SARS-CoV-2 Spike Protein XBB.1.5 Mutations Altered Four Conserved Antigenic Determinants

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• SARS-CoV-2 continuously evolves, leading to variants like XBB.1.5 with altered infectivity and immune evasion properties.
• The XBB.1.5 subvariant exhibits significant evasion of neutralizing antibodies due to numerous mutations in its spike protein.

Purpose of the Study:

• To analyze the mechanistic effects of XBB.1.5 spike protein mutations on structural stability, antigenic markers, and antibody epitopes.
• To understand how XBB.1.5 maintains ACE2 engagement while altering antibody targets.

Main Methods:

• Homology modeling
• Epitope prediction
• Protein stability analysis
• Coarse-grained dynamic simulations
• Chain-specific interface mapping

Main Results:

• Identified 38 amino acid substitutions in XBB.1.5 spike protein versus Wuhan-Hu-1, with 22 in the receptor-binding region.
• Conserved prefusion trimeric fold with localized rearrangements; moderate residue-level overlap in B-cell epitopes (Jaccard ≈ 0.40-0.62) indicating epitope alteration.
• ~45% of substitutions potentially affect protein function; preserved ACE2 engagement with redistributed antibody targets.

Conclusions:

• XBB.1.5 spike protein mutations alter antigenic determinants and B-cell epitopes while maintaining ACE2 binding.
• Findings highlight the need for updated vaccine formulations and therapeutic antibodies to address immune evasion by SARS-CoV-2 variants.