants, consistent with antigenic distances. 2. **Neutralizing Antibodies**: MAb S309 is unable to neutralize BA.2.86 due to a D339H mutation, which disrupts the binding epitope. 3. **Infectivity and Fusogenicity**: BA.2.86 exhibits decreased infectivity in 293T-ACE2 cells but increased infectivity and fusogenicity in CaLu-3 cells, suggesting a different conformational stability of the spike protein. 4. **Antigenic Mapping**: BA.2.86 is antigenically more similar to early Omicron subvariants BA.1, BA.2, and BA.4/5, while FLip is more antigenically distinct from these subvariants. The study underscores the need for continued monitoring of SARS-CoV-2 variants and the development of updated vaccines to maintain effective protection against emerging variants.The study investigates the immune evasion, infectivity, and fusogenicity of the SARS-CoV-2 BA.2.86 and FLip variants. BA.2.86 is less resistant to neutralization by bivalent vaccine-induced antibodies compared to FLip and other XBB variants but more resistant to mAb S309. BA.2.86 shows higher fusogenicity and infectivity in CaLu-3 cells compared to 293T-ACE2 cells. The study highlights the importance of ongoing variant surveillance and the need for updated COVID-19 vaccines. Key findings include: 1. **Immune Evasion**: BA.2.86 is less immune evasive compared to FLip and other XBB variants, consistent with antigenic distances. 2. **Neutralizing Antibodies**: MAb S309 is unable to neutralize BA.2.86 due to a D339H mutation, which disrupts the binding epitope. 3. **Infectivity and Fusogenicity**: BA.2.86 exhibits decreased infectivity in 293T-ACE2 cells but increased infectivity and fusogenicity in CaLu-3 cells, suggesting a different conformational stability of the spike protein. 4. **Antigenic Mapping**: BA.2.86 is antigenically more similar to early Omicron subvariants BA.1, BA.2, and BA.4/5, while FLip is more antigenically distinct from these subvariants. The study underscores the need for continued monitoring of SARS-CoV-2 variants and the development of updated vaccines to maintain effective protection against emerging variants.