Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2
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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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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
Ethics not detected. Sex as a biological variable Mouse vaccination: Vaccine immunogenicity study used 6 weeks old female C57BL/6Ncr (B6) mice purchased from Charles River. Randomization Replication, randomization, blinding and reagent validations: Biological or technical replicate samples were randomized where appropriate. Blinding Replication, randomization, blinding and reagent validations: Biological or technical replicate samples were randomized where appropriate. Power Analysis not detected. Cell Line Authentication Contamination: All cell lines tested negative for mycoplasma. Table 2: Resources
Antibodies Sentences Resources Cells were washed twice after the primary stain and incubated with PE–anti-human … 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
Ethics not detected. Sex as a biological variable Mouse vaccination: Vaccine immunogenicity study used 6 weeks old female C57BL/6Ncr (B6) mice purchased from Charles River. Randomization Replication, randomization, blinding and reagent validations: Biological or technical replicate samples were randomized where appropriate. Blinding Replication, randomization, blinding and reagent validations: Biological or technical replicate samples were randomized where appropriate. Power Analysis not detected. Cell Line Authentication Contamination: All cell lines tested negative for mycoplasma. Table 2: Resources
Antibodies Sentences Resources 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 , 410708suggested: NoneAnti-mouse secondary antibody (Fisher, Cat# A-10677) at 1:2500 dilution in blocking buffer was incubated at room temperature for one hour. Anti-mousesuggested: (Thermo Fisher Scientific Cat# A-10677, RRID:AB_2534060)Experimental Models: Cell Lines Sentences Resources 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. HEK293Tsuggested: NoneBriefly, 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). 293FTsuggested: NoneTo normalize pseudovirus tilter, 0.01 x106 293T-hACE2 cells were plated in each well of a 96-well plate. 293T-hACE2suggested: NoneExperimental Models: Organisms/Strains Sentences Resources Mouse vaccination: Vaccine immunogenicity study used 6 weeks old female C57BL/6Ncr (B6) mice purchased from Charles River. C57BL/6Ncrsuggested: RRID:MGI:2160593)Recombinant DNA Sentences Resources The accessory plasmids for pseudovirus assay including pHIVNLGagPol and pCCNanoLuc2AEGFP were from Dr. pCCNanoLuc2AEGFPsuggested: None1.1.529 variant S protein (Omicron variant-Δ19) were made based on the pSARS-CoV-2-Δ19. pSARS-CoV-2-Δ19suggested: NoneSoftware and Algorithms Sentences Resources Data was collected on BD FACSAria II Cell Sorter (BD) and analyzed using FlowJo software. FlowJosuggested: (FlowJo, RRID:SCR_008520)The 50% inhibitory concentration (IC50) was calculated with a four-parameter logistic regression using GraphPad Prism (GraphPad Software Inc.). GraphPad Prismsuggested: (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. GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Schematic illustrations: Schematic illustrations were created with Affinity Designer or BioRender. BioRendersuggested: (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.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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