Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2

  1. Zhenhao Fang
  2. Lei Peng
  3. Renata Filler
  4. Kazushi Suzuki
  5. Andrew McNamara
  6. Qianqian Lin
  7. Paul A. Renauer
  8. Luojia Yang
  9. Bridget Menasche
  10. Angie Sanchez
  11. Ping Ren
  12. Qiancheng Xiong
  13. Madison Strine
  14. Paul Clark
  15. Chenxiang Lin
  16. Albert I. Ko
  17. Nathan D. Grubaugh
  18. Craig B. Wilen
  19. Sidi Chen

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Abstract

The Omicron variant of SARS-CoV-2 recently swept the globe and showed high level of immune evasion. Here, we generate an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and test its activity in animals, both alone and as a heterologous booster to WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicits strong antibody response in vaccination-naïve mice. Mice that received two-dose WT LNP-mRNA show a > 40-fold reduction in neutralization potency against Omicron than WT two weeks post boost, which further reduce to background level after 3 months. The WT or Omicron LNP-mRNA booster increases the waning antibody response of WT LNP-mRNA vaccinated mice against Omicron by 40 fold at two weeks post injection. Interestingly, the heterologous Omicron booster elicits neutralizing titers 10-20 fold higher than the homologous WT booster against Omicron variant, with comparable titers against Delta variant. All three types of vaccination, including Omicron alone, WT booster and Omicron booster, elicit broad binding antibody responses against SARS-CoV-2 WA-1, Beta, Delta variants and SARS-CoV. These data provide direct assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to WT mRNA vaccine.

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  1. Version published to 10.1038/s41467-022-30878-4
  2. Version published to 10.1101/2022.02.14.480449v2 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2022.02.14.480449: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variableMouse vaccination: Vaccine immunogenicity study used 6 weeks old female C57BL/6Ncr (B6) mice purchased from Charles River.
    RandomizationReplication, randomization, blinding and reagent validations: Biological or technical replicate samples were randomized where appropriate.
    BlindingReplication, randomization, blinding and reagent validations: Biological or technical replicate samples were randomized where appropriate.
    Power Analysisnot detected.
    Cell Line AuthenticationContamination: All cell lines tested negative for mycoplasma.

    Table 2: Resources

    Antibodies
    SentencesResources
    Cells were washed twice after the primary stain and incubated with PE–anti-human Fc antibody (Biolegend, 410708) in MACS buffer for 20 min on ice.
    PE–anti-human Fc antibody ( Biolegend , 410708
    suggested: None
    Anti-mouse secondary antibody (Fisher, Cat# A-10677) at 1:2500 dilution in blocking buffer was incubated at room temperature for one hour.
    Anti-mouse
    suggested: (Thermo Fisher Scientific Cat# A-10677, RRID:AB_2534060)
    Experimental Models: Cell Lines
    SentencesResources
    Validation of LNP-mRNA mediated spike expression in vitro and receptor binding capability of expressed Omicron HexaPro spikes: On day 1, HEK293T cells were seeded at 50% confluence in 24-well plate and mixed with 2 μg Omicron LNP-mRNA.
    HEK293T
    suggested: None
    Briefly, 293FT cells were seeded in 150 mm plates, and transfected with 21 μg pHIVNLGagPol, 21 μg pCCNanoLuc2AEGFP, and 7.5 μg of corresponding plasmids, in the presence of 198 μl PEI (1mg/ml, PEI MAX, Polyscience).
    293FT
    suggested: None
    To normalize pseudovirus tilter, 0.01 x106 293T-hACE2 cells were plated in each well of a 96-well plate.
    293T-hACE2
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Mouse vaccination: Vaccine immunogenicity study used 6 weeks old female C57BL/6Ncr (B6) mice purchased from Charles River.
    C57BL/6Ncr
    suggested: RRID:MGI:2160593)
    Recombinant DNA
    SentencesResources
    The accessory plasmids for pseudovirus assay including pHIVNLGagPol and pCCNanoLuc2AEGFP were from Dr.
    pCCNanoLuc2AEGFP
    suggested: None
    1.1.529 variant S protein (Omicron variant-Δ19) were made based on the pSARS-CoV-2-Δ19.
    pSARS-CoV-2-Δ19
    suggested: None
    Software and Algorithms
    SentencesResources
    Data was collected on BD FACSAria II Cell Sorter (BD) and analyzed using FlowJo software.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    The 50% inhibitory concentration (IC50) was calculated with a four-parameter logistic regression using GraphPad Prism (GraphPad Software Inc.).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    The statistical significance was labeled as follows: n.s., not significant; * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. Prism (GraphPad Software) and RStudio were used for these analyses.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Schematic illustrations: Schematic illustrations were created with Affinity Designer or BioRender.
    BioRender
    suggested: (Biorender, RRID:SCR_018361)

    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:
    While a limitation of our study is that these are animal data, although the antibody responses to vaccination is highly conserved between mouse and human (and that the mouse is a widely used preclinical model by major vaccine makers36,37). In fact, a very recent report showed waning immunity in vaccinated individuals24 and that a booster shot using the original WA-1 based mRNA vaccine helps recover partial immunity. However, the neutralizing antibody titers even after the boost with a WA-1 based vaccine titer were still significantly lower against Omicron as compared to WA-1 and other variants, urging for development and testing of an Omicron-specific vaccine not studied before. We tested the Omicron-specific LNP-mRNA vaccine candidate in the context of WA-1 vaccinated animals. While animals almost completely lost antibody protection against Omicron even though they received two doses of WA-1 mRNA vaccine 3.5 months ago, our results showed that a single dose of Omicron mRNA vaccination boosted neutralizing antibody titers over 1000-fold against Omicron. In addition, the Omicron-specific vaccine also brought back neutralizing titers against WA-1 and Delta variants to a level comparable to peak titers by WA-1 mRNA vaccine. The Omicron booster shot provided superior protection against Omicron variant and comparable humoral defense against WA-1 and Delta variants. Such surge of antibody titer by Omicron booster shot, and the neutralization activities against WA-1 and Delta, two o...

    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: Please consider improving the rainbow (“jet”) colormap(s) used on page 32. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    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.

  4. Version published to 10.1101/2022.02.14.480449v1 on bioRxiv