An elite broadly neutralizing antibody protects SARS-CoV-2 Omicron variant challenge

  1. Biao Zhou
  2. Runhong Zhou
  3. Jasper Fuk-Woo Chan
  4. Mengxiao Luo
  5. Qiaoli Peng
  6. Shuofeng Yuan
  7. Bobo Wing-Yee Mok
  8. Bohao Chen
  9. Pui Wang
  10. Vincent Kwok-Man Poon
  11. Hin Chu
  12. Chris Chung-Sing Chan
  13. Jessica Oi-Ling Tsang
  14. Chris Chun-Yiu Chan
  15. Ka-Kit Au
  16. Hiu-On Man
  17. Lu Lu
  18. Kelvin Kai-Wang To
  19. Honglin Chen
  20. Kwok-Yung Yuen
  21. Zhiwei Chen

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Abstract

The strikingly high transmissibility and antibody evasion of SARS-CoV-2 Omicron variant have posted great challenges on the efficacy of current vaccines and antibody immunotherapy.Here, we screened 34 BNT162b2-vaccinees and cloned a public broadly neutralizing antibody (bNAb) ZCB11 from an elite vaccinee. ZCB11 neutralized all authentic SARS-CoV-2 variants of concern (VOCs), including Omicron and OmicronR346K with potent IC50 concentrations of 36.8 and 11.7 ng/mL, respectively. Functional analysis demonstrated that ZCB11 targeted viral receptor-binding domain (RBD) and competed strongly with ZB8, a known RBD-specific class II NAb. Pseudovirus-based mapping of 57 naturally occurred single mutations or deletions revealed that only S371L resulted in 11-fold neutralization resistance, but this phenotype was not observed in the Omicron variant. Furthermore,prophylactic ZCB11 administration protected lung infection against both the circulating pandemic Delta and Omicron variants in golden Syrian hamsters. These results demonstrated that vaccine-induced ZCB11 is a promising bNAb for immunotherapy against pandemic SARS-CoV-2 VOCs.

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  1. ScreenIT

    SciScore for 10.1101/2022.01.05.475037: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: Written informed consent was obtained from all study subjects.
    IRB: This study was approved by the Institutional Review Board of The University of Hong Kong/Hospital Authority Hong Kong West Cluster (Ref No. UW 21-120 452).
    Sex as a biological variableBriefly, 6-10-week-old male and female hamsters were obtained from the Chinese University of Hong Kong Laboratory Animal Service Centre through the HKU Centre for Comparative Medicine Research.
    RandomizationThe hamsters were randomized from different litters into experimental groups.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Serially diluted plasma from healthy individuals or previously published monoclonal antibodies against SARS-CoV-2 (B8) were used as negative controls.
    SARS-CoV-2
    suggested: None
    Two consecutive staining steps were conducted: the first one used an antibody and spike cocktail incubation of 30 min at 4 °C; the second staining involved staining with anti-His-APC and anti-His-FITC antibodies (Abcam) at 4 °C for 30 min to detect the His tag of the RBD.
    anti-His-APC
    suggested: (Miltenyi Biotec Cat# 130-101-322, RRID:AB_2800415)
    anti-His-FITC
    suggested: (Miltenyi Biotec Cat# 130-092-675, RRID:AB_1103226)
    Cells were further permeabilized with 0.2% Triton X-100 and incubated with cross-reactive rabbit sera anti-SARS-CoV-2-N for 1 hour at RT before adding an Alexa Fluor 488 goat anti-rabbit IgG (H+L) cross-adsorbed secondary antibody (Life Technologies).
    anti-SARS-CoV-2-N
    suggested: None
    anti-rabbit IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Cell lines: HEK293T cells, HEK293T-hACE2 cells and Vero-E6-TMPRSS2 cells were maintained in DMEM containing 10% FBS, 2 mM L-glutamine, 100 U/mL/mL penicillin and incubated at 37 □in a 5% CO2 setting 51
    HEK293T
    suggested: None
    HEK293T-hACE2
    suggested: RRID:CVCL_A7UK)
    Vero-E6-TMPRSS2
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    Briefly, The pseudovirus was generated by co-transfection of 293T cells with pVax-1-S-COVID19 and pNL4-3Luc_Env_Vpr, carrying the optimized spike (S) gene (QHR63250) and a human immunodeficiency virus type 1 backbone, respectively 54
    293T
    suggested: None
    The antibody-virus mixtures were subsequently added to pre-seeded HEK 293T-ACE2 cells.
    HEK 293T-ACE2
    suggested: RRID:CVCL_A7UK)
    Mixtures were then transferred to 96-well plates pre-seeded with 1×104/well Vero E6 cells and incubated at 37°C for 24 hours.
    Vero E6
    suggested: None
    Recombinant DNA
    SentencesResources
    Briefly, The pseudovirus was generated by co-transfection of 293T cells with pVax-1-S-COVID19 and pNL4-3Luc_Env_Vpr, carrying the optimized spike (S) gene (QHR63250) and a human immunodeficiency virus type 1 backbone, respectively 54
    pVax-1-S-COVID19
    suggested: None
    pNL4-3Luc_Env_Vpr
    suggested: None
    Software and Algorithms
    SentencesResources
    https://www.ncbi.nlm.nih.gov/igblast/).
    https://www.ncbi.nlm.nih.gov/igblast/
    suggested: (IgBLAST, RRID:SCR_002873)
    Sequences were aligned using Clustal W in the BioEdit sequence analysis package (Version 7.2)
    BioEdit
    suggested: (BioEdit, RRID:SCR_007361)
    Half-maximal (IC50) or 90% (IC90) inhibitory concentrations of the evaluated antibody were determined by inhibitor vs. normalized response --4 Variable slope using GraphPad Prism 8 or later (GraphPad Software Inc.)
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    The fluorescence density of SARS-CoV-2 infected cells were scanned using a Sapphire Biomolecular Imager (Azure Biosystems) and the neutralization effects were then quantified using Fiji software (NIH)
    Fiji
    suggested: (Fiji, RRID:SCR_002285)
    The structure alignment, cartoon representations, labeling of amino acids in RBD (from PDB 7K45) were generated by PyMOL.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    Quantification and statistical analysis: Statistical analysis was performed using PRISM 8.0 or later.
    PRISM
    suggested: (PRISM, RRID:SCR_005375)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations of the study: ZCB11 probably represents the broadest breadth among bNAbs reported thus far with comparable potency against all current SARS-CoV-2 VOCs including Omicron and OmicronR346K. We are still in the process in determining its mode of action by solving structures of the RBD-ZCB11 Fab complex. Such information will be useful to guide vaccine design as mentioned because the frequency of elite vaccine remains low (2/34 in this study). To understand the frequency of ZCB11-like bNAb among BNT162b2-vaccinees, we need to investigate other elite responders who show equally potent bNAb responses. More ZCB11-like bNAbs should be also discovered to improve current antibody-based cocktail immunotherapy. For animal challenge experiments, we have done a single dose efficacy experiment. Different doses and routes of administration or antibody combination will be tested in future experiments to provide useful information to support clinical development of ZCB11 and ZCB11-like bNAb.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2022.01.05.475037v1 on bioRxiv