BCG Vaccine Derived Peptides Induce SARS-CoV-2 T Cell Cross-Reactivity

  1. Peter J. Eggenhuizen
  2. Boaz H. Ng
  3. Janet Chang
  4. Ashleigh L. Fell
  5. Rachel M. Y. Cheong
  6. Wey Y. Wong
  7. Poh-Yi Gan
  8. Stephen R. Holdsworth
  9. Joshua D. Ooi

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Abstract

Epidemiological studies and clinical trials suggest Bacillus Calmette-Guérin (BCG) vaccine has protective effects against coronavirus disease 2019 (COVID-19). There are now over 30 clinical trials evaluating if BCG vaccination can prevent or reduce the severity of COVID-19. However, the mechanism by which BCG vaccination can induce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses is unknown. Here, we identify 8 novel BCG-derived peptides with significant sequence homology to either SARS-CoV-2 NSP3 or NSP13-derived peptides. Using an in vitro co-culture system, we show that human CD4+ and CD8+ T cells primed with a BCG-derived peptide developed enhanced reactivity to its corresponding homologous SARS-CoV-2-derived peptide. As expected, HLA differences between individuals meant that not all persons developed immunogenic responses to all 8 BCG-derived peptides. Nevertheless, all of the 20 individuals that were primed with BCG-derived peptides developed enhanced T cell reactivity to at least 7 of 8 SARS-CoV-2-derived peptides. These findings provide an in vitro mechanism that may account, in part, for the epidemiologic observation that BCG vaccination confers some protection from COVID-19.

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  1. Version published to 10.3389/fimmu.2021.692729
  2. ScreenIT

    SciScore for 10.1101/2020.11.21.20236018: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: Ethics statement: The study was conducted according to the Declaration of Helsinki and approved by Monash University Human Research Ethics Committee project ID 25834.
    Consent: All donors provided written informed consent.
    Randomizationnot detected.
    BlindingThe investigators were not blinded to allocation during experiments and assessment of outcomes.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Donors with current or recent symptoms of COVID-19 or who tested positive for serum IgG or IgM SARS-CoV-2 antibodies by SARS-CoV-2 Colloidal Gold Immunochromatography Assay Kit (MyBioSource) were excluded.
    IgM SARS-CoV-2
    suggested: None
    On day 9 of co-culture, cells were restimulated by washing twice with 250μL PBS then 10,000 freshly-cultured, immature DCs were added per well with 10μg/mL of SARS-CoV-2 peptide from PP1-8 (Fig. 1) or control peptide CLIP103-117 and 1μg/mL anti-human CD28 monoclonal antibody (clone CD28.2, eBioscience) in serum-free RPMI.
    Fig . 1
    suggested: None
    anti-human CD28
    suggested: None
    Single colour controls were prepared using UltraComp eBeads (Invitrogen) for single colour control antibodies and ArC amine reactive compensation bead kit (Invitrogen) for Live/Dead single colour control.
    ArC
    suggested: None
    Software and Algorithms
    SentencesResources
    Protein BLAST search of the SARS-CoV-2 proteome (sequence ID NC_045512.2) restricted to Mycobacterium bovis (BCG) was performed using the NCBI blastp suite (
    BLAST
    suggested: (BLASTX, RRID:SCR_001653)
    https://blast.ncbi.nlm.nih.gov/Blast.cgi).
    https://blast.ncbi.nlm.nih.gov/Blast.cgi
    suggested: (TBLASTX, RRID:SCR_011823)
    After staining, cells were resuspended in 0.5% BSA, 2mM EDTA/PBS and acquired on an LSR-Fortessa X20 flow cytometer (BD) using BD FACSDiva software version 8.0.1.
    BD FACSDiva
    suggested: (BD FACSDiva Software, RRID:SCR_001456)
    .fcs files were analysed in FlowJo 10.6.2.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    Statistics: Flow cytometry data was exported from FlowJo 10.6.2 (BD) and analysed using R Studio version 1.3.959 before being analysed in GraphPad Prism 7 (Graphpad Software Inc.)
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Graphpad
    suggested: (GraphPad, RRID:SCR_000306)

    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 found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on pages 32, 33 and 36. 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.
    • 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

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  3. Version published to 10.1101/2020.11.21.20236018v1 on medRxiv