Warning: This is a preliminary report that has not been peer-reviewed. It should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.

Jian F, Yang S, Yu Y, Song W, Yisimayi A, Chen X, Xu Y, Wang P, Yu L, Wang J, Liu L, Niu X, Wang J, Xiao T, Gu Q, Shao F, Jin R, Shen Z, Wang Y, Cao YR

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of XBB lineages on the receptor-binding domain (RBD) L455F and F456L is observed, resulting in variants like EG.5, FL.1.5.1, XBB.1.5.70, and HK.3. Here, we show that neutralizing antibody (NAb) evasion drives ...

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the convergent evolution of F456L, while the epistatic shift caused by F456L enables the subsequent convergence of L455F through ACE2 binding enhancement and further immune evasion. Specifically, L455F and F456L evades Class 1 NAbs, which could reduce the neutralization efficacy of XBB breakthrough infection (BTI) and reinfection convalescent plasma. Importantly, L455F single substitution significantly dampens receptor binding; however, the combination of L455F and F456L forms an adjacent residue flipping, which leads to enhanced NAbs resistance and ACE2 binding affinity. Our results indicate the evolution flexibility contributed by epistasis cannot be underestimated, and the evolution potential of SARS-CoV-2 RBD remains high.HighlightsO_LIL455F and F456L enhance the resistance to Class 1 NAbsC_LIO_LIL455F and F456L lower neutralization of XBB BTI convalescent plasmaC_LIO_LIL455F+F456L flipping significantly increases ACE2 binding affinityC_LI

Date: Aug. 31, 2023

Status: Preliminary Report

View Source: doi: 10.1101/2023.08.30.555211

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