BCG vaccination of Diversity Outbred mice induces cross-reactive antibodies to SARS-CoV-2 spike protein
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Abstract
The Bacillus Calmette-Guérin (BCG) vaccine, the only vaccine against tuberculosis, induces cross-protection against pathogens unrelated to Mycobacterium , including viruses. Epidemiological studies have identified potential benefits of BCG vaccination against SARS-CoV-2 infection. While BCG’s heterologous effects have been widely attributable to trained immunity , we hypothesized BCG vaccination could induce cross-reactive antibodies against the spike protein of SARS-CoV-2 Wuhan-Hu-1. The concentration of IgG reactive to SARS-CoV-2 spike protein from the sera of BCG-vaccinated, Diversity Outbred (DO) mice and C57BL/6J inbred mice was measured using ELISA. Sera from 10/15 BCG-vaccinated DO mice possessed more IgG reactive to recombinant spike protein than sera from BCG-vaccinated C57BL/6J mice and unvaccinated DO mice. Amino acid sequences common to BCG cell wall/membrane proteins and SARS-CoV-2 spike protein were identified as potential antigen candidates for future study. These results imply a humoral mechanism, influenced by genotype, by which BCG vaccination could confer immunity to SARS-CoV-2.
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SciScore for 10.1101/2022.04.18.488640: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: BCG-vaccinated mice: Studies were performed under protocols approved by the Animal Care and Use Committee (ACUC) of CBER/FDA protocol #2011-14. Sex as a biological variable Briefly, female C57BL/6J and female Diversity Outbred (DO) mice, purchased from Jackson Laboratories (Bar Harbor, ME), were used at 6-10 weeks of age. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources In-house ELISA to SARS-CoV-2 Antigens: We optimized an in-house ELISA to detect cross-reactive IgG antibodies in mouse sera. SARS-CoV-2suggested: NoneAntigenssuggested: NoneIgGsuggested: NoneOn day 3, the same detection antibody, goat anti-mouse … SciScore for 10.1101/2022.04.18.488640: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: BCG-vaccinated mice: Studies were performed under protocols approved by the Animal Care and Use Committee (ACUC) of CBER/FDA protocol #2011-14. Sex as a biological variable Briefly, female C57BL/6J and female Diversity Outbred (DO) mice, purchased from Jackson Laboratories (Bar Harbor, ME), were used at 6-10 weeks of age. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Antibodies Sentences Resources In-house ELISA to SARS-CoV-2 Antigens: We optimized an in-house ELISA to detect cross-reactive IgG antibodies in mouse sera. SARS-CoV-2suggested: NoneAntigenssuggested: NoneIgGsuggested: NoneOn day 3, the same detection antibody, goat anti-mouse IgG-HRP, was added followed by the addition of TMB and then HCl, as described above. anti-mouse IgG-HRPsuggested: NoneExperimental Models: Organisms/Strains Sentences Resources Briefly, female C57BL/6J and female Diversity Outbred (DO) mice, purchased from Jackson Laboratories (Bar Harbor, ME), were used at 6-10 weeks of age. C57BL/6Jsuggested: NoneSoftware and Algorithms Sentences Resources Basic Local Alignment Search Tool (BLAST) from NCBI was used to align the selected epitopes with the Swiss-Prot reviewed proteome of BCG strain Pasteur (Mycobacterium bovis (strain BCG / Pasteur 1173P2). BLASTsuggested: NoneNCBIsuggested: (NCBI, RRID:SCR_006472)The BCG protein and cellular component, as described on the UniprotKB database, was obtained for each peptide fitting the above criteria. UniprotKBsuggested: (UniProtKB, RRID:SCR_004426)Figures 4a and 4b were created using the R software package ggplot2. ggplot2suggested: NoneConcentration of bound-IgG was computed based on a 4-parameter logistic (4PL) regression model of the standard curve using the program Gen5. Gen5suggested: (Gen5, RRID:SCR_017317)Statistical Analysis: Graphs were made using Prism GraphPad version 9.1.0. Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (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: We detected the following sentences addressing limitations in the study:Future research could explore this study’s limitations by characterizing the binding site of the cross-reactive IgG antibodies and assessing the antibodies for neutralizing efficacy, or by investigating the genetic basis for the cross-reactive humoral response in DO mice. To the first point, affinity purification mass spectrometry (AP-MS) could confirm antibody concentration and purify the cross-reactive antibodies for affinity testing against peptides identified by our in silico analysis. To the second point, genotype-phenotype association studies, such as quantitative trait locus mapping, could be performed on larger sample sizes to identify gene candidates and polymorphisms.
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT03296423 Completed Bacillus Calmette-guérin Vaccination to Prevent Infections o… NCT04327206 Active, not recruiting BCG Vaccination to Protect Healthcare Workers Against COVID-… NCT04369794 Active, not recruiting COVID-19: BCG As Therapeutic Vaccine, Transmission Limitatio… 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.
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