Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• The emergence of SARS-CoV-2 Omicron variant with numerous spike protein mutations raises concerns.
• Mutations in the Omicron spike protein, particularly in the receptor-binding domain (RBD), may affect viral binding and antibody neutralization.

Purpose of the Study:

• To investigate the binding affinity of Omicron RBD to human and mouse ACE2.
• To assess the neutralizing activity of convalescent and vaccine-induced plasma against Omicron.
• To evaluate the effectiveness of monoclonal antibodies against the Omicron variant.

Main Methods:

• Binding assays to determine ACE2 affinity.
• Pseudovirus neutralization assays using plasma from convalescent and vaccinated individuals.
• In vitro neutralization assays for monoclonal antibodies against Omicron pseudovirus.

Main Results:

• Omicron RBD exhibits enhanced binding to human ACE2 and binds to mouse ACE2.
• Significant reductions in neutralizing activity were observed in plasma post-Omicron infection/vaccination, with less impact after a third vaccine dose.
• Most RBD-targeted monoclonal antibodies lost activity, while some broadly neutralizing antibodies targeting conserved epitopes retained potency.

Conclusions:

• Omicron represents a major antigenic shift in SARS-CoV-2 due to immune evasion.
• Broadly neutralizing monoclonal antibodies targeting conserved sarbecovirus epitopes are crucial for pandemic control and future zoonotic threats.