Reduced antigenicity of Omicron lowers host serologic response

  1. Jérôme Tubiana
  2. Yufei Xiang
  3. Li Fan
  4. Haim J. Wolfson
  5. Kong Chen
  6. Dina Schneidman-Duhovny
  7. Yi Shi

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Abstract

SARS-CoV-2 Omicron variant of concern (VOC) contains fifteen mutations on the receptor binding domain (RBD), evading most neutralizing antibodies from vaccinated sera. Emerging evidence suggests that Omicron breakthrough cases are associated with substantially lower antibody titers than other VOC cases. However, the mechanism remains unclear. Here, using a novel geometric deep-learning model, we discovered that the antigenic profile of Omicron RBD is distinct from the prior VOCs, featuring reduced antigenicity in its remodeled receptor binding sites (RBS). To substantiate our deep-learning prediction, we immunized mice with different recombinant RBD variants and found that the Omicron’s extensive mutations can lead to a drastically attenuated serologic response with limited neutralizing activity in vivo , while the T cell response remains potent. Analyses of serum cross-reactivity and competitive ELISA with epitope-specific nanobodies revealed that the antibody response to Omicron was reduced across RBD epitopes, including both the variable RBS and epitopes without any known VOC mutations. Moreover, computational modeling confirmed that the RBS is highly versatile with a capacity to further decrease antigenicity while retaining efficient receptor binding. Longitudinal analysis showed that this evolutionary trend of decrease in antigenicity was also found in hCoV229E, a common cold coronavirus that has been circulating in humans for decades. Thus, our study provided unprecedented insights into the reduced antibody titers associated with Omicron infection, revealed a possible trajectory of future viral evolution and may inform the vaccine development against future outbreaks.

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  1. ScreenIT

    SciScore for 10.1101/2022.02.15.480546: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Antibodies
    SentencesResources
    Since there was no antibody-hCoV229E spike protein complex in the training set of ScanNet, we used all the 55 networks trained for antibody binding site prediction (including the 11 used elsewhere that were not trained on SARS-CoV-1/2 data).
    antibody-hCoV229E
    suggested: None
    The plate was washed by the washing buffer to remove the unbound hACE2. 1:5,000 diluted Pierce™ High Sensitivity NeutrAvidin™-HRP (Thermo Fisher cat# 31030) or 1:7,500 diluted T7-tag polyclonal antibody-HRP (Thermo Fisher, cat# PA1-31449) were incubated with the plate for 1 hr at room temperature.
    antibody-HRP
    suggested: (Thermo Fisher Scientific Cat# PA1-31449, RRID:AB_1960906)
    Experimental Models: Cell Lines
    SentencesResources
    Pseudotyped SARS-CoV-2 neutralization assay: The 293T-hsACE2 stable cell line (Integral Molecular, cat# C-HA101, Lot# TA060720MC) and pseudotyped SARS-CoV-2 (Wuhan-Hu-1 strain D614G and Omicron) particles with luciferase reporters were purchased from the Integral Molecular.
    293T-hsACE2
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    The isotonic regression fit was performed using scikit-learn (sklearn.isotonic.IsotonicRegression, default parameters)32. Mice: 8 weeks old female C57BL/6 mice were ordered from The Jackson Laboratory and housed in pathogen-free conditions at the core animal facility at the University of Pittsburgh Medical Center with the approval from the University of Pittsburgh Institutional Animal Care and Use Committee.
    C57BL/6
    suggested: None
    Software and Algorithms
    SentencesResources
    Construction of the MSA: Homologs of the WT RBD were first searched in the UniprotKB using BLAST.
    UniprotKB
    suggested: (UniProtKB, RRID:SCR_004426)
    BLAST
    suggested: (BLASTX, RRID:SCR_001653)
    The isotonic regression fit was performed using scikit-learn (sklearn.isotonic.IsotonicRegression, default parameters)32. Mice: 8 weeks old female C57BL/6 mice were ordered from The Jackson Laboratory and housed in pathogen-free conditions at the core animal facility at the University of Pittsburgh Medical Center with the approval from the University of Pittsburgh Institutional Animal Care and Use Committee.
    scikit-learn
    suggested: (scikit-learn, RRID:SCR_002577)
    The raw data were processed by Prism 9 (GraphPad) to fit into a 4PL curve and to calculate IC50/logIC50.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    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.

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  2. Version published to 10.1101/2022.02.15.480546v1 on bioRxiv