SARS-CoV-2 Subunit Virus-Like Vaccine Demonstrates High Safety Profile and Protective Efficacy: Preclinical Study

  1. A.V. Vakhrusheva
  2. A.V. Kudriavtsev
  3. N.A. Kryuchkov
  4. R.V. Deev
  5. M.E. Frolova
  6. K.A. Blagodatskikh
  7. M. Djonovic
  8. A.A. Nedorubov
  9. E. Odintsova
  10. A.V. Ivanov
  11. E.A. Romanovskaya-Romanko
  12. M.A. Stukova
  13. A.A. Isaev
  14. I.V. Krasilnikov

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Abstract

Public health threat coming from a rapidly developing COVID-19 pandemic calls for developing safe and effective vaccines with innovative designs. This paper presents preclinical trial results of “Betuvax-CoV-2”, a vaccine developed as a subunit vaccine containing a recombinant RBD-Fc fusion protein and betulin-based spherical virus-like nanoparticles as an adjuvant (“Betuspheres”). The aim of the study was to demonstrate vaccine safety in mice, rats, and Chinchilla rabbits through acute, subchronic, and reproductive toxicity studies. Along with safety, the vaccine demonstrated protective efficacy through SARS-CoV-2-neutralizing antibody production in mice, rats, hamsters, rabbits, and primates (rhesus macaque), and lung damage and infection protection in hamsters and rhesus macaque model. Eventually, “Betuvax-CoV-2” was proved to confer superior efficacy and protection against the SARS-CoV-2 in preclinical studies. Based on the above results, the vaccine was enabled to enter clinical trials that are currently underway.

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  1. ScreenIT

    SciScore for 10.1101/2022.05.18.492452: (What is this?)

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

    Table 1: Rigor

    EthicsField Sample Permit: The animals were infected at the FGBU (Federal State Budgetary Institution) Central Research Institute No. 48 of the Russian Ministry of Defense, Sergiev Posad, Russia.
    Sex as a biological variableReproductive toxicity in female rats: The reproductive toxicity of the vaccine was studied in female (n=60) and male (n=30) outbred rats.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Antibody titers were expressed as log base 2 (Log2).
    Log2
    suggested: None
    An immunohistochemical study was performed to immunotype infiltrated cells in the lungs using antibodies against the T-lymphocyte marker (CD3 — Cell Marque, 103-R94, Rocklin, California, USA) and macrophages M2-phenotype (CD163 MsmAb —
    CD3
    suggested: None
    Antibodies against vascular endothelial cells (CD31 Mon. mouse – Cell Marque, JC-70, Rocklin, California, USA) were also used.
    CD31
    suggested: None
    For immunohistochemical evaluation of the coronavirus proteins (S- and N-proteins), SARS-CoV2 spike (Genetex, GTX135356, Irvine, California, USA) and SARS-CoV2 nucleocapsid (Invitrogen, MA1-7404, Waltham, Massachusetts, USA) antibodies were used.
    GTX135356
    suggested: (GeneTex Cat# GTX135356, RRID:AB_2887482)
    SARS-CoV2 nucleocapsid
    suggested: (HistoSure by Synaptic Systems Cat# HS-452 111BT, RRID:AB_2891263)
    Experimental Models: Cell Lines
    SentencesResources
    The SARS-CoV-2 accumulation titer in the lungs was determined using the negative colonies method on the Vero C1008 cell culture.
    Vero C1008
    suggested: ECACC Cat# 85020206, RRID:CVCL_0574)
    Experimental Models: Organisms/Strains
    SentencesResources
    Animals & Ethics Statement: BALB/c and C57BL/6 mice used in the study were obtained from the Stolbovaya branch of the FSBI SCBT FMBA (Scientific Center of Biomedical Technologies of Federal Medical and Biological Agency) of Russia.
    BALB/c
    suggested: None
    C57BL/6
    suggested: None
    C57/ black mice (n=22) were immunized intraperitoneally twice at a dose of 5 or 20 μg or 40 μg /animal (n=7 per group) or PBS (n=8) over a 21-day period.
    C57/
    suggested: None
    Software and Algorithms
    SentencesResources
    Animal husbandry was compliant with each facility’s SOPs and sanitary and epidemiological rules SR 2.2.1.3218-14 “Sanitary and Epidemiological Requirements for the Device, Equipment and Maintenance of Experimental Biological Clinics
    Experimental Biological
    suggested: None
    Using a computer video system (IBM PC + microscope Leica DM 1000, Leica Camera, Wetzlar, Germany) and the ImageScope-M software package (Systems for Microscopy and Analysis, Moscow, Russia), the “airiness” parameter, specific area of the histological section occupied by air and free from infiltration or exudate from the alveolar space, was determined in a semi-automatic mode.
    ImageScope-M
    suggested: None
    Statistical Analysis: The obtained data were analyzed with Microsoft Office Excel 2010 (
    Microsoft Office Excel
    suggested: (Microsoft Excel, RRID:SCR_016137)
    (Microsoft, Redmond, Washington, USA) and GraphPad Prism v6.01 software (GraphPad Software, San Diego, California, USA) for geometric mean, standard deviation, arithmetic mean, and standard errors.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT05270954Active, not recruitingSafety, Tolerability and Immunogenicity of Recombinant COVID…

    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.
    • No funding statement was detected.
    • 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.

  2. Version published to 10.1101/2022.05.18.492452v1 on bioRxiv