Neutralization, effector function and immune imprinting of Omicron variants.

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Convergent mutations in SARS-CoV-2 Receptor-Binding Domain (RBD) impact viral properties.
• Understanding variant evolution and immune response is crucial for effective treatments.

Purpose of the Study:

• To investigate the binding affinity and membrane fusion efficiency of BQ.1.1 and XBB.1.5 SARS-CoV-2 variants.
• To analyze the structural basis for antibody recognition and immune evasion.
• To evaluate the therapeutic potential of sotrovimab and vaccine-induced immunity.

Main Methods:

• Structural analysis of RBD-ACE2 and RBD-antibody complexes.
• In vitro assays for membrane fusion and antibody binding.
• In vivo studies using mouse and hamster models challenged with SARS-CoV-2 variants.

Main Results:

• BQ.1.1 and XBB.1.5 exhibit enhanced ACE2 binding and membrane fusion compared to earlier Omicron variants.
• Structural studies reveal mechanisms of antibody binding preservation and immune evasion.
• Sotrovimab demonstrates avid binding, promotes effector functions, and provides protection against BQ.1.1 and XBB.1.5 infections.
• Vaccine-elicited antibodies show cross-reactivity and effector functions against Omicron variants, despite reduced neutralization.

Conclusions:

• Sotrovimab remains effective against current SARS-CoV-2 variants, offering a potential therapeutic strategy.
• Vaccine-induced immunity contributes to protection through cross-reactive antibodies and effector functions.
• Immune imprinting plays a role in maintaining a memory B cell response to SARS-CoV-2.