Highly Thermotolerant SARS-CoV-2 Vaccine Elicits Neutralising Antibodies against Delta and Omicron in Mice

  1. Petrus Jansen van Vuren
  2. Alexander J. McAuley
  3. Michael J. Kuiper
  4. Nagendrakumar Balasubramanian Singanallur
  5. Matthew P. Bruce
  6. Shane Riddell
  7. Sarah Goldie
  8. Shruthi Mangalaganesh
  9. Simran Chahal
  10. Trevor W. Drew
  11. Kim R. Blasdell
  12. Mary Tachedjian
  13. Leon Caly
  14. Julian D. Druce
  15. Shahbaz Ahmed
  16. Mohammad Suhail Khan
  17. Sameer Kumar Malladi
  18. Randhir Singh
  19. Suman Pandey
  20. Raghavan Varadarajan
  21. Seshadri S. Vasan

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Abstract

As existing vaccines fail to completely prevent COVID-19 infections or community transmission, there is an unmet need for vaccines that can better combat SARS-CoV-2 variants of concern (VOC). We previously developed highly thermo-tolerant monomeric and trimeric receptor-binding domain derivatives that can withstand 100 °C for 90 min and 37 °C for four weeks and help eliminate cold-chain requirements. We show that mice immunised with these vaccine formulations elicit high titres of antibodies that neutralise SARS-CoV-2 variants VIC31 (with Spike: D614G mutation), Delta and Omicron (BA.1.1) VOC. Compared to VIC31, there was an average 14.4-fold reduction in neutralisation against BA.1.1 for the three monomeric antigen-adjuvant combinations and a 16.5-fold reduction for the three trimeric antigen-adjuvant combinations; the corresponding values against Delta were 2.5 and 3.0. Our findings suggest that monomeric formulations are suitable for upcoming Phase I human clinical trials and that there is potential for increasing the efficacy with vaccine matching to improve the responses against emerging variants. These findings are consistent with in silico modelling and AlphaFold predictions, which show that, while oligomeric presentation can be generally beneficial, it can make important epitopes inaccessible and also carries the risk of eliciting unwanted antibodies against the oligomerisation domain.

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  1. Version published to 10.3390/v14040800
  2. Version published to 10.1101/2022.03.03.481940v3 on bioRxiv
  3. ScreenIT

    SciScore for 10.1101/2022.03.03.481940: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: All animal studies were approved by the Institutional Animal Ethics Committee (IAEC no. CAF/ETHICS/799/2020).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    In brief, 100 μL cell culture supernatant from infected Vero E6 cells was combined with 300 μL TRIzol reagent (Thermo Fisher Scientific) and RNA was purified using a Direct-zol RNA Miniprep kit (Zymo Research; Irvine, CA, USA).
    Vero E6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Mouse immunisation: The purified protein antigens (20 μg per animal) were intramuscularly immunised in 6-8 weeks old female BALB/c mice (n=5) with ‘MF59’ equivalent squalene-based oil-in-water emulsion AddaVax or SWE adjuvants, on Day 0 (prime), Day 21 (first boost), and Day 42 (second boost).
    BALB/c
    suggested: None
    Recombinant DNA
    SentencesResources
    Thermostable monomer-adjuvant formulations: The RBD of SARS-CoV-2 and its mutants were cloned in the pcDNA3.4 vector for expression in Expi293F cells as described earlier [10,11].
    pcDNA3.4
    suggested: None
    Software and Algorithms
    SentencesResources
    Denatured libraries were sequenced on an Illumina MiniSeq using a 300-cycle Mid-Output Reagent kit as per the manufacturer’s protocol.
    MiniSeq
    suggested: None

    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.

    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 10.1101/2022.03.03.481940v2 on bioRxiv
  5. Version published to 10.1101/2022.03.03.481940v1 on bioRxiv