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Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike

Nature volume 624, pages 639–644 (2023)Cite this article

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Abstract

A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant, BA.2.86, has emerged and spread to numerous countries worldwide, raising alarm because its spike protein contains 34 additional mutations compared with its BA.2 predecessor1. We examined its antigenicity using human sera and monoclonal antibodies (mAbs). Reassuringly, BA.2.86 was no more resistant to human sera than the currently dominant XBB.1.5 and EG.5.1, indicating that the new subvariant would not have a growth advantage in this regard. Importantly, sera from people who had XBB breakthrough infection exhibited robust neutralizing activity against all viruses tested, suggesting that upcoming XBB.1.5 monovalent vaccines could confer added protection. Although BA.2.86 showed greater resistance to mAbs to subdomain 1 (SD1) and receptor-binding domain (RBD) class 2 and 3 epitopes, it was more sensitive to mAbs to class 1 and 4/1 epitopes in the ‘inner face’ of the RBD that is exposed only when this domain is in the ‘up’ position. We also identified six new spike mutations that mediate antibody resistance, including E554K that threatens SD1 mAbs in clinical development. The BA.2.86 spike also had a remarkably high receptor affinity. The ultimate trajectory of this new SARS-CoV-2 variant will soon be revealed by continuing surveillance, but its worldwide spread is worrisome.

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Fig. 1: Divergence of the BA.2.86 spike sequence from major SARS-CoV-2 variants.
Fig. 2: Serum neutralization of BA.2.86 compared with BA.2, XBB.1.5 and EG.5.1.
Fig. 3: Neutralization of BA.2.86 and its point mutants in BA.2 by a panel of mAbs.
Fig. 4: BA.2.86 exhibited stronger receptor affinity than BA.2, XBB.1.5 and EG.5.1.

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Data availability

All experimental data are provided in the manuscript. Materials used in this study will be available under an appropriated Materials Transfer Agreement. Antigenic maps were generated using the Racmacs package (v.1.1.4, https://acorg.github.io/Racmacs/) in R v.4.0.3. Severe acute respiratory syndrome coronavirus 2 spike sequences were downloaded from the Global Initiative on Sharing Avian Flu Data database (https://www.gisaid.org/). The structures used for analysis in this study are available from the Protein Data Bank under identification codes 7KRR, 7WKA, 8D8Q, 7MMO, 7TAS, 7TCA and 7ZF7.

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Acknowledgements

This study was supported by funding from the National Institutes of Health (NIH) Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) Assessment of Viral Evolution Program and through the NIH Collaborative Influenza Vaccine Innovation Center (Grant 75N93021C00014 to D.D.H.) and the NIH, National Institute of Allergy and Infectious Diseases (Contract 75N93019C00051 to A.G.). We acknowledge funding support from the National Science Foundation (Grant MCB-2032259 to H.H.W.). We thank all who contributed their data to the Global Initiative on Sharing Avian Flu Data database. We express our gratitude to D. Manthei, C. Gherasim, V. Blanc, P. Bennett-Baker, S. Sneeringer, L. Warsinske, T. Kowalski-Dobson, A. Meyers, Z. Chu, H. Kuiken, L. Barnes, A. Eckard, K. Lindsey, D. Davis, A. Rico, G. Simjanovski, M. Patel and N. Vydiswaran of the Immunity Associated with SARS-CoV-2 Study team for supplying serum samples. We acknowledge M. T. Yin and M. E. Sobieszczyk at Columbia University Medical Center for providing serum samples.

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  1. These authors contributed equally: Qian Wang, Yicheng Guo, Liyuan Liu

Authors and Affiliations

  1. Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

    Qian Wang, Yicheng Guo, Zhiteng Li, Manoj S. Nair, Jerren Ho, Richard M. Zhang, Sho Iketani, Jian Yu, Yaoxing Huang, Lihong Liu & David D. Ho

  2. Department of Systems Biology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

    Liyuan Liu, Logan T. Schwanz, Yiming Huang, Yiming Qu & Harris H. Wang

  3. Department of Pathobiology and Mechanisms of Disease, Columbia University Irving Medical Center, New York, NY, USA

    Logan T. Schwanz

  4. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    Riccardo Valdez

  5. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Adam S. Lauring

  6. Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA

    Adam S. Lauring

  7. Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

    Yaoxing Huang, Lihong Liu & David D. Ho

  8. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA

    Aubree Gordon

  9. Department of Microbiology and Immunology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

    David D. Ho

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Contributions

Lihong Liu and D.D.H. conceived and supervised this project. Q.W. managed the project. Liyuan Liu, L.T.S., Yiming Huang, Y.Q. and H.H.W. constructed the spike expression plasmids. Q.W., J.H., R.M.Z. and Lihong Liu conducted pseudovirus neutralization assays. M.S.N. and Yaoxing Huang conducted authentic virus neutralization assays. Q.W. and Lihong Liu purified severe acute respiratory syndrome coronavirus 2 soluble spike proteins and hACE2 protein. Y.G. conducted bioinformatic analyses. Q.W., Lihong Liu, J.H., S.I. and J.Y. purified antibodies. Z.L. performed surface plasmon resonance assay. R.V., A.S.L. and A.G. provided clinical samples. Q.W., Y.G., Lihong Liu and D.D.H. analysed the results and wrote the manuscript. All authors reviewed the results and approved the final version of the manuscript.

Corresponding authors

Correspondence to Lihong Liu or David D. Ho.

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Competing interests

Lihong Liu, S.I., J.Y. and D.D.H. are inventors on a provisional patent application on 10-40 described in this manuscript, titled “Isolation, characterization, and sequences of potent and broadly neutralizing monoclonal antibodies against SARS-CoV-2 and its variants as well as related coronaviruses” (63/271,627). D.D.H. is a co-founder of TaiMed Biologics and RenBio; consultant to WuXi Biologics and Brii Biosciences; and a board director for Vicarious Surgical. A.G. serves on a scientific advisory board for Janssen Pharmaceuticals. The remaining authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Spike sequence alignment of WA1 and BA.2 with BA.2.86 from human cases deposited to GISAID as of September 5, 2023.

The sequence numbering is based on WA1. Red boxes indicate the alignments of amino acids at position 16 and 670. “X”, low-quality sequencing data.

Extended Data Fig. 2 Serum neutralization of authentic BA.2.86 compared with EG.5.1.

Neutralizing ID50 titre of serum samples from “XBB breakthrough” cohort against authentic BA.2.86 and EG.5.1. The geometric mean ID50 titre (GMT) are presented above symbols. The neutralization assay limit of detection (dotted line) is 100. Statistical analysis was performed by employing Wilcoxon matched-pairs signed-rank test. GMT of BA.2.86 is around 1.2-fold (1.2X) higher than that of EG.5.1. n, sample size. dpi, days post infection.

Extended Data Table 1 Demographics of clinical cohorts
Full size table
Extended Data Table 2 Neutralization activity of mAbs against the indicated viruses
Full size table
Extended Data Table 3 Neutralization activity of mAbs against BA.2.86 carrying back mutations
Full size table

Supplementary information

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Wang, Q., Guo, Y., Liu, L. et al. Antigenicity and receptor affinity of SARS-CoV-2 BA.2.86 spike. Nature 624, 639–644 (2023). https://doi.org/10.1038/s41586-023-06750-w

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