{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:53:38Z","timestamp":1792788818304,"version":"4.5.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011825","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T00:00:00Z","timestamp":1701907200000}}],"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T00:00:00Z","timestamp":1701043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["75N93019C00070"],"award-info":[{"award-number":["75N93019C00070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-026296"],"award-info":[{"award-number":["INV-026296"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH\/NIAID","award":["U19AI135976"],"award-info":[{"award-number":["U19AI135976"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Despite widespread immunization with Bacille-Calmette-Gu\u00e9rin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality globally. There are many TB vaccine candidates in the developmental pipeline, but the lack of a robust animal model to assess vaccine efficacy has hindered our ability to prioritize candidates for human clinical trials. Here we use a murine ultra-low dose (ULD)\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (Mtb) challenge model to assess protection conferred by BCG vaccination. We show that BCG confers a reduction in lung bacterial burdens that is more durable than that observed after conventional dose challenge, curbs Mtb dissemination to the contralateral lung, and, in a small percentage of mice, prevents detectable infection. These findings are consistent with the ability of human BCG vaccination to mediate protection, particularly against disseminated disease, in specific human populations and clinical settings. Overall, our findings demonstrate that the ultra-low dose Mtb infection model can measure distinct parameters of immune protection that cannot be assessed in conventional dose murine infection models and could provide an improved platform for TB vaccine testing.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011825","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T14:25:49Z","timestamp":1701095149000},"page":"e1011825","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Assessing vaccine-mediated protection in an ultra-low dose Mycobacterium tuberculosis murine model"],"prefix":"10.1371","volume":"19","author":[{"given":"Courtney R.","family":"Plumlee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly W.","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danica E.","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie A.","family":"Lien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Cross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara B.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul T.","family":"Edlefsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0088-1066","authenticated-orcid":true,"given":"Kevin B.","family":"Urdahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"issue":"1 Pt 1","key":"ppat.1011825.ref001","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1542\/peds.96.1.29","article-title":"The efficacy of bacillus Calmette-Guerin vaccination of newborns and infants in the prevention of tuberculosis: meta-analyses of the published literature","volume":"96","author":"GA Colditz","year":"1995","journal-title":"Pediatrics"},{"issue":"4","key":"ppat.1011825.ref002","doi-asserted-by":"crossref","first-page":"470","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"},{"issue":"37","key":"ppat.1011825.ref003","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3310\/hta17370","article-title":"Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guerin vaccination against tuberculosis","volume":"17","author":"I Abubakar","year":"2013","journal-title":"Health Technol Assess"},{"issue":"11","key":"ppat.1011825.ref004","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1136\/thoraxjnl-2020-216794","article-title":"Timing of Mycobacterium tuberculosis exposure explains variation in BCG effectiveness: a systematic review and meta-analysis","volume":"76","author":"JM Trauer","year":"2021","journal-title":"Thorax"},{"issue":"3","key":"ppat.1011825.ref005","doi-asserted-by":"crossref","first-page":"e28","DOI":"10.1016\/S1473-3099(19)30625-5","article-title":"The status of tuberculosis vaccine development","volume":"20","author":"LK Schrager","year":"2020","journal-title":"Lancet Infect Dis"},{"issue":"1","key":"ppat.1011825.ref006","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/imr.12270","article-title":"Tuberculosis vaccines: barriers and prospects on the quest for a transformative tool","volume":"264","author":"CL Karp","year":"2015","journal-title":"Immunol Rev"},{"key":"ppat.1011825.ref007","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ijid.2017.01.030","article-title":"Experimental animal modelling for TB vaccine development","volume":"56","author":"PJ Cardona","year":"2017","journal-title":"Int J Infect Dis"},{"issue":"12","key":"ppat.1011825.ref008","doi-asserted-by":"crossref","first-page":"6311","DOI":"10.4049\/jimmunol.1300248","article-title":"Control of chronic mycobacterium tuberculosis infection by CD4 KLRG1- IL-2-secreting central memory cells","volume":"190","author":"T Lindenstrom","year":"2013","journal-title":"J Immunol"},{"issue":"7","key":"ppat.1011825.ref009","doi-asserted-by":"crossref","first-page":"e1008655","DOI":"10.1371\/journal.ppat.1008655","article-title":"Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection","volume":"16","author":"J Nemeth","year":"2020","journal-title":"PLoS Pathog"},{"issue":"3","key":"ppat.1011825.ref010","doi-asserted-by":"crossref","DOI":"10.1128\/microbiolspec.MCHD-0006-2015","article-title":"Mechanisms of Defense against Intracellular Pathogens Mediated by Human Macrophages.","volume":"4","author":"BR Bloom","year":"2016","journal-title":"Microbiol Spectr."},{"issue":"1","key":"ppat.1011825.ref011","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.chom.2020.10.003","article-title":"Ultra-low Dose Aerosol Infection of Mice with Mycobacterium tuberculosis More Closely Models Human Tuberculosis","volume":"29","author":"CR Plumlee","year":"2021","journal-title":"Cell Host Microbe"},{"issue":"3","key":"ppat.1011825.ref012","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1086\/422394","article-title":"Immune response to postprimary tuberculosis in mice: Mycobacterium tuberculosis and Miycobacterium bovis bacille Calmette-Guerin induce equal protection","volume":"190","author":"HJ Mollenkopf","year":"2004","journal-title":"J Infect Dis"},{"issue":"4","key":"ppat.1011825.ref013","doi-asserted-by":"crossref","first-page":"807","DOI":"10.4049\/jimmunol.1900108","article-title":"Cutting Edge: Bacillus Calmette-Guerin-Induced T Cells Shape Mycobacterium tuberculosis Infection before Reducing the Bacterial Burden","volume":"203","author":"JL Delahaye","year":"2019","journal-title":"J Immunol"},{"issue":"6","key":"ppat.1011825.ref014","doi-asserted-by":"crossref","first-page":"106963","DOI":"10.1016\/j.isci.2023.106963","article-title":"Attenuated Mycobacterium tuberculosis vaccine protection in a low-dose murine challenge model","volume":"26","author":"SJ Vidal","year":"2023","journal-title":"iScience"},{"issue":"4\u20135","key":"ppat.1011825.ref015","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/S0171-2985(11)80445-6","article-title":"Mycobacterial infection in guinea pigs","volume":"191","author":"V Balasubramanian","year":"1994","journal-title":"Immunobiology"},{"issue":"9","key":"ppat.1011825.ref016","doi-asserted-by":"crossref","first-page":"972","DOI":"10.5588\/ijtld.18.0173","article-title":"Droplets, dust and guinea pigs: an historical review of tuberculosis transmission research, 1878\u20131940.","volume":"22","author":"PR Donald","year":"2018","journal-title":"Int J Tuberc Lung Dis."},{"issue":"11","key":"ppat.1011825.ref017","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/S0041-3879(41)80017-8","article-title":"Infective dose in pulmonary tuberculosis","volume":"22","author":"AL Jacobs","year":"1941","journal-title":"Tubercle"},{"issue":"3","key":"ppat.1011825.ref018","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.chom.2018.08.001","article-title":"Alveolar Macrophages Provide an Early Mycobacterium tuberculosis Niche and Initiate Dissemination","volume":"24","author":"SB Cohen","year":"2018","journal-title":"Cell Host Microbe"},{"issue":"10","key":"ppat.1011825.ref019","doi-asserted-by":"crossref","first-page":"e0206384","DOI":"10.1371\/journal.pone.0206384","article-title":"Cough-aerosol cultures of Mycobacterium tuberculosis in the prediction of outcomes after exposure. A household contact study in Brazil.","volume":"13","author":"C Acuna-Villaorduna","year":"2018","journal-title":"PLoS One"},{"key":"ppat.1011825.ref020","doi-asserted-by":"crossref","first-page":"S51","DOI":"10.1016\/j.ijmyco.2016.10.037","article-title":"What is in a cough?","volume":"51","author":"KP Fennelly","year":"2016","journal-title":"Int J Mycobacteriol."},{"issue":"5","key":"ppat.1011825.ref021","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1164\/rccm.200308-1101OC","article-title":"Cough-generated aerosols of Mycobacterium tuberculosis: a new method to study infectiousness","volume":"169","author":"KP Fennelly","year":"2004","journal-title":"Am J Respir Crit Care Med"},{"issue":"5","key":"ppat.1011825.ref022","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1164\/rccm.201203-0444OC","article-title":"Variability of infectious aerosols produced during coughing by patients with pulmonary tuberculosis","volume":"186","author":"KP Fennelly","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"ppat.1011825.ref023","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1093\/cid\/ciw199","article-title":"Cough Aerosols of Mycobacterium tuberculosis in the Prediction of Incident Tuberculosis Disease in Household Contacts","volume":"63","author":"EC Jones-Lopez","year":"2016","journal-title":"Clin Infect Dis"},{"key":"ppat.1011825.ref024","first-page":"150","article-title":"Experimental Airborne Tuberculosis.","volume":"12","author":"FR O\u2019Grady","year":"1963","journal-title":"Advances in Tuberculosis Research"},{"issue":"1","key":"ppat.1011825.ref025","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/oxfordjournals.aje.a117542","article-title":"Aerial dissemination of pulmonary tuberculosis. A two-year study of contagion in a tuberculosis ward. 1959","volume":"142","author":"RL Riley","year":"1995","journal-title":"Am J Epidemiol"},{"issue":"4","key":"ppat.1011825.ref026","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1056\/NEJM199507273330404","article-title":"Outbreak of tuberculosis among regular patrons of a neighborhood bar","volume":"333","author":"SE Kline","year":"1995","journal-title":"N Engl J Med"},{"key":"ppat.1011825.ref027","first-page":"358","article-title":"Tuberculosis disseminators. A study of the variability of aerial infectivity of tuberculous patients","volume":"82","author":"L Sultan","year":"1960","journal-title":"Am Rev Respir Dis"},{"issue":"3","key":"ppat.1011825.ref028","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1097\/EDE.0b013e3182878e19","article-title":"A sign of superspreading in tuberculosis: highly skewed distribution of genotypic cluster sizes","volume":"24","author":"RJ Ypma","year":"2013","journal-title":"Epidemiology"},{"issue":"7","key":"ppat.1011825.ref029","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1159\/000509522","article-title":"Anton Ghon and His Colleagues and Their Studies of the Primary Focus and Complex of Tuberculosis Infection and Their Relevance for the Twenty-First Century.","volume":"100","author":"PR Donald","year":"2021","journal-title":"Respiration"},{"issue":"1","key":"ppat.1011825.ref030","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nm.3412","article-title":"Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing","volume":"20","author":"PL Lin","year":"2014","journal-title":"Nat Med"},{"issue":"3","key":"ppat.1011825.ref031","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00312-17","article-title":"Digitally Barcoding Mycobacterium tuberculosis Reveals In Vivo Infection Dynamics in the Macaque Model of Tuberculosis.","volume":"8","author":"CJ Martin","year":"2017","journal-title":"mBio"},{"issue":"11","key":"ppat.1011825.ref032","doi-asserted-by":"crossref","first-page":"7222","DOI":"10.4049\/jimmunol.178.11.7222","article-title":"B cells moderate inflammatory progression and enhance bacterial containment upon pulmonary challenge with Mycobacterium tuberculosis","volume":"178","author":"PJ Maglione","year":"2007","journal-title":"J Immunol"},{"issue":"6","key":"ppat.1011825.ref033","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1016\/j.immuni.2011.12.002","article-title":"Innate and adaptive interferons suppress IL-1alpha and IL-1beta production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection","volume":"35","author":"KD Mayer-Barber","year":"2011","journal-title":"Immunity"},{"issue":"3","key":"ppat.1011825.ref034","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1093\/oxfordjournals.bmb.a072277","article-title":"BCG vaccination against tuberculosis and leprosy","volume":"44","author":"PE Fine","year":"1988","journal-title":"Br Med Bull"},{"issue":"6","key":"ppat.1011825.ref035","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1038\/s41591-019-0441-3","article-title":"IFN-gamma-independent immune markers of Mycobacterium tuberculosis exposure","volume":"25","author":"LL Lu","year":"2019","journal-title":"Nat Med"},{"key":"ppat.1011825.ref036","doi-asserted-by":"crossref","first-page":"l5770","DOI":"10.1136\/bmj.l5770","article-title":"Is Mycobacterium tuberculosis infection life long?","volume":"367","author":"MA Behr","year":"2019","journal-title":"BMJ"},{"issue":"2","key":"ppat.1011825.ref037","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1038\/nm.4473","article-title":"Prevention of tuberculosis in rhesus macaques by a cytomegalovirus-based vaccine","volume":"24","author":"SG Hansen","year":"2018","journal-title":"Nat Med"},{"issue":"2","key":"ppat.1011825.ref038","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41591-018-0319-9","article-title":"Prevention of tuberculosis infection and disease by local BCG in repeatedly exposed rhesus macaques","volume":"25","author":"K Dijkman","year":"2019","journal-title":"Nat Med"},{"issue":"7788","key":"ppat.1011825.ref039","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41586-019-1817-8","article-title":"Prevention of tuberculosis in macaques after intravenous BCG immunization","volume":"577","author":"PA Darrah","year":"2020","journal-title":"Nature"},{"issue":"7600","key":"ppat.1011825.ref040","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nature17655","article-title":"Normalizing the environment recapitulates adult human immune traits in laboratory mice","volume":"532","author":"LK Beura","year":"2016","journal-title":"Nature"},{"key":"ppat.1011825.ref041","article-title":"Network stress test reveals novel drug potentiators in Mycobacterium tuberculosis","author":"R. Ma SM","year":"2018","journal-title":"submitted"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1011825","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T00:00:00Z","timestamp":1701907200000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011825","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,7]],"date-time":"2023-12-07T14:00:41Z","timestamp":1701957641000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011825"}},"subtitle":[],"editor":[{"given":"Padmini","family":"Salgame","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,11,27]]},"references-count":41,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1011825","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,27]]}}}