Structural and functional dissection of neutralisation differences among SARS-CoV-2 variants using antigenicity...

Area of Science:

• Virology and Immunology
• Computational Biology
• Structural Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, particularly those with mutations in the spike glycoprotein's receptor-binding domain (RBD) and N-terminal domain (NTD), drive COVID-19 waves.
• Mutations in these immunodominant regions can alter antigenic surfaces, impacting antibody recognition and vaccine effectiveness.
• Understanding variant-specific antibody responses is crucial for public health strategies.

Purpose of the Study:

• To experimentally and computationally characterize SARS-CoV-2 variant neutralization across different immune exposure histories (infection, vaccination, hybrid).
• To investigate how mutations in spike proteins affect antibody binding and neutralization.
• To integrate experimental data with in silico analyses for a comprehensive understanding of variant-specific immune responses.

Main Methods:

• Pseudovirus-based neutralization assays were performed using spike proteins from SARS-CoV-2 variants (B.1, Delta, Omicron) and plasma from infected, vaccinated, and hybrid immunity cohorts.
• Epitope prediction, antigenicity profiling, and structural modeling were used to analyze spike protein sequences.
• Docking simulations (HADDOCK) and binding affinity estimations (PRODIGY) were employed to assess interactions between monoclonal antibody CR3022 and variant RBDs.

Main Results:

• Neutralization responses varied significantly across cohorts and SARS-CoV-2 variants, with Omicron and Delta showing reduced susceptibility to infection-elicited antibodies.
• Computational analyses revealed variant-associated differences in predicted antigenicity and epitope landscapes within the RBD and NTD.
• Structural modeling and docking suggested that spike mutations influence the CR3022-RBD interaction interface, correlating with observed changes in neutralization.

Conclusions:

• The study successfully combined experimental and computational approaches to characterize SARS-CoV-2 variant-specific neutralization.
• The integration of pseudovirus neutralization data with structural and in silico analyses provides a framework for contextualizing antibody responses and epitope recognition across variants.
• Findings offer insights into the mechanisms underlying reduced neutralization by antibodies against emerging SARS-CoV-2 variants.