Spike mutations that affect the function and antigenicity of recent KP.3.1.1-like SARS-CoV-2 variants

Area of Science:

• Virology
• Immunology
• Evolutionary Biology

Background:

• SARS-CoV-2 continuously evolves, acquiring spike protein mutations that can evade human antibody responses.
• Understanding these mutations is crucial for developing effective vaccines and therapeutics against emerging variants.

Purpose of the Study:

• To assess the impact of mutations in the KP.3.1.1 SARS-CoV-2 strain's spike protein on viral function and antibody neutralization.
• To identify specific mutations affecting ACE2 binding, RBD conformation, and recognition by human sera and clinical antibodies.

Main Methods:

• Utilized pseudovirus-based deep mutational scanning to analyze spike protein mutations.
• Measured effects on cell entry, ACE2 receptor binding, and RBD up/down motion.
• Assessed neutralization by human sera (pre- and post-vaccination/infection) and specific monoclonal antibodies.

Main Results:

• Identified mutations, particularly outside the RBD, that modulate RBD up/down movement and impact serum neutralization.
• Observed that neutralization escape sites can shift based on prior vaccination or infection history.
• Found that specific RBD sites (475, 478, 487) and non-RBD sites significantly reduce neutralization by post-vaccination/infection sera.

Conclusions:

• Spike protein mutations, including those outside the RBD, are critical drivers of SARS-CoV-2 immune evasion.
• The study provides insights into the evolutionary pressures shaping SARS-CoV-2 and aids in forecasting antigenic drift.
• Findings are valuable for assessing the impact of new variants on vaccine efficacy and antibody-based prophylactics.