Construction of a potent pan-vaccine based on the evolutionary tendency of SARS-CoV-2 spike protein

  1. Yongliang Zhao
  2. Wenjia Ni
  3. Simeng Liang
  4. Lianghui Dong
  5. Min Xiang
  6. Zeng Cai
  7. Danping Niu
  8. Qiuhan Zhang
  9. Dehe Wang
  10. Yucheng Zheng
  11. Zhen Zhang
  12. Dan Zhou
  13. Wenhua Guo
  14. Yongbing Pan
  15. Xiaoli Wu
  16. Yimin Yang
  17. Zhaofei Jing
  18. Yongzhong Jiang
  19. SARS-CoV-2 Vaccine Task Force Group
  20. Yu Chen
  21. Huan Yan
  22. Yu Zhou
  23. Ke Xu
  24. Ke Lan

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Abstract

SARS-CoV-2 continued to spread globally along with different variants. Here, we systemically analyzed viral infectivity and immune-resistance of SARS-CoV-2 variants to explore the underlying rationale of viral mutagenesis. We found that the Beta variant harbors both high infectivity and strong immune resistance, while the Delta variant is the most infectious with only a mild immune-escape ability. Remarkably, the Omicron variant is even more immune-resistant than the Beta variant, but its infectivity increases only in Vero E6 cells implying a probable preference for the endocytic pathway. A comprehensive analysis revealed that SARS-CoV-2 spike protein evolved into distinct evolutionary paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance, resulting in a narrow spectrum of the current single-strain vaccine. In light of these findings and the phylogenetic analysis of 2674 SARS-CoV-2 S-protein sequences, we generated a consensus antigen (S 6 ) taking the most frequent mutations as a pan-vaccine against heterogeneous variants. As compared to the ancestry SWT vaccine with significantly declined neutralizations to emerging variants, the S 6 vaccine elicits broadly neutralizing antibodies and full protections to a wide range of variants. Our work highlights the importance and feasibility of a universal vaccine strategy to fight against antigen drift of SARS-CoV-2.

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  1. ScreenIT

    SciScore for 10.1101/2021.12.21.473594: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: The corresponding animal experiments have been approved by the Animal Committee of Wuhan University.
    Sex as a biological variableImmunization of mice: Female K18-hACE2 transgenic mice were obtained from GemPharmatech Co.,
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Cell lines: The A549-hACE2, Caco-2, Vero E6 cell lines were obtained from ATCC and maintained in Dulbecco’s modified Eagle’s medium (DMEM; Gibco) supplemented with 10% fetal bovine serum (FBS).
    Caco-2
    suggested: None
    Forty-eight hours post-transfection, 500 μl pseudotyped VSV-ΔG bearing VSV-G protein was used to infect Vero E6 cells.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Neutralization assays: The day before neutralization assays, the BHK21-hACE2 cells were seeded into 96-well culture plates at an appropriate density.
    BHK21-hACE2
    suggested: None
    Then, the CHO-K1 cells were transfected with the Swt, S6, or S15 plasmids by Bio-Rad Gene Pulser Xcell system, respectively.
    CHO-K1
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Immunization of mice: Female K18-hACE2 transgenic mice were obtained from GemPharmatech Co.,
    K18-hACE2
    suggested: RRID:IMSR_GPT:T037657)
    The K18-hACE2 or BALB/C mice aged 6–7 weeks were immunized twice by intramuscular injection (100 μL in each of the left and right quadriceps femoris muscles per mouse) at 2 weeks apart.
    BALB/C
    suggested: None
    Recombinant DNA
    SentencesResources
    Plasmid and Site-directed mutagenesis: The DNA sequences of human codon-optimized S proteins from SARS-COV-2 variants (B.1.1.7, GISAID: EPI-ISL-601443; B.1.351, GISAID: EPI_ISL_678597; P.1, GISAID: EPI_ISL_906075; B. 1.525, GISAID: EPI_ISL_1093472; B.1.2, GISAID: EPI_ISL_2000505; B. 1.617.1 GISAID: EPI_ISL_1660428 S1; B.1.627.2, GISAID: EPI_ISL_2029113; C.37, GISAID: EPI_ISL_3023383; B.1.1.529, GISAID:EPI_ISL_7162071) and S protein mutations were commercially synthesized or generated by overlapping-PCR based mutagenesis using pCAGGS-SARS-CoV-2-S-C9 (gifted from Dr. Wenhui Li, National Institute of Biological Science, Beijing, China) as a template and cloned into pCAGGS vector with C-terminal 18 aa truncation to improve VSV pseudotyping efficiency (47).
    pCAGGS-SARS-CoV-2-S-C9
    suggested: None
    pCAGGS
    suggested: RRID:Addgene_127347)
    To produce pseudotyped VSV-ΔG-Luc bearing SARS-CoV-2 spike protein (pseudo-SARS-CoV-2), Vero E6 cells were seeded in 10-cm dishes and transfected simultaneously with 15 μg SARS-CoV-2-S-Δ18 plasmid using Lipofectamine 2000 (
    SARS-CoV-2-S-Δ18
    suggested: None
    The sequences were synthesized and constructed between Hind III and Not I site into GS-KS001 plasmid (Quacell biotechnology).
    GS-KS001
    suggested: None
    Software and Algorithms
    SentencesResources
    The 50 % neutralization dilution titer (NT50) and Geometric Mean Titers (GMT) with NT50 were calculated by GraphPad Prism 7 (GraphPad Software, Inc.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Immunization of mice: Female K18-hACE2 transgenic mice were obtained from GemPharmatech Co.,
    GemPharmatech
    suggested: (GemPharmatech, RRID:SCR_017239)
    The structural figures were obtained using the PyMOL Molecular Graphics System, Version 1.0.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)
    MAFFT (v7.487) was used to align each peptide sequence to the reference sequence (Wuhan-Hu-1/2019), and the mutation information was parsed using a custom python script.
    MAFFT
    suggested: (MAFFT, RRID:SCR_011811)

    Results from OddPub: Thank you for sharing your data.

    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.

    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 10.1101/2021.12.21.473594 on bioRxiv