Low-dose bivalent mRNA vaccine is highly effective against different SARS-CoV-2 variants in a transgenic mouse model

  1. Björn Corleis
  2. Donata Hoffmann
  3. Susanne Rauch
  4. Charlie Fricke
  5. Nicole Roth
  6. Janina Gergen
  7. Kristina Kovacikova
  8. Kore Schlottau
  9. Nico Joel Halwe
  10. Lorenz Ulrich
  11. Jacob Schön
  12. Kerstin Wernike
  13. Marek Widera
  14. Sandra Ciesek
  15. Stefan O. Mueller
  16. Thomas C. Mettenleiter
  17. Benjamin Petsch
  18. Martin Beer
  19. Anca Dorhoi

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Abstract

Combining optimized spike (S) protein-encoding mRNA vaccines to target multiple SARS-CoV-2 variants could improve COVID-19 control. We compared monovalent and bivalent mRNA vaccines encoding B.1.351 (Beta) and/or B.1.617.2 (Delta) SARS-CoV-2 S-protein, primarily in a transgenic mouse model and a Wistar rat model. The low-dose bivalent mRNA vaccine contained half the mRNA of each respective monovalent vaccine, but induced comparable neutralizing antibody titres, enrichment of lung-resident memory CD8 + T cells, specific CD4 + and CD8 + responses, and fully protected transgenic mice from SARS-CoV-2 lethality. The bivalent mRNA vaccine significantly reduced viral replication in both Beta- and Delta-challenged mice. Sera from bivalent mRNA vaccine immunized Wistar rats also contained neutralizing antibodies against the B.1.1.529 (Omicron BA.1) variant. These data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines encoding distinct S-proteins is a feasible approach for increasing the potency of vaccines against emerging and co-circulating SARS-CoV-2 variants.

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    SciScore for 10.1101/2022.04.20.485440: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: Ethics: The animal experiments were evaluated and approved by the ethics committee of the State Office of Agriculture, Food safety, and Fishery in Mecklenburg–Western Pomerania (LALLF M-V: LVL MV/TSD/7221.3-1-055/20) and the State Office for Occupational Safety, Consumer Protection and Health in Brandenburg (LAVG: 2347-5-2021).
    Euthanasia Agents: The animals were infected under short-term isoflurane inhalation anesthesia with 25 μl of either 104.4 TCID50 SARS-CoV-2 lineage B.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    To discriminate between parenchymal and vascular T cells, vaccinated mice received 3 μg (in PBS) of anti-mouse CD45 antibody (retro-orbital administration) for 3 minutes during lethal anesthesia.
    anti-mouse CD45
    suggested: None
    Unspecific antibody binding was blocked with TruStain FcX (anti-mouse CD16/32) solution (BioLegend) for 5 minutes at 4°C before adding freshly prepared antibody cocktails.
    anti-mouse CD16/32
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    The virus was harvested after 72 hours, titrated on Vero E6 cells and stored at −80 °C until further use.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Experimental Models: Organisms/Strains
    SentencesResources
    Study design: K18-hACE2 transgenic mice were vaccinated on Day 0 (prime) and Day 28 (boost) and infected (challenge) on Day 56, as detailed in Fig.
    K18-hACE2
    suggested: RRID:IMSR_GPT:T037657)
    Samples (mouse swabs/organs) that tested positive for viral genomic RNA were evaluated using an assay specifically detecting sgRNA of the ORF7a as described in Hoffmann et al 2021.26 Wistar rats were vaccinated on Day 0 (prime) and Day 21 (booster), as detailed in Fig.
    Wistar
    suggested: None

    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.
    • 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

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  2. Version published to 10.1101/2022.04.20.485440v1 on bioRxiv