An ecological study to evaluate the association of Bacillus Calmette-Guerin (BCG) vaccination on cases of SARS-CoV2 infection and mortality from COVID-19

Lucy Chimoyi; Kavindhran Velen; Gavin J. Churchyard; Robert Wallis; James J. Lewis; Salome Charalambous

doi:10.1371/journal.pone.0243707

Peer Review History

Original SubmissionAugust 27, 2020
6 Oct 2020 Decision Letter - Angelo A. Izzo, Editor PONE-D-20-26939 An ecological study to evaluate the association of Bacillus Calmette-Guerin (BCG) vaccination on cases of SARS-CoV2 infection and mortality from COVID-19 PLOS ONE Dear Dr. Chimoyi, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Nov 20 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Its a good descriptive analysis of prevailing COVID 19 pandemic and ecological paramenters in the sampled countries and its association with BCG vaccination policy. However, authors are encouraged to discuss in detail the observed association with confounding variables. Authors should clearly describe fallacy of ecological study in ascertaining association between two variables and is descriptive in nature rather than analytical. It is appreciated however that authors have observed caution with conclusion since confounders can mislead with both association and non association. 1. Authors should describe in details the method of selection of countries with a flow chart. 2. They should describe the possible alternative tools being referred in conclusion. 3. Elaborate on methods used for data collection eg. immunization schedule was it standardized across the countries. 4. Provide reference for no BCG policy criteria for being used less than 30 yrs and data on current rates of BCG immunization in BCG policy states. classification of current, ever and never 5. Please explain why were the countries with less than 1 million population excluded. 6. Why weren't control countries (with limited or no COVID cases) considered in the study for comparison. 7. Significant association of COVID cases with population and testing rates, tabulated with BCG policy fo some understanding. 8. Figure 2 is not well explanatory, Kindly redesign. 9. Unpublished studies mentioned should be referred or identified. Reviewer #2: These are my comments about the manuscript "An ecological study to evaluate the association of Bacillus Calmette-Guerin (BCG) vaccination on cases of SARS-CoV2 infection and mortality from COVID-19" that I was asked to evaluate. The authors report the results of an ecological study aimed at evaluating the association between national BCG vaccination status and rates of COVID-19 incidence and mortality. They do so by utilizing national-level data from various sources while, implementing log-linear regression models, adjusting for a host of factors that could be confounders or mediators. They conclude that there is no association between BCG status and COVID-19. First, the topic is of great importance on a global level, and much has been written about the theoretical protective effect of BCG against severe COVID-19. These speculations have even initiated several large clinical studies, as well as mass vaccination in Japan that has caused supply shortages of BCG. For that reason, I believe that, though the topic is not novel, it is still of great interest to the scientific community. The manuscript is well written, and the internal flow is clear. The use of ecological studies has been greatly criticized and is inherently open to confounding. The authors have gone to great lengths to minimize this effect by adjustments to a host of variables and by selecting outcomes that are less prone to bias, but it is still an ecological study. My main comment would be that it seems that some time has passed since the manuscript was finalized, and several papers have been published on the same topic, none of which is mentioned and discussed, leaving the manuscript somewhat outdated. Just to give a few examples, of many others: Lindestam Arlehamn CS, Sette A, Peters B. Lack of evidence for BCG vaccine protection from severe COVID-19. Proc Natl Acad Sci U S A. 2020 Sep 29:202016733. doi: 10.1073/pnas.2016733117. Online ahead of print. PMID: 32994350 de Chaisemartin C, de Chaisemartin L BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden. Clin Infect Dis. 2020 Aug 23:ciaa1223. doi: 10.1093/cid/ciaa1223. Online ahead of print. PMID: 32829400 Hamiel U, Kozer E, Youngster I. SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults. JAMA. 2020 Jun 9;323(22):2340-2341. doi: 10.1001/jama.2020.8189. PMID: 32401274 Thus, I would recommend extensively revising and updating the background and discussion to reflect this, both in terms of content and in terms of references. Thank you for allowing me to review your work ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. 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Revision 1
6 Nov 2020 Author Response PLEASE FIND MY RESPONSES IN CAPS 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf THE MANUSCRIPT MAIN BODY HAS BEEN REVISED ACCORDING TO THE JOURNAL REQUIREMENTS THE TITLE PAGE HAS BEEN REVISED ACCORDING TO THE SPECIFIED REQUIREMENTS 2. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service. Whilst you may use any professional scientific editing service of your choice, PLOS has partnered with both American Journal Experts (AJE) and Editage to provide discounted services to PLOS authors. Both organizations have experience helping authors meet PLOS guidelines and can provide language editing, translation, manuscript formatting, and figure formatting to ensure your manuscript meets our submission guidelines. To take advantage of our partnership with AJE, visit the AJE website (http://learn.aje.com/plos/) for a 15% discount off AJE services. To take advantage of our partnership with Editage, visit the Editage website (www.editage.com) and enter referral code PLOSEDIT for a 15% discount off Editage services. If the PLOS editorial team finds any language issues in text that either AJE or Editage has edited, the service provider will re-edit the text for free. WE HAVE REVIEWED THE MANUSCRIPT AND HAVE EDITED THE CONTENTS FOR LANGUAGE USE, GRAMMAR AND SPELLING. Upon resubmission, please provide the following: The name of the colleague or the details of the professional service that edited your manuscript A copy of your manuscript showing your changes by either highlighting them or using track changes (uploaded as a supporting information file) A clean copy of the edited manuscript (uploaded as the new manuscript file) 3. We note that Figure 2 in your submission contain map images which may be copyrighted. All PLOS content is published under the Creative Commons Attribution License (CC BY 4.0), which means that the manuscript, images, and Supporting Information files will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution. For these reasons, we cannot publish previously copyrighted maps or satellite images created using proprietary data, such as Google software (Google Maps, Street View, and Earth). For more information, see our copyright guidelines: http://journals.plos.org/plosone/s/licenses-and-copyright. THIS MAP HAS NOT BEEN COPYRIGHTED FROM ANY SOURCE. IT HAS BEEN CREATED WITH PUBLICLY AVAILABLE INFORMATION BY THE AUTHOR (LC) We require you to either (1) present written permission from the copyright holder to publish these figures specifically under the CC BY 4.0 license, or (2) remove the figures from your submission: N/A 3.1. You may seek permission from the original copyright holder of Figure 2 to publish the content specifically under the CC BY 4.0 license. N/A We recommend that you contact the original copyright holder with the Content Permission Form (http://journals.plos.org/plosone/s/file?id=7c09/content-permission-form.pdf) and the following text: “I request permission for the open-access journal PLOS ONE to publish XXX under the Creative Commons Attribution License (CCAL) CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/). Please be aware that this license allows unrestricted use and distribution, even commercially, by third parties. Please reply and provide explicit written permission to publish XXX under a CC BY license and complete the attached form.” N/A Please upload the completed Content Permission Form or other proof of granted permissions as an "Other" file with your submission. In the figure caption of the copyrighted figure, please include the following text: “Reprinted from [ref] under a CC BY license, with permission from [name of publisher], original copyright [original copyright year].” N/A 3.2. If you are unable to obtain permission from the original copyright holder to publish these figures under the CC BY 4.0 license or if the copyright holder’s requirements are incompatible with the CC BY 4.0 license, please either i) remove the figure or ii) supply a replacement figure that complies with the CC BY 4.0 license. Please check copyright information on all replacement figures and update the figure caption with source information. If applicable, please specify in the figure caption text when a figure is similar but not identical to the original image and is therefore for illustrative purposes only. N/A The following resources for replacing copyrighted map figures may be helpful: USGS National Map Viewer (public domain): http://viewer.nationalmap.gov/viewer/ The Gateway to Astronaut Photography of Earth (public domain): http://eol.jsc.nasa.gov/sseop/clickmap/ Maps at the CIA (public domain): https://www.cia.gov/library/publications/the-world-factbook/index.html and https://www.cia.gov/library/publications/cia-maps-publications/index.html NASA Earth Observatory (public domain): http://earthobservatory.nasa.gov/ Landsat: http://landsat.visibleearth.nasa.gov/ USGS EROS (Earth Resources Observatory and Science (EROS) Center) (public domain): http://eros.usgs.gov/# Natural Earth (public domain): http://www.naturalearthdata.com/ 4. Please include a separate caption for each figure in your manuscript. THIS HAS BEEN INCLUDED IN THE MANUSCRIPT BEFORE THE REFERENCES. WE HAVE USED PACE TO ENSURE THE FIGURES MEET THE JOURNAL REQUIREMENTS The responses to the reviewers comments are as follows; It is a good descriptive analysis of prevailing COVID 19 pandemic and ecological parameters in the sampled countries and its association with BCG vaccination policy. However, authors are encouraged to discuss in detail the observed association with confounding variables. THANK YOU FOR THIS OBSERVATION. WE HAVE INTERPRETED THE SIGNIFICANT ASSOCIATIONS OF COVID-19 CASES WITH OTHER CO-VARIATES IN THE DISCUSSION SECTION IN LINES 238-245 ON PAGE 13. Authors should clearly describe fallacy of ecological study in ascertaining association between two variables and is descriptive in nature rather than analytical. It is appreciated however that authors have observed caution with conclusion since confounders can mislead with both association and non-association. WE HAVE DESCRIBED THE CONCEPT OF ECOLOGICAL FALLACY IN THE DISCUSSION SECTION OF THE REVISED MANUSCRIPT IN LINES 338 AND 340 ON PAGE 16. Authors should describe in details the method of selection of countries with a flow chart. A FLOW CHART (FIG 1) DESCRIBING COUNTRY SELECTION HAS BEEN INCLUDED. They should describe the possible alternative tools being referred in conclusion. THE ALTERNATIVE TOOLS ARE RANDOMIZED CONTROLLED TRIALS WHICH IS ADDED IN LINES 332 AND 333 ON PAGE 16. Elaborate on methods used for data collection e.g. immunization schedule was it standardized across the countries. WE USED STANDARDISED DATABASES FOR MOST INDICATORS. WE HAVE INCLUDED THE WORD STANDARDIZED IN LINE 134 OF PAGE 5. FOR ALL INDICATORS THE SOURCES ARE SHOWN IN TABLE 1. Provide reference for no BCG policy criteria for being used less than 30 years and data on current rates of BCG immunization in BCG policy states. Classification of current, ever and never THE REFERENCE FOR BCG CRITERIA HAS BEEN INCLUDED ON PAGE 5; LINE 150. Please explain why the countries with less than 1 million population excluded. THIS WAS BECAUSE WE FELT THAT TRANSMISSION IN A VERY SMALL COUNTRY MAY BE AFFECTED IN A DIFFERENT WAY TO LARGER POPULATIONS. THIS HAS BEEN ADDED AT THE END OF THE PARAGRAPH ON PAGE 5; LINES 119 AND 120. IN MOST CASES THOSE COUNTRIES ALSO DID NOT HAVE INFORMATION ABOUT A BCG POLICY AND SO WOULD HAVE BEEN EXCLUDED DUE TO OTHER CRITERIA AS WELL. Why weren't control countries (with limited or no COVID cases) considered in the study for comparison? THE ECOLOGICAL ANALYSIS INCLUDED COUNTRIES WITH NO/LOW COVID-19 AGAINST THOSE WITH HIGH CASES/DEATHS. WE DID NOT SET OUT TO DO A COMPARISON. Significant association of COVID cases with population and testing rates, tabulated with BCG policy for some understanding. THANK YOU FOR THIS OBSERVATION. WE HAVE INTERPRETED THE SIGNIFICANT ASSOCIATIONS OF COVID-19 CASES WITH OTHER CO-VARIATES IN THE RESULTS AND EXPLAINED THIS ASSOCIATION IN THE DISCUSSION SECTION. Figure 2 is not well explanatory, Kindly redesign. THE MAP HAS BEEN REDESIGNED. WE HAVE CHANGED SHOWN THE VARIED DISTRIBUTION OF STRINGENCY MEASURES AT COUNTRY LEVEL USING SOLID COLOURS AS OPPOSED TO HASH DESIGNS. RED INDICATING LOW LEVELS (<25%) MEASURES AND GREEN SHOWING HIGH LEVELS (>75%) OF STRINGENCY MEASURES IMPLEMENTED BY THE 100TH REPORTED CASE. Unpublished studies mentioned should be referred or identified. THANK YOU FOR THIS OBSERVATION. THE REFERENCES HAVE BEEN ADDED AT THE END OF THIS STATEMENT AND THE REVISION IS FOUND ON PAGE 4; LINES 115 AND 116. Reviewer 2 These are my comments about the manuscript "An ecological study to evaluate the association of Bacillus Calmette-Guerin (BCG) vaccination on cases of SARS-CoV2 infection and mortality from COVID-19" that I was asked to evaluate. The authors report the results of an ecological study aimed at evaluating the association between national BCG vaccination status and rates of COVID-19 incidence and mortality. They do so by utilizing national-level data from various sources while, implementing log-linear regression models, adjusting for a host of factors that could be confounders or mediators. They conclude that there is no association between BCG status and COVID-19. First, the topic is of great importance on a global level, and much has been written about the theoretical protective effect of BCG against severe COVID-19. These speculations have even initiated several large clinical studies, as well as mass vaccination in Japan that has caused supply shortages of BCG. For that reason, I believe that, though the topic is not novel, it is still of great interest to the scientific community. EVEN THOUGH THE TOPIC IS NOT NOVEL, WE PROVED THAT THE APPARENT ASSOCIATION REPORTED EARLY ON IN THE EPIDEMIC HAD NOT TAKEN INTO ACCOUNT OTHER COUNTRY-LEVEL SPECIFIC FACTORS. WE FURTHER INVESTIGATED THIS ASSOCIATION OVER FOUR TIME PERIODS AND OUR FINDINGS SUGGESTED THAT AS THE TIME PERIOD PROGRESSED, THE ASSOCIATION WEAKENED AND WAS INSIGNIFICANT. THIS HAS BEEN EMPHASISED AS A STRENGTH OF THE PAPER. The manuscript is well written, and the internal flow is clear. The use of ecological studies has been greatly criticized and is inherently open to confounding. The authors have gone to great lengths to minimize this effect by adjustments to a host of variables and by selecting outcomes that are less prone to bias, but it is still an ecological study. My main comment would be that it seems that some time has passed since the manuscript was finalized, and several papers have been published on the same topic, none of which is mentioned and discussed, leaving the manuscript somewhat outdated. Just to give a few examples, of many others: Lindestam Arlehamn CS, Sette A, Peters B. Lack of evidence for BCG vaccine protection from severe COVID-19. Proc Natl Acad Sci U S A. 2020 Sep 29:202016733. doi: 10.1073/pnas.2016733117. Online ahead of print. PMID: 32994350 de Chaisemartin C, de Chaisemartin L BCG vaccination in infancy does not protect against COVID-19. Evidence from a natural experiment in Sweden. Clin Infect Dis. 2020 Aug 23:ciaa1223. doi: 10.1093/cid/ciaa1223. Online ahead of print. PMID: 32829400 Hamiel U, Kozer E, Youngster I. SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults. JAMA. 2020 Jun 9;323(22):2340-2341. doi: 10.1001/jama.2020.8189. PMID: 32401274 Thus, I would recommend extensively revising and updating the background and discussion to reflect this, both in terms of content and in terms of references. WE APPRECIATE THE POSITIVE COMMENTS FROM THE REVIEWER ON COHERENCE OF THE STUDY. WE THANK YOU FOR EXAMPLES OF PUBLISHED WORK WHICH WE HAVE INCLUDED THESE TOGETHER WITH OTHER ARTICLES TO UPDATE OUR DISCUSSION SECTION LINES 248-256; PAGE 13. https://doi.org/10.1371/journal.pone.0243707.r002
30 Nov 2020 Decision Letter - Angelo A. Izzo, Editor An ecological study to evaluate the association of Bacillus Calmette-Guerin (BCG) vaccination on cases of SARS-CoV2 infection and mortality from COVID-19 PONE-D-20-26939R1 Dear Dr. Chimoyi, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Angelo A. Izzo Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: (No Response) Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: (No Response) Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: (No Response) Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: The authors have addressed my concerns; I have no further comments. Thank you for allowing me to review your work ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No https://doi.org/10.1371/journal.pone.0243707.r003
Formally Accepted
9 Dec 2020 Acceptance Letter - Angelo A. Izzo, Editor PONE-D-20-26939R1 An ecological study to evaluate the association of Bacillus Calmette-Guerin (BCG) vaccination on cases of SARS-CoV2 infection and mortality from COVID-19 Dear Dr. Chimoyi: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Angelo A. Izzo Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0243707.r004

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