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Aerosol vaccination with the\n                    <jats:italic>Mtb\u0394sigH<\/jats:italic>\n                    mutant protects 2 species of nonhuman primates against lethal TB challenge by invoking vastly superior T and B cell responses in the lungs through superior antigen presentation and interferon conditioning. Since the Geneva Consensus on essential steps toward the development of live mycobacterial vaccines recommends that live TB vaccines incorporate at least 2 independent gene knockouts, we have now generated several rationally designed, double-knockout (DKO) and triple-knockout (TKO) mutants in\n                    <jats:italic>Mtb<\/jats:italic>\n                    , each containing the\n                    <jats:italic>\u0394sigH<\/jats:italic>\n                    deletion. Here, we report preclinical studies in the rhesus macaque model of aerosol infection and SIV\/HIV coinfection, aimed at assessing the safety of these\n                    <jats:italic>Mtb\u0394sigH<\/jats:italic>\n                    -based DKOs and TKOs. We found that most of these mutant strains were attenuated in both immunocompetent and SIV-coinfected macaques, and combinatorial infection with these generated strong cellular immune responses in the lung, akin to\n                    <jats:italic>Mtb\u0394sigH<\/jats:italic>\n                    . Aerosol infection with these KO strains elicited inducible bronchus-associated lymphoid tissue, which is a correlate of protection from TB.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.195947","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T16:00:16Z","timestamp":1756396816000},"source":"Crossref","is-referenced-by-count":2,"title":["Development and preclinical evaluation of next-generation \u0394sigH-based live candidate vaccines"],"prefix":"10.1172","volume":"10","author":[{"given":"Garima","family":"Arora","sequence":"first","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caden W.","family":"Munson","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mushtaq","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Chicago, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4625-954X","authenticated-orcid":true,"given":"Vinay","family":"Shivanna","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annu","family":"Devi","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkata S.R.","family":"Devireddy","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basil","family":"Antony","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3268-4438","authenticated-orcid":true,"given":"Shannan","family":"Hall-Ursone","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6447-9183","authenticated-orcid":true,"given":"Olga D.","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Edward J.","family":"Dick","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinnaswamy","family":"Jagannath","sequence":"additional","affiliation":[{"name":"Houston Methodist Research Institute, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4129-3546","authenticated-orcid":true,"given":"Xavier","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smriti","family":"Mehra","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9545-4982","authenticated-orcid":true,"given":"Shabaana A.","family":"Khader","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Chicago, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5507-1197","authenticated-orcid":true,"given":"Dhiraj K.","family":"Singh","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3521-1257","authenticated-orcid":true,"given":"Deepak","family":"Kaushal","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(22)00359-7"},{"key":"B2","unstructured":"WHO. 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