{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T10:25:28Z","timestamp":1777890328012,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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:sub>+<\/jats:sub>\n                      T cells in the lungs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In BCG-primed mice, immunization with intramuscular followed by intranasal ID93 + GLA-3M-052-LS boosts significantly reduced Mtb burden in the lungs after challenge vs. 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1797767","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:35:35Z","timestamp":1777613735000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ID93 + GLA-3M-052-LS vaccine candidate administered by heterologous routes improves BCG efficacy against TB"],"prefix":"10.3389","volume":"17","author":[{"given":"Emily","family":"Voigt","sequence":"first","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anas","family":"Alsharaydeh","sequence":"additional","affiliation":[{"name":"Population Health Program, Texas Biomedical Research Institute","place":["San Antonio, TX, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darshan N.","family":"Kasal","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeleine Farber","family":"Jennewein","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devin S.","family":"Brandt","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Lin","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasneet","family":"Singh","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Bakken","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raodoh","family":"Mohamath","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pauline","family":"Fusco","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi B.","family":"Torrelles","sequence":"additional","affiliation":[{"name":"Population Health Program, Texas Biomedical Research Institute","place":["San Antonio, TX, United States"]},{"name":"International Center for the Advancement of Research & Education (I\u00b7CARE), Texas Biomedical Research Institute","place":["San Antonio, TX, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gillian","family":"Beamer","sequence":"additional","affiliation":[{"name":"Population Health Program, Texas Biomedical Research Institute","place":["San Antonio, TX, United States"]},{"name":"International Center for the Advancement of Research & Education (I\u00b7CARE), Texas Biomedical Research Institute","place":["San Antonio, TX, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher B.","family":"Fox","sequence":"additional","affiliation":[{"name":"Access to Advanced Health Institute","place":["Seattle, WA, United States"]},{"name":"Department of Global Health, University of Washington","place":["Seattle, WA, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz430","article-title":"Effectiveness of BCG vaccination against Mycobacterium tuberculosis infection in adults: A cross-sectional analysis of a UK-based cohort","volume":"221","author":"Katelaris","year":"2020","journal-title":"J Infect Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268818001760","article-title":"Quantifying TB transmission: A systematic review of reproduction number and serial interval estimates for tuberculosis","volume":"146","author":"Ma","year":"2018","journal-title":"Epidemiol Infect"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202006-2394PP","article-title":"The epidemiological importance of subclinical tuberculosis. A critical reappraisal","volume":"203","author":"Kendall","year":"2021","journal-title":"Am J Respir Crit Care Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1909953","article-title":"Final analysis of a trial of M72\/AS01(E) vaccine to prevent tuberculosis","volume":"381","author":"Tait","year":"2019","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","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","author":"Sagawa","year":"2023","journal-title":"Nat Commun"},{"key":"B6","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.jconrel.2016.11.011","article-title":"Adsorption of a synthetic TLR7\/8 ligand to aluminum oxyhydroxide for enhanced vaccine adjuvant activity: A formulation approach","volume":"244","author":"Fox","year":"2016","journal-title":"J Control Release"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2023.03.027","article-title":"Preclinical evaluation of immunogenicity, efficacy and safety of a recombinant plant-based SARS-CoV-2 RBD vaccine formulated with 3M-052-Alum adjuvant","volume":"41","author":"Phoolcharoen","year":"2023","journal-title":"Vaccine"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abb1025","article-title":"3M-052, a synthetic TLR-7\/8 agonist, induces durable HIV-1 envelope-specific plasma cells and humoral immunity in nonhuman primates","volume":"5","author":"Kasturi","year":"2020","journal-title":"Sci Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1039\/c9nr09936k","article-title":"Physicochemical structure of a polyacrylic acid stabilized nanoparticle alum (nanoalum) adjuvant governs TH1 differentiation of CD4+ T cells","volume":"12","author":"Khandhar","year":"2020","journal-title":"Nanoscale"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-018-0094-0","article-title":"Reprogramming the adjuvant properties of aluminum oxyhydroxide with nanoparticle technology","volume":"4","author":"Orr","year":"2019","journal-title":"NPJ Vaccines"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2024.2374147","article-title":"Immunogenicity and safety of an Entamoeba histolytica adjuvanted protein vaccine candidate (LecA+GLA-3M-052 liposomes) in rhesus macaques","volume":"20","author":"Abhyankar","year":"2024","journal-title":"Hum Vaccin Immunother"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.683157","article-title":"Optimizing a multi-component intranasal Entamoeba histolytica vaccine formulation using a design of experiments strategy","volume":"12","author":"Abhyankar","year":"2021","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1038\/s41541-021-00399-0","article-title":"Development of COVID-19 vaccine using a dual Toll-like receptor ligand liposome adjuvant","volume":"6","author":"Abhyankar","year":"2021","journal-title":"NPJ Vaccines"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3679","article-title":"Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells","volume":"18","author":"Keller","year":"2017","journal-title":"Nat Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12022","article-title":"MAIT cells and microbial immunity","volume":"96","author":"Meermeier","year":"2018","journal-title":"Immunol Cell Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12271","article-title":"MR1-restricted mucosal associated invariant T (MAIT) cells in the immune response to Mycobacterium tuberculosis","volume":"264","author":"Gold","year":"2015","journal-title":"Immunol Rev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S159839","article-title":"Development of a thermostable nanoemulsion adjuvanted vaccine against tuberculosis using a design-of-experiments approach","volume":"13","author":"Kramer","year":"2018","journal-title":"Int J Nanomedicine"},{"key":"B18","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.jconrel.2013.07.030","article-title":"Adjuvant formulation structure and composition are critical for the development of an effective vaccine against tuberculosis","volume":"172","author":"Orr","year":"2013","journal-title":"J Control Release"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-75203-5_6","article-title":"Genetic dissection of host resistance to Mycobacterium tuberculosis: The sst1 locus and the Ipr1 gene","volume":"321","author":"Kramnik","year":"2008","journal-title":"Curr topics Microbiol Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00097-20","article-title":"The Diversity Outbred mouse population is an improved animal model of vaccination against tuberculosis that reflects heterogeneity of protection","volume":"5","author":"Kurtz","year":"2020","journal-title":"mSphere"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011915","article-title":"Systems genetics uncover new loci containing functional gene candidates in Mycobacterium tuberculosis-infected Diversity Outbred mice","volume":"20","author":"Gatti","year":"2024","journal-title":"PloS Pathog"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1172\/jci167762","article-title":"Host genetic background is a barrier to broadly effective vaccine-mediated protection against tuberculosis","volume":"133","author":"Lai","year":"2023","journal-title":"J Clin Invest"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2013.09.006","article-title":"In vitro evaluation of TLR4 agonist activity: Formulation effects","volume":"113","author":"Misquith","year":"2014","journal-title":"Colloids Surf B Biointerfaces"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abh3634","article-title":"A yeast expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates","volume":"6","author":"Pino","year":"2021","journal-title":"Sci Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-008-9113-1","article-title":"The Collaborative Cross, developing a resource for mammalian systems genetics: A status report of the Wellcome Trust cohort","volume":"19","author":"Iraqi","year":"2008","journal-title":"Mamm genome: Off J Int Mamm Genome Soc"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-008-9135-8","article-title":"The Collaborative Cross at Oak Ridge National Laboratory: Developing a powerful resource for systems genetics","volume":"19","author":"Chesler","year":"2008","journal-title":"Mamm genome: Off J Int Mamm Genome Soc"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-012-9410-6","article-title":"Status and access to the Collaborative Cross population","volume":"23","author":"Welsh","year":"2012","journal-title":"Mamm genome: Off J Int Mamm Genome Soc"},{"key":"B28","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1038\/s41541-022-00549-y","article-title":"A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability","volume":"7","author":"Voigt","year":"2022","journal-title":"NPJ Vaccines"},{"key":"B29","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41467-025-64829-6","article-title":"Intranasal replicon vaccine establishes mucosal immunity and protects against H5N1 and H7N9 influenza","volume":"17","author":"Ykema","year":"2026","journal-title":"Nat Commun"},{"key":"B30","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/s41541-020-00228-w","article-title":"Preclinical optimization of an enterotoxigenic Escherichia coli adjuvanted subunit vaccine using response surface design of experiments","volume":"5","author":"Poncet","year":"2020","journal-title":"NPJ Vaccines"},{"key":"B31","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1038\/s41541-023-00608-y","article-title":"Semi-synthetic terpenoids with differential adjuvant properties as sustainable replacements for shark squalene in vaccine emulsions","volume":"8","author":"Fisher","year":"2023","journal-title":"NPJ Vaccines"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201142054","article-title":"CBA\/J mice generate protective immunity to soluble Ag85 but fail to respond efficiently to Ag85 during natural Mycobacterium tuberculosis infection","volume":"42","author":"Beamer","year":"2012","journal-title":"Eur J Immunol"},{"key":"B33","doi-asserted-by":"publisher","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","author":"Beamer","year":"2008","journal-title":"Clin Vaccine Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.8.5545","article-title":"Interleukin-10 promotes Mycobacterium tuberculosis disease progression in CBA\/J mice","volume":"181","author":"Beamer","year":"2008","journal-title":"J Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00263-23","article-title":"B cells in perivascular and peribronchiolar granuloma-associated lymphoid tissue and B-cell signatures identify asymptomatic Mycobacterium tuberculosis lung infection in Diversity Outbred mice","volume":"92","author":"Koyuncu","year":"2024","journal-title":"Infect Immun"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.020867","article-title":"Lung necrosis and neutrophils reflect common pathways of susceptibility to Mycobacterium tuberculosis in genetically diverse, immune-competent mice","volume":"8","author":"Niazi","year":"2015","journal-title":"Dis Model Mech"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1422836","article-title":"Detailed phenotyping reveals diverse and highly skewed neutrophil subsets in both the blood and airways during active tuberculosis infection","volume":"15","author":"Nhamoyebonde","year":"2024","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200297","article-title":"Prime-pull immunization of mice with a BcfA-adjuvanted vaccine elicits sustained mucosal immunity that prevents SARS-CoV-2 infection and pathology","volume":"210","author":"Shamseldin","year":"2023","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105185","article-title":"Intranasal SARS-CoV-2 Omicron variant vaccines elicit humoral and cellular mucosal immunity in female mice","volume":"105","author":"Slamanig","year":"2024","journal-title":"EBioMedicine"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2019.03.009","article-title":"The Collaborative Cross: A systems genetics resource for studying host-pathogen interactions","volume":"25","author":"Noll","year":"2019","journal-title":"Cell Host Microbe"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2012.11.001","article-title":"Systems approaches to influenza-virus host interactions and the pathogenesis of highly virulent and pandemic viruses","volume":"25","author":"Korth","year":"2013","journal-title":"Semin Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107587","article-title":"Complex genetic architecture underlies regulation of influenza-A-virus-specific antibody responses in the Collaborative Cross","volume":"31","author":"Noll","year":"2020","journal-title":"Cell Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1177\/0300985811429313","article-title":"The pathology of Mycobacterium tuberculosis infection","volume":"49","author":"Sakamoto","year":"2012","journal-title":"Vet Pathol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.medj.2021.11.006","article-title":"Protection against tuberculosis by Bacillus Calmette-Gu\u00e9rin (BCG) vaccination: A historical perspective","volume":"3","author":"Setiabudiawan","year":"2022","journal-title":"Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/app11199250","article-title":"Tuberculosis vaccines: An update of recent and ongoing clinical trials","volume":"11","author":"Saramago","year":"2021","journal-title":"Appl Sci"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.03154","article-title":"Clinical development of new TB vaccines: Recent advances and next steps","volume":"10","author":"Hatherill","year":"2020","journal-title":"Front Microbiol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1797767\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T05:35:36Z","timestamp":1777613736000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1797767\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,1]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2026.1797767"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1797767","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,1]]},"article-number":"1797767"}}