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

## TL;DR

The XBB.1.5 variant of SARS-CoV-2 has mutations that change key parts of the spike protein, helping it evade antibodies and highlighting the need for updated vaccines.

## Contribution

This study identifies four conserved antigenic determinants altered by XBB.1.5 mutations, providing insights into immune evasion mechanisms.

## Key findings

- XBB.1.5 has 38 amino acid substitutions compared to the original Wuhan-Hu-1 strain.
- Four conserved antigenic determinants are altered, reducing antibody recognition.
- The spike protein maintains structural stability and ACE2 binding despite mutations.

## Abstract

The continuous evolution of SARS-CoV-2 affects its infectivity and ability to evade the immune system. The XBB.1.5 subvariant carries numerous mutations compared to previous Omicron variants and exhibits significant evasion of polyclonal neutralizing antibodies. In this study, the mechanistic effects of mutations in the XBB.1.5 spike protein on structural stability, antigenic markers, and antibody epitopes were analyzed using homology modeling, epitope prediction, protein stability analysis, coarse-grained dynamic simulations, and chain-specific interface mapping. Thirty-eight amino acid substitutions were identified relative to Wuhan-Hu-1, including 22 in the receptor-binding region. The prefusion trimeric fold was conserved, with localized rearrangements in the N-terminal domain, receptor-binding domain, and S1/S2 region. Linear B-cell epitope prediction yielded similar epitope counts and length distributions in wild-type and XBB.1.5, but only moderate residue-level overlap (Jaccard ≈ 0.40–0.62), indicating epitope turnover and alteration of four conserved antigenic determinants. Functional screening suggested that ~45% of substitutions could affect protein function. Chain-specific interface analysis of the A–B protomer interface indicated preserved inter-protomer coupling with modest repacking of the polar/directional contacts. Overall, XBB.1.5 appears to maintain ACE2 engagement while redistributing antibody targets, underscoring the need for updated vaccine formulations and therapeutic antibodies.