{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T03:17:26Z","timestamp":1774581446822,"version":"3.50.1"},"posted":{"date-parts":[[2025,11,1]]},"group-title":"Immunology","reference-count":30,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institutes of Health (NIH) under the National Institute of Allergy and Infectious Diseases","award":["R61 AI169026"],"award-info":[{"award-number":["R61 AI169026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  New vaccine approaches are needed against tuberculosis (TB). We sought to optimize mucosal immunogenicity and protective efficacy by modulating the adjuvant component and route of immunization of a next-generation TB vaccine using the recombinant TB vaccine antigen (Ag) ID93. ID93-specific mucosal and systemic immunogenicity and protective efficacy were assessed in the Collaborative Cross 004 mouse strain, a mouse strain susceptible to\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (\n                  <jats:italic>Mtb<\/jats:italic>\n                  ) infection, as a suitable model of\n                  <jats:italic>Mtb<\/jats:italic>\n                  susceptible populations. Immunogenicity data from various vaccine candidates were used to select lead vaccine candidates with the most preferred immunostimulatory profiles using a pre-determined desirability index. A liposomal adjuvant system containing synthetic TLR4 and TLR7\/8 ligands (GLA-3M-052-LS), administered by a heterologous intramuscular-intranasal regimen, induced an optimal comprehensive immune response profile including high levels of mucosal antibody and Th1 CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells in the lungs. In BCG-primed mice, immunization with intramuscular followed by intranasal ID93 + GLA-3M-052-LS boosts significantly reduced\n                  <jats:italic>Mtb<\/jats:italic>\n                  burden in the lungs after challenge\n                  <jats:italic>vs.<\/jats:italic>\n                  BCG vaccinated mice alone. Thus, ID93 + GLA-3M-052-LS represents a promising next-generation TB vaccine candidate suitable for testing in additional preclinical models.\n                <\/jats:p>","DOI":"10.1101\/2025.10.31.685426","type":"posted-content","created":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T13:25:11Z","timestamp":1762003511000},"source":"Crossref","is-referenced-by-count":1,"title":["The ID93 + GLA-3M-052-LS vaccine candidate elicits mucosal and systemic immunogenicity and protective efficacy against\n                  <i>Mycobacterium tuberculosis<\/i>\n                  challenge in BCG-primed Collaborative Cross inbred mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5177-4063","authenticated-orcid":false,"given":"Emily A.","family":"Voigt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anas","family":"Alsharaydeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2718-7971","authenticated-orcid":false,"given":"Darshan N.","family":"Kasal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeleine F.","family":"Jennewein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devin S.","family":"Brandt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasneet","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Bakken","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raodoh","family":"Mohamath","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pauline","family":"Fusco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi B.","family":"Torrelles","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6782-4424","authenticated-orcid":false,"given":"Gillian","family":"Beamer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4644-2619","authenticated-orcid":false,"given":"Christopher B.","family":"Fox","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025110408150846000_2025.10.31.685426v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz430"},{"key":"2025110408150846000_2025.10.31.685426v1.2","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268818001760"},{"key":"2025110408150846000_2025.10.31.685426v1.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202006-2394PP"},{"key":"2025110408150846000_2025.10.31.685426v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1909953"},{"key":"2025110408150846000_2025.10.31.685426v1.5","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1038\/s41467-023-36789-2","article-title":"Safety and immunogenicity of a thermostable ID93 + GLA-SE tuberculosis vaccine candidate in healthy adults","volume":"14","year":"2023","journal-title":"Nat Commun"},{"key":"2025110408150846000_2025.10.31.685426v1.6","doi-asserted-by":"crossref","unstructured":"Lai, R. et al. Host genetic background is a barrier to broadly effective vaccine\u2013 mediated protection against tuberculosis. 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Semi-synthetic terpenoids with differential adjuvant properties as sustainable replacements for shark squalene in vaccine emulsions. npj Vaccines 8, 14 (2023).","DOI":"10.1038\/s41541-023-00608-y"},{"key":"2025110408150846000_2025.10.31.685426v1.20","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1128\/CVI.00408-07","article-title":"Peripheral Blood Gamma Interferon Release Assays Predict Lung Responses and Mycobacterium tuberculosis Disease Outcome in Mice","volume":"15","year":"2008","journal-title":"Clinical and Vaccine Immunology"},{"key":"2025110408150846000_2025.10.31.685426v1.21","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201142054"},{"key":"2025110408150846000_2025.10.31.685426v1.22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.8.5545"},{"key":"2025110408150846000_2025.10.31.685426v1.23","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.020867"},{"key":"2025110408150846000_2025.10.31.685426v1.24","doi-asserted-by":"crossref","unstructured":"Nhamoyebonde, S. et al. Detailed phenotyping reveals diverse and highly skewed neutrophil subsets in both the blood and airways during active tuberculosis infection. Front. 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