{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T02:42:01Z","timestamp":1773628921678,"version":"3.50.1"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2014,6,3]],"date-time":"2014-06-03T00:00:00Z","timestamp":1401753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T00:00:00Z","timestamp":1404172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The only tuberculosis (TB) vaccine in use today, bacillus Calmette-Gu\u00e9rin (BCG), provides insufficient protection and can cause adverse events in immunocompromised individuals, such as BCGosis in HIV\n            <jats:sup>+<\/jats:sup>\n            newborns. We previously reported improved preclinical efficacy and safety of the recombinant vaccine candidate BCG \u0394\n            <jats:italic>ureC<\/jats:italic>\n            ::\n            <jats:italic>hly<\/jats:italic>\n            , which secretes the pore-forming listeriolysin O of\n            <jats:named-content content-type=\"genus-species\">Listeria monocytogenes<\/jats:named-content>\n            . Here, we evaluate a second-generation construct, BCG \u0394\n            <jats:italic>ureC<\/jats:italic>\n            ::\n            <jats:italic>hly<\/jats:italic>\n            \u0394\n            <jats:italic>pdx1<\/jats:italic>\n            , which is deficient in pyridoxine synthase, an enzyme that is required for biosynthesis of the essential cofactor vitamin B\n            <jats:sub>6<\/jats:sub>\n            . This candidate was auxotrophic for vitamin B\n            <jats:sub>6<\/jats:sub>\n            in a concentration-dependent manner, as was its survival\n            <jats:italic>in vivo<\/jats:italic>\n            . BCG \u0394\n            <jats:italic>ureC<\/jats:italic>\n            ::\n            <jats:italic>hly<\/jats:italic>\n            \u0394\n            <jats:italic>pdx1<\/jats:italic>\n            showed markedly restricted dissemination in subcutaneously vaccinated mice, which was ameliorated by dietary supplementation with vitamin B\n            <jats:sub>6<\/jats:sub>\n            . The construct was safer in severe combined immunodeficiency mice than the parental BCG \u0394\n            <jats:italic>ureC<\/jats:italic>\n            ::\n            <jats:italic>hly<\/jats:italic>\n            . A prompt innate immune response to vaccination, measured by secretion of interleukin-6, granulocyte colony-stimulating factor, keratinocyte cytokine, and macrophage inflammatory protein-1\u03b1, remained independent of vitamin B\n            <jats:sub>6<\/jats:sub>\n            administration, while acquired immunity, notably stimulation of antigen-specific CD4 T cells, B cells, and memory T cells, was contingent on vitamin B\n            <jats:sub>6<\/jats:sub>\n            administration. The early protection provided by BCG \u0394\n            <jats:italic>ureC<\/jats:italic>\n            ::\n            <jats:italic>hly<\/jats:italic>\n            \u0394\n            <jats:italic>pdx1<\/jats:italic>\n            in a murine\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis<\/jats:named-content>\n            aerosol challenge model consistently depended on vitamin B\n            <jats:sub>6<\/jats:sub>\n            supplementation. Prime-boost vaccination increased protection against the canonical\n            <jats:named-content content-type=\"genus-species\">M. tuberculosis<\/jats:named-content>\n            H37Rv laboratory strain and a clinical isolate of the Beijing\/W lineage. We demonstrate that the efficacy of a profoundly attenuated recombinant BCG vaccine construct can be modulated by external administration of a small molecule. This principle fosters the development of safer vaccines required for immunocompromised individuals, notably HIV\n            <jats:sup>+<\/jats:sup>\n            infants.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis<\/jats:named-content>\n            can synthesize the essential cofactor vitamin B\n            <jats:sub>6<\/jats:sub>\n            , while humans depend on dietary supplementation. Unlike the lipophilic vitamins A, D, and E, water-soluble vitamin B\n            <jats:sub>6<\/jats:sub>\n            is well tolerated at high doses. We generated a vitamin B\n            <jats:sub>6<\/jats:sub>\n            auxotroph of the phase II clinical tuberculosis vaccine candidate bacillus Calmette-Gu\u00e9rin \u0394\n            <jats:italic>ureC<\/jats:italic>\n            ::\n            <jats:italic>hly<\/jats:italic>\n            . The next-generation candidate was profoundly attenuated compared to the parental strain. Adaptive immunity and protection in mice consistently depended on increased dietary vitamin B\n            <jats:sub>6<\/jats:sub>\n            above the daily required dose. Control of vaccine efficacy via food supplements such as vitamin B\n            <jats:sub>6<\/jats:sub>\n            could provide a fast track toward improved safety. Safer vaccines are urgently needed for HIV-infected individuals at high risk of adverse events in response to live vaccines.\n          <\/jats:p>","DOI":"10.1128\/mbio.01262-14","type":"journal-article","created":{"date-parts":[[2014,6,4]],"date-time":"2014-06-04T05:44:45Z","timestamp":1401860685000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["Dietary Pyridoxine Controls Efficacy of Vitamin B\n            <sub>6<\/sub>\n            -Auxotrophic Tuberculosis Vaccine Bacillus Calmette-Gu\u00e9rin \u0394\n            <i>ureC<\/i>\n            ::\n            <i>hly<\/i>\n            \u0394\n            <i>pdx1<\/i>\n            in Mice"],"prefix":"10.1128","volume":"5","author":[{"given":"Martin","family":"Gengenbacher","sequence":"first","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Vogelzang","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Schuerer","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doris","family":"Lazar","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peggy","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan H. E.","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1688"},{"key":"e_1_3_3_3_2","volume-title":"La vaccination pr\u00e9ventive contre la tuberculose par le \u201cBCG.\u201d","author":"Calmette A","year":"1927","unstructured":"CalmetteA Gu\u00e9rinC BoquetA N\u00e9greL . 1927. La vaccination pr\u00e9ventive contre la tuberculose par le \u201cBCG.\u201d Masson, Paris, France."},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2012.03.007"},{"key":"e_1_3_3_5_2","volume-title":"Global tuberculosis report 2013","author":"WHO","year":"2013","unstructured":"WHO . 2013. Global tuberculosis report 2013. WHO, Geneva, Switzerland. http:\/\/www.who.int\/tb\/publications\/global_report\/en\/."},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.20.10961"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.20.10955"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0396-334"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.67.6.2867-2873.1999"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm765"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.72.5.3031-3037.2004"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.5.2888-2898.2000"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.7.4190-4192.2003"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.2.1196-1203.2005"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.04.066"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2010.07381.x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508696200"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja042792t"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.04.068"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2009.06.009"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604950103"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2011.11.015"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24617"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2012.12.053"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/31159"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700869104"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0078966"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200737322"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid0805.020002"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1586\/14760584.2014.905746"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni981"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2012.00331.x"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2012.01799.x"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.05.059"},{"key":"e_1_3_3_35_2","first-page":"99","volume-title":"Advanced nutrition: micronutrients","author":"Berdanier CD","year":"1998","unstructured":"BerdanierCD . 1998. Vitamin B6, p 99\u2013105. In Advanced nutrition: micronutrients. CRC Press, Boca Raton, FL."},{"key":"e_1_3_3_36_2","volume-title":"Pharmaceutical substances\u2014syntheses, patents, applications","author":"Kleeman A","year":"2001","unstructured":"KleemanA EngelJ KutscherB ReichertD . 2001. Pharmaceutical substances\u2014syntheses, patents, applications. Thieme Medical Publishers, Stuttgart, Germany."},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132703"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.2.621-629.2000"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2274"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1373\/49.1.155"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/53.6.1436"},{"key":"e_1_3_3_42_2","volume-title":"Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline","author":"Institute of Medicine","year":"1998","unstructured":"Institute of Medicine . 1998. Vitamin B6, p 150\u2013195. In Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.National Acadamies Press, Washington, DC. http:\/\/www.nap.edu\/catalog.php?record_id=6015."},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.1993.tb03109.x"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-148-10-3007"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1097(03)00003-X"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/351456a0"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.01262-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.01262-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T01:46:58Z","timestamp":1646704018000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.01262-14"}},"subtitle":[],"editor":[{"given":"Rino","family":"Rappuoli","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2014,7]]},"references-count":45,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2014,7]]}},"alternative-id":["10.1128\/mBio.01262-14"],"URL":"https:\/\/doi.org\/10.1128\/mbio.01262-14","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7]]},"assertion":[{"value":"2014-04-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-05-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-06-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01262-14"}}