{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T10:53:20Z","timestamp":1780570400177,"version":"3.54.1"},"update-to":[{"DOI":"10.12688\/f1000research.14239.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2018,6,27]],"date-time":"2018-06-27T00:00:00Z","timestamp":1530057600000}}],"reference-count":41,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2018,6,27]],"date-time":"2018-06-27T00:00:00Z","timestamp":1530057600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009660","name":"London School of Hygiene and Tropical Medicine","doi-asserted-by":"crossref","award":["Athena SWAN Career Re-Entry Fellowship"],"award-info":[{"award-number":["Athena SWAN Career Re-Entry Fellowship"]}],"id":[{"id":"10.13039\/100009660","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"crossref","award":["643381"],"award-info":[{"award-number":["643381"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    The only available tuberculosis (TB) vaccine, Bacillus Calmette-Gu\u00e9rin\u00a0(BCG), has variable efficacy. New vaccines are therefore urgently needed. Why BCG fails is incompletely understood, and the tools used for early assessment of new vaccine candidates do not account for BCG variability. Taking correlates of risk of TB disease observed in human studies and back-translating them into mice to create models of BCG variability should allow novel vaccine candidates to be tested early in animal models that are more representative of the human populations most at risk. Furthermore, this could help to elucidate the immunological mechanisms leading to BCG failure. We have chosen the monocyte to lymphocyte (ML) ratio as a correlate of risk of TB disease and have back-translated this into a mouse model.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods<\/ns4:bold>\n                    : Four commercially available, inbred mouse strains were chosen. We investigated their baseline ML ratio by flow cytometry; extent of BCG-mediated protection from M\n                    <ns4:italic>ycobacterium tuberculosis<\/ns4:italic>\n                    infection by experimental challenge; vaccine-induced interferon gamma (IFN\u03b3) response by ELISPOT assay; and tissue distribution of BCG by plating tissue homogenates.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    The ML ratio varied significantly between A\/J, DBA\/2, C57Bl\/6 and 129S2 mice. A\/J mice showed the highest BCG-mediated protection and lowest ML ratio, while 129S2 mice showed the lowest protection and higher ML ratio. We also found that A\/J mice had a lower antigen specific IFN\u03b3 response than 129S2 mice. BCG tissue distribution appeared higher in A\/J mice, although this was not statistically significant.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    These results suggest that the ML ratio has an impact on BCG-mediated protection in mice, in alignment with observations from clinical studies. A\/J and 129S2 mice may therefore be useful models of BCG vaccine variability for early TB vaccine testing. We speculate that failure of BCG to protect from TB disease is linked to poor tissue distribution in a ML high immune environment.\n                  <\/ns4:p>","DOI":"10.12688\/f1000research.14239.2","type":"journal-article","created":{"date-parts":[[2018,6,27]],"date-time":"2018-06-27T05:41:03Z","timestamp":1530078063000},"page":"296","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis"],"prefix":"10.12688","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9621-4406","authenticated-orcid":false,"given":"Andrea","family":"Zelmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Stockdale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3808-0638","authenticated-orcid":false,"given":"Satria A.","family":"Prabowo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Cia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Spink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6774-9943","authenticated-orcid":false,"given":"Matthew","family":"Gibb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayad","family":"Eddaoudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0435-1006","authenticated-orcid":false,"given":"Helen A.","family":"Fletcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2018,6,27]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"470-80","DOI":"10.1093\/cid\/cit790","article-title":"Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.","volume":"58","author":"P Mangtani","year":"2014","journal-title":"Clin Infect Dis."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"698-702","DOI":"10.1001\/jama.1994.03510330076038","article-title":"Efficacy of BCG vaccine in the prevention of tuberculosis. 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(Edinb)."},{"key":"ref-37","article-title":"Donahue 5","author":"L Donahue"},{"key":"ref-38","doi-asserted-by":"publisher","DOI":"10.5256\/f1000research.14239.d207942","article-title":"Dataset 1 in: High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis.","author":"A Zelmer","year":"2018","journal-title":"F1000Research."},{"key":"ref-39","doi-asserted-by":"publisher","DOI":"10.5256\/f1000research.14239.d197118","article-title":"Dataset 2 in: High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis.","author":"A Zelmer","year":"2018","journal-title":"F1000Research."},{"key":"ref-40","doi-asserted-by":"publisher","DOI":"10.5256\/f1000research.14239.d197136","article-title":"Dataset 3 in: High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis.","author":"A Zelmer","year":"2018","journal-title":"F1000Research."},{"key":"ref-41","doi-asserted-by":"publisher","DOI":"10.5256\/f1000research.14239.d197137","article-title":"Dataset 4 in: High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis.","author":"A Zelmer","year":"2018","journal-title":"F1000Research."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/7-296\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/7-296\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/7-296\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T06:22:20Z","timestamp":1604470940000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/7-296\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,27]]},"references-count":41,"URL":"https:\/\/doi.org\/10.12688\/f1000research.14239.2","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.16467.r35522","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.16467.r35522","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,27]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/7-296\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.16467.r35522, Nacho Aguilo, Department of Microbiology, Preventive Medicine, and Public Health, University of Zaragoza, Zaragoza, Spain, 04 Jul 2018, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/7-296\/v2#referee-response-35522","order":0,"name":"referee-response-35522","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.15495.r32475, Maximiliano G Gutierrez, Host-Pathogen Interactions\u00a0in\u00a0Tuberculosis Laboratory, Francis Crick Institute, London, USA, 20 Apr 2018, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/7-296\/v1#referee-response-32475","order":1,"name":"referee-response-32475","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Andrea Zelmer<\/b>; <i>Posted: 19 Jun 2018<\/i>; Dear Dr Gutierrez We would like to thank you for taking the time to review our manuscript, and for the thoughtful feedback provided. We address your individual comments below.&nbsp; &nbsp; <b>The work from Zelmer and collaborators is very interesting, timely, well executed and clearly written. I anticipate a great interest in the tuberculosis vaccine field. I have only minor comments and suggestions:<\/b> &nbsp; <b>Regarding introduction and\/or discussion, it would be important the authors discuss what are the main genetic differences between the 4 mouse strainsselected for this study.<\/b> &nbsp; We have now included a paragraph in the Discussion to address this. &nbsp; <b>In Figure 4, it is right to state that colonies vary in tissues but only 2 tissues were analysed here so it would be more appropriate to state &quot;between lung and spleen&quot;. Moreover, would it be possible to get the data in lymph nodes as well? Lymph nodes are critical for the responses to vaccination.<\/b> &nbsp; We have now specified \u201clung and spleen\u201d in the legend to Fig. 4 and also in the sub-heading in the results section.&nbsp; It would be very interesting to look at tissue distribution to lymph nodes, and this is a point both reviewers have brought up. Unfortunately, we do not have the samples available and no additional funding is available at the moment to repeat this study. Furthermore, we believe it would be difficult to justify the use of further animals solely for this purpose; however, we will investigate this in future experiments and thank you for the suggestion. &nbsp; <b>The variation in CFU\/organ seem to be higher in animals that have high levels of protection in this study (e.g. A\/J mice). Could the authors comment on this<\/b> <b>? Is it possible to know the ML ratio in the 2 mice showing high CFU\/lung from Fig 4A?<\/b> &nbsp; Since a different set of animals was used for flow cytometry and BCG distribution studies (outlined in the Methods section), it is not possible to directly compare the ML ratio and BCG CFU of individual animals. With regards to variation in Fig. 4, we believe this is likely to be a technical effect \u2013 we detected very few bacilli in general, and especially in the lung, we did not detect any bacteria in some samples from lesser protected animals. This does not mean there are non \u2013 it just means that we were not able to detect them with the method used. As such, it is difficult to interpret the real variation within those mouse strains. &nbsp; <b>Not sure if the authors have the samples available, but it would have been interesting to see the profiles of Type I\/II IFN in tissue at least by qPCR. This information could be of great interest for the tuberculosis field.<\/b> &nbsp; Unfortunately we do not have those samples available. It is an important point, and would indeed be very relevant. We plan to investigate this in future studies. &nbsp; <b>The authors should discuss the limitations of a relatively low number of biological experiments in this work.<\/b> We have added a comment to this effect at the end of the results section.","URL":"https:\/\/f1000research.com\/articles\/7-296\/v2#referee-comment-3744","order":2,"name":"referee-comment-3744","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The work in this article was funded by a grant to HF from the European Commission HORIZON2020 program (TBVAC2020 grant no. 643381) and an Athena SWAN Career Re-entry award funded by the London School of Hygiene and Tropical Medicine to AZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).","order":0,"name":"copyright-info","label":"Copyright"}]}}