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No licensed vaccine against melioidosis exists. In preclinical vaccine studies, demonstrating protection against respiratory infection in the highly sensitive BALB\/c mouse has been especially challenging. To address this challenge, we have used a safe yet potent live attenuated platform vector, LVS \u0394\n                      <jats:italic>capB<\/jats:italic>\n                      , previously used successfully to develop vaccines against the Tier 1 select agents of tularemia, anthrax, and plague, to develop a melioidosis vaccine. We have engineered melioidosis vaccines (rLVS \u0394\n                      <jats:italic>capB<\/jats:italic>\n                      \/Bp) expressing multiple immunoprotective Bp antigens among type VI secretion system proteins Hcp1, Hcp2, and Hcp6, and membrane protein LolC. Administered intradermally, rLVS \u0394\n                      <jats:italic>capB<\/jats:italic>\n                      \/Bp vaccines strongly protect highly sensitive BALB\/c mice against lethal respiratory Bp challenge, but protection is overwhelmed at very high challenge doses. In contrast, administered intranasally, rLVS \u0394\n                      <jats:italic>capB<\/jats:italic>\n                      \/Bp vaccines remain strongly protective against even very high challenge doses. Under some conditions, the LVS \u0394\n                      <jats:italic>capB<\/jats:italic>\n                      vector itself provides significant protection against Bp challenge, and consistent with this, both the vector and vaccines induce humoral immune responses to Bp antigens. Three-antigen vaccines expressing Hcp6-Hcp1-Hcp2 or Hcp6-Hcp1-LolC are among the most potent and provide long-term protection and protection even with a single intranasal immunization. Protection via the intranasal route was either comparable to or statistically significantly better than the single-deletional Bp mutant Bp82, which served as a positive control. Thus, rLVS \u0394\n                      <jats:italic>capB<\/jats:italic>\n                      \/Bp vaccines are exceptionally promising safe and potent melioidosis vaccines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Melioidosis, a major neglected disease caused by the intracellular bacterial pathogen\n                      <jats:italic>Burkholderia pseudomallei<\/jats:italic>\n                      , is endemic in many tropical areas of the world and causes an estimated 165,000 cases and 89,000 deaths in humans annually. Moreover,\n                      <jats:italic>B. pseudomallei<\/jats:italic>\n                      is categorized as a Tier 1 select agent of bioterrorism, largely because inhalation of low doses can cause rapidly fatal pneumonia. No licensed vaccine is available to prevent melioidosis. Here, we describe a safe and potent melioidosis vaccine that protects against lethal respiratory challenge with\n                      <jats:italic>B. pseudomallei<\/jats:italic>\n                      in a highly sensitive small animal model\u2014even a single immunization is highly protective, and the vaccine gives long-term protection. The vaccine utilizes a highly attenuated replicating intracellular bacterium as a vector to express multiple key proteins of\n                      <jats:italic>B. pseudomallei<\/jats:italic>\n                      ; this vector platform has previously been used successfully to develop potent vaccines against other Tier 1 select agent diseases including tularemia, anthrax, and plague.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00186-24","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T09:00:28Z","timestamp":1711011628000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":6,"title":["LVS \u0394\n                    <i>capB<\/i>\n                    -vectored multiantigenic melioidosis vaccines protect against lethal respiratory\n                    <i>Burkholderia pseudomallei<\/i>\n                    challenge in highly sensitive BALB\/c mice"],"prefix":"10.1128","volume":"15","author":[{"given":"Michael V.","family":"Tullius","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Center for Health Sciences, School of Medicine, University of California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Bowen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Back","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Center for Health Sciences, School of Medicine, University of California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa\u0161a","family":"Masle\u0161a-Gali\u0107","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Center for Health Sciences, School of Medicine, University of California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Nava","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Center for Health Sciences, School of Medicine, University of California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6525-7147","authenticated-orcid":true,"given":"Marcus A.","family":"Horwitz","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Center for Health Sciences, School of Medicine, University of California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.18.2.383-416.2005"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2015.8"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldr007"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid2106.141480"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1398389"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00192-10"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/spectrum.05035-22"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-021-00321-8"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-24581-y"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2016.08.041"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00154"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01218-10"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00404-07"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.provac.2010.03.013"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201040881"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000407"},{"key":"e_1_3_5_18_2","first-page":"10","article-title":"Rapid, scarless cloning of gene fragments using the electra vector system","volume":"33","author":"Whitman L","year":"2013","unstructured":"Whitman L, Gore M, Ness J, Theodorou E, Gustafsson C, Minshull J. 2013. 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