Chimeric mRNA based COVID-19 vaccine induces protective immunity against Omicron and Delta

  1. Qidong Hu
  2. Ying Zhao
  3. Namir Shaabani
  4. Xiaoxuan Lyu
  5. Haotian Sun
  6. Vincent Cruz
  7. Yi Kao
  8. Jia Xu
  9. Amber Fossier
  10. Karen Stegman
  11. Zhihao Wang
  12. Zhenping Wang
  13. Yue Hu
  14. Yi Zheng
  15. Lilian Kyaw
  16. Cipriano Zuluaga
  17. Hua Wang
  18. Hong Pei
  19. Colin Powers
  20. Robert Allen
  21. Hui Xie
  22. Henry Ji
  23. Runqiang Chen

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Abstract

The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the efficacy and effectiveness of the two FDA-approved mRNA vaccines. Here, we explored various strategies to develop novel mRNAs vaccines to achieve safer and wider coverage of VOCs. Firstly, we constructed a cohort of mRNAs that feature a furin cleavage mutation in the spike (S) protein of predominant VOCs, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2). Not present in the mRNA vaccines currently in use, the mutation abolished the cleavage between the S1 and S2 subunits, potentially enhancing the safety profile of the immunogen. Secondly, we systematically evaluated the induction of neutralizing antibodies (nAb) in vaccinated mice, and discovered that individual VOC mRNAs elicited strong neutralizing activity in a VOC-specific manner. Thirdly, the IgG produced in mice immunized with Beta-Furin and Washington (WA)-Furin mRNAs showed potent cross-reactivity with other VOCs, which was further corroborated by challenging vaccinated mice with the live virus of VOCs. However, neither WA-Furin nor Beta-Furin mRNA elicited strong neutralizing activity against the Omicron variant. Hence, we further developed an Omicron-specific mRNA vaccine that restored protection against the original and the sublineages of Omicron variant. Finally, to broaden the protection spectrum of the new Omicron mRNA vaccine, we tested the concept of bivalent immunogen. Instead of just fusing two RBDs head-to-tail, we for the first time constructed an mRNA-based chimeric immunogen by introducing the RBD of Delta variant into the entire S antigen of Omicron. The resultant chimeric mRNA was capable of inducing potent and broadly acting nAb against Omicron (both BA.1 and BA.2) and Delta, which paves the way to develop new vaccine candidate to target emerging variants in the future.

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  1. Version published to 10.1101/2022.03.04.483032v2 on bioRxiv
  2. ScreenIT

    SciScore for 10.1101/2022.03.04.483032: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: All protocols were approved by the Institutional Animal Care and Use Committee (IACUC).
    Sex as a biological variableAnimals and in vivo studies: 7-week-old BALB/cJ female mice were purchased from the Jackson Laboratory.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    200ul FACS buffer was used to wash the cells twice with the same speed and time after 30-minute incubation, followed by rat anti-human Fc antibody conjugated to APC (Cat: 410712, BioLegend; 1:100 dilution) for 15 min on ice in the dark for secondary detection.
    anti-human Fc
    suggested: (BioLegend Cat# 410712, RRID:AB_2565790)
    APC
    suggested: (BioLegend Cat# 410712, RRID:AB_2565790)
    The next day, SARS-CoV-2 Spike pseudotyped ΔG-VSV-luciferase was incubated with a dilution series of mouse serum (dilutions as indicated) and anti-VSV-G (Kerafast; 1 μg/mL) antibody for 30 minutes at room temperature and added to the HEK-Blue 293 hACE2-TMPRSS2 cells.
    anti-VSV-G
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Flow cytometry: The collected cell pellets were washed with 250ul of FACS buffer (DPBS + 0.5% BSA) in 96 wells treated plate followed by 30-minute incubation with the in-house STI-2020 (for DCs) or 10A3 (for 293T cells) primary antibody (1:1000) to detect SARS Cov-2 spike.
    293T
    suggested: None
    SARS-CoV-2 Spike pseudotyped ΔG-VSV-luciferase was generated by nucleofection of BHK cells (maintained in DMEM/F12 with 10%FBS and 5%TPB) with Spike-expressing plasmid followed by transduction with G-pseudotyped ΔG-luciferase (G*ΔG-luciferase) rVSV (Kerafast) 18-24 hours later.
    BHK
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Animals and in vivo studies: 7-week-old BALB/cJ female mice were purchased from the Jackson Laboratory.
    BALB/cJ
    suggested: RRID:MGI:5652576)
    Recombinant DNA
    SentencesResources
    In vitro transcription and purification of RNA: To generate the template for RNA synthesis, the sequences of the SARS-Cov-2 Spike protein of VOC were codon optimized and cloned into pVAX1-based backbone which features 5⍰-UTR, 3⍰-UTR and Poly-A tail.
    pVAX1-based
    suggested: None
    Software and Algorithms
    SentencesResources
    200ul FACS buffer was used to wash the cells twice with the same speed and time after 30-minute incubation, followed by rat anti-human Fc antibody conjugated to APC (Cat: 410712, BioLegend; 1:100 dilution) for 15 min on ice in the dark for secondary detection.
    BioLegend
    suggested: (BioLegend, RRID:SCR_001134)

    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: 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.
    • No funding statement was detected.
    • 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.

  3. Version published to 10.1101/2022.03.04.483032v1 on bioRxiv