{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:57:08Z","timestamp":1787021828140,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.pntd.0012710","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000}}],"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T00:00:00Z","timestamp":1740096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["643558"],"award-info":[{"award-number":["643558"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012507","name":"St George and Sutherland Medical Research Foundation","doi-asserted-by":"publisher","award":["Discretionary fund"],"award-info":[{"award-number":["Discretionary fund"]}],"id":[{"id":"10.13039\/100012507","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["International collaboration"],"award-info":[{"award-number":["International collaboration"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"VALIDATE Network","award":["Pump-priming project"],"award-info":[{"award-number":["Pump-priming project"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>\n                    Buruli ulcer (BU) disease, a neglected necrotizing tropical skin infection caused by\n                    <jats:italic>Mycobacterium ulcerans<\/jats:italic>\n                    , is the third most common mycobacterial disease after tuberculosis and leprosy. Infections mostly occur in remote, rural areas of Central and West Africa, but also in Australia, Japan and Papua New Guinea. There is currently no vaccine against Buruli ulcer disease and all previous attempts using closely related bacteria and subunit proteins have been partially successful only. Here, we tested in mice a composite subunit formulation incorporating the\n                    <jats:italic>Mycobacterium ulcerans<\/jats:italic>\n                    toxin mycolactone as the immunomodulator, and the antigens Ag85A and Polyketide Synthase Enzyme Ketoreductase A (KRA), formulated with Quil-A adjuvant (\u2018Burulivac\u2019). Burulivac induced Ag85A and KRA antigen-specific antibodies, T cells and a mixed pro- and anti-inflammatory cytokine responses, which conferred absolute protection against Buruli ulcer disease in the mouse footpad model over a 14-week period of observation. This was superior to both live attenuated mycobacterial vaccines, that is, BCG and an avirulent\n                    <jats:italic>M. ulcerans<\/jats:italic>\n                    strain that lacks the mycolactone toxin (\n                    <jats:italic>Mu\u0394<\/jats:italic>\n                    ). Interleukin 10 was found to be strongly associated with protection. We suggest that Burulivac is a promising vaccine candidate against Buruli ulcer disease that warrants further exploration.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0012710","type":"journal-article","created":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T13:44:17Z","timestamp":1740145457000},"page":"e0012710","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["A composite subunit vaccine confers full protection against Buruli ulcer disease in the mouse footpad model of Mycobacterium ulcerans infection"],"prefix":"10.1371","volume":"19","author":[{"given":"Justice Kofi","family":"Boakye-Appiah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy C.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard O.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Wansbrough-Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4351-8355","authenticated-orcid":true,"given":"Rajko","family":"Reljic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"key":"pntd.0012710.ref001","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-030-11114-4_1","article-title":"Buruli ulcer: history and disease burden.","volume-title":"Buruli ulcer: mycobacterium ulcerans disease","author":"K Roltgen","year":"2019"},{"issue":"4","key":"pntd.0012710.ref002","doi-asserted-by":"crossref","first-page":"e0005553","DOI":"10.1371\/journal.pntd.0005553","article-title":"Mycobacterium ulcerans low infectious dose and mechanical transmission support insect bites and puncturing injuries in the spread of Buruli ulcer","volume":"11","author":"JR Wallace","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"issue":"2","key":"pntd.0012710.ref003","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41564-023-01553-1","article-title":"Mosquitoes provide a transmission route between possums and humans for Buruli ulcer in southeastern Australia","volume":"9","author":"PT Mee","year":"2024","journal-title":"Nat Microbiol"},{"issue":"4","key":"pntd.0012710.ref004","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s40475-018-0166-2","article-title":"Buruli ulcer: a review of the current knowledge","volume":"5","author":"RR Yotsu","year":"2018","journal-title":"Curr Trop Med Rep"},{"issue":"2","key":"pntd.0012710.ref005","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1128\/IAI.66.2.587-593.1998","article-title":"Partial purification and characterization of biological effects of a lipid toxin produced by Mycobacterium ulcerans","volume":"66","author":"KM George","year":"1998","journal-title":"Infect Immun"},{"issue":"5403","key":"pntd.0012710.ref006","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1126\/science.283.5403.854","article-title":"Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence","volume":"283","author":"KM George","year":"1999","journal-title":"Science"},{"issue":"4","key":"pntd.0012710.ref007","doi-asserted-by":"crossref","first-page":"478","DOI":"10.7164\/antibiotics.34.478","article-title":"Extraction and characterization of plasmids from macrolide antibiotic-producing streptomycetes","volume":"34","author":"S Omura","year":"n.d","journal-title":"J Antibiot (Tokyo)"},{"issue":"2","key":"pntd.0012710.ref008","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1128\/IAI.68.2.877-883.2000","article-title":"A Mycobacterium ulcerans toxin, mycolactone, causes apoptosis in guinea pig ulcers and tissue culture cells","volume":"68","author":"KM George","year":"2000","journal-title":"Infect Immun"},{"issue":"5","key":"pntd.0012710.ref009","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1001\/archderm.1974.01630110073023","article-title":"Toxin of Mycobacterium ulcerans. 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Fraga","year":"2011","journal-title":"Infect Immun"},{"issue":"12","key":"pntd.0012710.ref031","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1002\/cbic.200600285","article-title":"Ketoreduction in mycolactone biosynthesis: insight into substrate specificity and stereocontrol from studies of discrete ketoreductase domains in vitro","volume":"7","author":"S Bali","year":"2006","journal-title":"Chembiochem"},{"issue":"8","key":"pntd.0012710.ref032","doi-asserted-by":"crossref","first-page":"e00098-17","DOI":"10.1128\/CVI.00098-17","article-title":"Antibody-based correlates of protection against cholera analysis of a challenge study in a cholera-na\u00efve population","volume":"24","author":"DJ Haney","year":"2017","journal-title":"Clin Vaccine Immunol"},{"key":"pntd.0012710.ref033","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/1471-2334-14-202","article-title":"Kinetics of mycolactone in human subcutaneous tissue during antibiotic therapy for Mycobacterium 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