Immunogenicity of novel mRNA COVID-19 vaccine MRT5500 in mice and non-human primates

  1. Kirill V. Kalnin
  2. Timothy Plitnik
  3. Michael Kishko
  4. Jinrong Zhang
  5. Donghui Zhang
  6. Adrien Beauvais
  7. Natalie G. Anosova
  8. Timothy Tibbitts
  9. Joshua M. DiNapoli
  10. Po-Wei D. Huang
  11. James Huleatt
  12. Deanne Vincent
  13. Katherine Fries
  14. Shrirang Karve
  15. Rebecca Goldman
  16. Hardip Gopani
  17. Anusha Dias
  18. Khang Tran
  19. Minnie Zacharia
  20. Xiaobo Gu
  21. Lianne Boeglin
  22. Sudha Chivukula
  23. Ron Swearingen
  24. Victoria Landolfi
  25. Tong-Ming Fu
  26. Frank DeRosa
  27. Danilo Casimiro

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Abstract

An effective vaccine to address the global pandemic of coronavirus disease 2019 (COVID-19) is an urgent public health priority 1 . Novel synthetic mRNA and vector-based vaccine technologies offer an expeditious development path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on Spike (S) glycoprotein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus causing COVID-19. Several mRNA constructs expressing various structural conformations of S-protein, including wild type (WT), a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), were tested in a preclinical animal model for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques. The selected 2P/GSAS vaccine formulation, now designated MRT5500, elicited potent nAbs as measured in two types of neutralization assays. In addition, MRT5500 elicited T H 1-biased responses in both mouse and non-human primate species, a result that helps to address a hypothetical concern regarding potential vaccine-associated enhanced respiratory diseases associated with T H 2-biased responses. These data position MRT5500 as a viable vaccine candidate for clinical development against COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.10.14.337535: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIACUC: Animal studies: Animal experiments were carried out in compliance with all pertinent US National Institutes of Health regulations and were conducted with approved animal protocols from the Institutional Animal Care and Use Committee (IACUC) at the research facilities.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableFemale specific pathogen free BALB/c mice of 6-8-week-old were vaccinated in groups of 10, with 50 μL of the designated mRNA/LNP formulation into one hind leg for the prime (D0) and the contralateral hind leg for the boost (D21).
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    After washing and fixation of the Vero E6 cell monolayers, SARS-CoV-2 antigen production in cells was detected by successive incubations with an anti-SARS-CoV nucleoprotein mouse monoclonal antibody (Sino Biological catalog# 40143-MM05), HRP IgG conjugate (Jackson ImmunoResearch Laboratories, catalog #115-035-062), and a chromogenic substrate.
    anti-SARS-CoV nucleoprotein
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Briefly, 5X105 HEK293 cells were transfected using 1 μg of mRNA complexed with Lipofectamine 2000, and allowed to incubate 20 hs at 37°C.
    HEK293
    suggested: None
    The serum-virus mixtures were inoculated into wells of a 96-well microplate with preformed Vero E6 (ATCC® CRL-1586TM) cell monolayers and adsorbed at 37°C with 5% CO2 for 0.5 h.
    Vero E6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Female specific pathogen free BALB/c mice of 6-8-week-old were vaccinated in groups of 10, with 50 μL of the designated mRNA/LNP formulation into one hind leg for the prime (D0) and the contralateral hind leg for the boost (D21).
    BALB/c
    suggested: None
    Software and Algorithms
    SentencesResources
    Concanavalin A (CovA, Sigma C5275) at concentration of 1 μg/ml was used for a positive control stimulation.
    CovA
    suggested: (COVA, RRID:SCR_005175)

    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.

    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.

  2. Version published to 10.1101/2020.10.14.337535v1 on bioRxiv