mRNA-1273 efficacy in a severe COVID-19 model: attenuated activation of pulmonary immune cells after challenge
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Abstract
The mRNA-1273 vaccine was recently determined to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from interim Phase 3 results. Human studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibit more severe SARS-CoV-2 disease similar to hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and non-human primates, mRNA-1273- mediated immunity was non-sterilizing and coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high resolution analysis which is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a two-dose schedule and provides insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.
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SciScore for 10.1101/2021.01.25.428136: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: All animal protocols were approved by the Institutional Animal Care and Use Committee at UTMB. Randomization not detected. Blinding Samples were evaluated by a board-certified veterinary pathologist in a blinded manner. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources Bound antibodies were detected with HRP- conjugated goat anti-hamster IgG (1:10,000 Abcam AB7146). anti-hamster IgGsuggested: NoneAfter 3 days, plaques were immunostained with a human monoclonal antibody cocktail specific for the S protein (Distributed Bio) and an anti-human IgG HRP conjugated secondary antibody (Sera Care Cat … SciScore for 10.1101/2021.01.25.428136: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: All animal protocols were approved by the Institutional Animal Care and Use Committee at UTMB. Randomization not detected. Blinding Samples were evaluated by a board-certified veterinary pathologist in a blinded manner. Power Analysis not detected. Sex as a biological variable not detected. Table 2: Resources
Antibodies Sentences Resources Bound antibodies were detected with HRP- conjugated goat anti-hamster IgG (1:10,000 Abcam AB7146). anti-hamster IgGsuggested: NoneAfter 3 days, plaques were immunostained with a human monoclonal antibody cocktail specific for the S protein (Distributed Bio) and an anti-human IgG HRP conjugated secondary antibody (Sera Care Cat No.5220-0456). anti-human IgGsuggested: NoneA peroxide block (Leica) was applied for 5 min to quench endogenous peroxidase activity prior to applying the SARS-CoV-2 antibody (1:2000, GeneTex, GTX135357). SARS-CoV-2suggested: (GeneTex Cat# GTX135357, RRID:AB_2868464)GTX135357suggested: (GeneTex Cat# GTX135357, RRID:AB_2868464)Software and Algorithms Sentences Resources Titers were determined using a four-parameter logistic curve fit in GraphPad Prism (GraphPad Software, Inc.) and defined as the reciprocal dilution at approximately OD450nm = 1.5 (normalized to a hamster standard on each plate). GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Significant genes were clustered into functional modules using Louvain community clustering based on the functional similarity between genes in the lung tissue, as predicted by HumanBase (https://hb.flatironinstitute.org) (53) HumanBasesuggested: (HumanBase, RRID:SCR_016145)Statistical analysis: Statistical analysis was performed using GraphPad Prism software, version 6. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Data availability: RNA sequencing data have been deposited in NCBI’s Gene Expression Omnibus and are accessible through the GEO Series accession number GSE163838. CONTRIBUTIONS: M.M., D.E., A.C. and A.B, conceived and designed the study. Gene Expression Omnibussuggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)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.
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