{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T02:06:04Z","timestamp":1791511564906,"version":"4.3.4"},"posted":{"date-parts":[[2024,5,15]]},"group-title":"Microbiology","reference-count":20,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Tuberculosis, caused by\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (\n                  <jats:italic>Mtb<\/jats:italic>\n                  ), remains a leading infectious cause of mortality worldwide despite widespread use of the BCG vaccine and the availability of sterilizing pharmacopoeia. Recent research indicates that the intravenous administration of BCG confers sterilizing immunity against\n                  <jats:italic>Mtb<\/jats:italic>\n                  pulmonary challenge in non-human primates. However, while BCG is relatively safe, complications such as disseminated BCGosis have been observed in immunocompromised individuals. Double auxotrophic mutants of\n                  <jats:italic>Mtb<\/jats:italic>\n                  lacking the ability to synthesize leucine and pantothenate are safe and sterilized in immunocompromised mice and SIV-infected Rhesus macaques. We examined how immunization with a\n                  <jats:italic>Mtb<\/jats:italic>\n                  triple auxotrophic strain, mc\n                  <jats:sup>2<\/jats:sup>\n                  7902, which cannot synthesize leucine, pantothenate, and arginine, protects immunocompetent mice from a virulent\n                  <jats:italic>Mtb<\/jats:italic>\n                  infection. The route of immunization was a crucial factor for protection with mc\n                  <jats:sup>2<\/jats:sup>\n                  7902 with intravenous immunization being 100 times more effective in protecting immunocompetent mice from\n                  <jats:italic>Mtb<\/jats:italic>\n                  challenge when compared to conventional subcutaneous vaccination with BCG. To further increase the safety of the attenuated auxotroph for vaccine purposes, the type VII secretion system Esx1 responsible for BCG attenuation was deleted in mc\n                  <jats:sup>2<\/jats:sup>\n                  7902. When tested by prime-boost immunization of immunocompetent mice followed by aerosol challenge with virulent\n                  <jats:italic>Mtb<\/jats:italic>\n                  , mc\n                  <jats:sup>2<\/jats:sup>\n                  7902 \u0394\n                  <jats:italic>esx1<\/jats:italic>\n                  provided similar protection to mc\n                  <jats:sup>2<\/jats:sup>\n                  7902. This robust protection against\n                  <jats:italic>Mtb<\/jats:italic>\n                  infection conferred by mc\n                  <jats:sup>2<\/jats:sup>\n                  7902 and mc\n                  <jats:sup>2<\/jats:sup>\n                  7902 \u0394\n                  <jats:italic>esx1<\/jats:italic>\n                  in a mouse model paves the way for new TB vaccine development using highly attenuated, auxotrophic\n                  <jats:italic>Mtb<\/jats:italic>\n                  strains.\n                <\/jats:p>","DOI":"10.1101\/2024.05.15.594337","type":"posted-content","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T18:05:12Z","timestamp":1715796312000},"source":"Crossref","is-referenced-by-count":3,"title":["Intravenous Immunization with Triple Auxotrophs of\n                  <i>Mycobacterium tuberculosis<\/i>\n                  : A novel vaccine strategy against tuberculosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5960-6670","authenticated-orcid":false,"given":"Catherine","family":"Vilch\u00e8ze","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2201-8028","authenticated-orcid":false,"given":"Saranathan","family":"Rajagopalan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3321-3080","authenticated-orcid":false,"suffix":"Jr.","given":"William R.","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2024051809350532000_2024.05.15.594337v1.1","unstructured":"World Health Organization. 2023. Global tuberculosis report 2023. https:\/\/www.who.int\/teams\/global-tuberculosis-programme\/tb-reports\/global-tuberculosis-report-2023. Accessed 02\/01\/2024."},{"key":"2024051809350532000_2024.05.15.594337v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-0101(99)00086-0"},{"key":"2024051809350532000_2024.05.15.594337v1.3","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.BAI-0024-2019"},{"key":"2024051809350532000_2024.05.15.594337v1.4","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ijpam.2015.05.004","article-title":"BCG related complications: A single center, prospective observational study","volume":"2","year":"2015","journal-title":"Int J Pediatr Adolesc Med"},{"key":"2024051809350532000_2024.05.15.594337v1.5","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.jaci.2017.12.980","article-title":"Update: Vaccines in primary immunodeficiency","volume":"141","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"2024051809350532000_2024.05.15.594337v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2012.03.012"},{"key":"2024051809350532000_2024.05.15.594337v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1817-8"},{"key":"2024051809350532000_2024.05.15.594337v1.8","doi-asserted-by":"crossref","first-page":"e0022023","DOI":"10.1128\/mbio.00220-23","article-title":"Imprinting of Gut-Homing Receptors on Mtb-Specific Th1* Cells Is Associated with Reduced Lung Homing after Gavage BCG Vaccination of Rhesus Macaques","volume":"14","year":"2023","journal-title":"mBio"},{"key":"2024051809350532000_2024.05.15.594337v1.9","doi-asserted-by":"crossref","unstructured":"Larson EC , Ellis-Connell AL , Rodgers MA , Gubernat AK , Gleim JL , Moriarty RV , Balgeman AJ , Ameel CL , Jauro S , Tomko JA , Kracinovsky KB , Maiello P , Borish HJ , White AG , Klein E , Bucsan AN , Darrah PA , Seder RA , Roederer M , Lin PL , Flynn JL , O\u2019Connor SL , Scanga CA . 2023. Vaccination with intravenous BCG protects macaques with pre-existing SIV infection from tuberculosis. 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