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Spike mutations that affect the function and antigenicity of recent KP.3.1.1-like SARS-CoV-2 variants
Bernadeta Dadonaite1, Sheri Harari1, Brendan B Larsen1
1Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, Washington, 98109, USA.
Biorxiv : the Preprint Server for Biology
|September 2, 2025
Summary
SARS-CoV-2 spike mutations are evolving to evade antibodies, impacting vaccine and treatment effectiveness. Understanding these changes helps predict future viral evolution and inform antibody responses.
Area of Science:
- Virology and Immunology
- Molecular Biology
- Evolutionary Biology
Background:
- Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) exhibits rapid evolution, particularly in its spike protein.
- Mutations in the spike protein can alter its interaction with the human ACE2 receptor and evade neutralizing antibodies.
- Understanding these evolutionary pressures is crucial for developing effective vaccines and therapeutics.
Purpose of the Study:
- To investigate the impact of SARS-CoV-2 spike mutations from the KP.3.1.1 strain on viral properties.
- To assess how these mutations affect neutralization by human sera and clinically relevant antibodies.
- To elucidate the evolutionary trajectory of SARS-CoV-2 and its implications for public health.
Main Methods:
- Pseudovirus-based deep mutational scanning was employed to analyze spike protein mutations.
- Assays measured effects on cell entry, ACE2 receptor binding, and receptor-binding domain (RBD) conformational changes.
- Neutralization capacity of human sera and specific monoclonal antibodies against mutated spike proteins was evaluated.
Main Results:
- Spike mutations significantly impact neutralization by human sera, with effects varying based on prior vaccination or infection history.
- Key mutations in the RBD (e.g., at sites 475, 478, 487) and outside the RBD (affecting RBD movement) substantially reduce antibody neutralization.
- Mutations' effects on neutralization by specific antibodies (VYD222, BD55-1205, SA55) were quantified.
Conclusions:
- SARS-CoV-2 spike protein evolution is driven by selection pressures to escape polyclonal antibody neutralization.
- Vaccination and infection history alter the hierarchy of antibody responses, influencing which mutations are most impactful.
- These findings provide insights into SARS-CoV-2 evolution and can aid in forecasting antigenic drift relevant to vaccine and antibody efficacy.
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