{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:21:37Z","timestamp":1784557297463,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,16]]},"group-title":"Immunology","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AI134246"],"award-info":[{"award-number":["R01AI134246"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["75N93019C00070"],"award-info":[{"award-number":["75N93019C00070"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (Mtb) remains the leading cause of death from a single infectious agent. Although BCG protects against disseminated tuberculosis in infants, it has failed to curb transmission among adults. Animal models are used to prioritize vaccines entering clinical trials, but current models use Mtb-na\u00efve mice, limiting their relevance to humans in endemic settings, the primary targets of vaccine trials. Here we used a mouse model of Mtb exposure, CoMtb, where a cervical lymph node Mtb infection protects against aerosol challenge, consistent with historical observations in humans that prior Mtb exposure reduces disease risk. When we compared the impact of CoMtb on vaccine efficacy, BCG failed to provide added protection over CoMtb, while protein subunit vaccination further reduced lung burdens. This protection was associated with decreased KLRG1+ vascular CD4+ T cells and enhanced polyfunctional lung CD4+ T cells before and after aerosol challenge. Our findings were corroborated in an analysis of vaccinated humans stratified by QuantiFERON-TB status, which revealed a similar enrichment of polyfunctional CD4+ T cells in Mtb-exposed individuals. These data support the use of CoMtb to test vaccine efficacy in Mtb-exposed individuals and highlight the potential of subunit vaccines in endemic regions.\n                <\/jats:p>","DOI":"10.64898\/2026.07.10.737547","type":"posted-content","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:35:19Z","timestamp":1784262919000},"source":"Crossref","is-referenced-by-count":0,"title":["Subunit vaccination enhances protection conferred by prior\n                  <i>Mycobacterium tuberculosis<\/i>\n                  exposure"],"prefix":"10.64898","author":[{"given":"Sara B.","family":"Cohen","sequence":"first","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Center for Global Infectious Disease Research, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua S.","family":"Woodworth","sequence":"additional","affiliation":[{"name":"Statens Serum Institut, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Lindenstr\u00f8m","sequence":"additional","affiliation":[{"name":"Statens Serum Institut, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anele","family":"Gela","sequence":"additional","affiliation":[{"name":"South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fergal J.","family":"Duffy","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Center for Global Infectious Disease Research, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Aitchison","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Center for Global Infectious Disease Research, Seattle, WA, USA"},{"name":"University of Washington, Department of Pediatrics, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0641-1359","authenticated-orcid":false,"given":"Thomas J.","family":"Scriba","sequence":"additional","affiliation":[{"name":"South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Nemes","sequence":"additional","affiliation":[{"name":"South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus","family":"Mortensen","sequence":"additional","affiliation":[{"name":"Statens Serum Institut, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin B.","family":"Urdahl","sequence":"additional","affiliation":[{"name":"Seattle Children\u2019s Research Institute, Center for Global Infectious Disease Research, Seattle, WA, USA"},{"name":"University of Washington, Department of Pediatrics, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072007000947000_2026.07.10.737547v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit790"},{"key":"2026072007000947000_2026.07.10.737547v1.2","doi-asserted-by":"publisher","DOI":"10.3310\/hta17370"},{"key":"2026072007000947000_2026.07.10.737547v1.3","unstructured":"Diel R , Nienhaus A . Risk of tuberculosis transmission by healthcare workers to children -a comprehensive review. GMS Hyg Infect Control. 2023;18:Doc26."},{"key":"2026072007000947000_2026.07.10.737547v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2285"},{"key":"2026072007000947000_2026.07.10.737547v1.5","first-page":"1973","article-title":"High Antigen Dose Is Detrimental to Post-Exposure Vaccine Protection against Tuberculosis","volume":"8","year":"2017","journal-title":"Front Immunol"},{"key":"2026072007000947000_2026.07.10.737547v1.6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080579"},{"key":"2026072007000947000_2026.07.10.737547v1.7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.585359"},{"key":"2026072007000947000_2026.07.10.737547v1.8","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202011-4239PP"},{"key":"2026072007000947000_2026.07.10.737547v1.9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158849"},{"key":"2026072007000947000_2026.07.10.737547v1.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008655"},{"key":"2026072007000947000_2026.07.10.737547v1.11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011871"},{"key":"2026072007000947000_2026.07.10.737547v1.12","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.2.3493.1130"},{"key":"2026072007000947000_2026.07.10.737547v1.13","doi-asserted-by":"crossref","unstructured":"Miranda-Hernandez S , Kumar M , Henderson A , Graham E , Tan X , Taylor J , et al. CD8(+) T cells sustain vaccination-induced immunity against dissemination of contained tuberculosis in immunosuppressed hosts. Nat Commun. 2026;17(1).","DOI":"10.1038\/s41467-026-70911-4"},{"key":"2026072007000947000_2026.07.10.737547v1.14","doi-asserted-by":"crossref","unstructured":"Zheng W , Limberis JD , Howard ZP , Mohapatra A , Takagi E , Ernst JD. Impaired IFN\u03b3 responsiveness of monocyte-derived lung cells limits immunity to <em>Mycobacterium tuberculosis<\/em>. bioRxiv. 2026:2025.10.06.680719.","DOI":"10.1101\/2025.10.06.680719"},{"key":"2026072007000947000_2026.07.10.737547v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2010.12.135"},{"key":"2026072007000947000_2026.07.10.737547v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45526-2"},{"key":"2026072007000947000_2026.07.10.737547v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2014.10.036"},{"key":"2026072007000947000_2026.07.10.737547v1.18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0801592"},{"key":"2026072007000947000_2026.07.10.737547v1.19","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ebiom.2017.12.004","article-title":"T Cells Primed by Live Mycobacteria Versus a Tuberculosis Subunit Vaccine Exhibit Distinct Functional Properties","volume":"27","year":"2018","journal-title":"EBioMedicine"},{"key":"2026072007000947000_2026.07.10.737547v1.20","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00550-12"},{"issue":"1","key":"2026072007000947000_2026.07.10.737547v1.21","doi-asserted-by":"crossref","first-page":"8959","DOI":"10.1038\/s41467-024-52863-9","article-title":"MINCLE and TLR9 agonists synergize to induce Th1\/Th17 vaccine memory and mucosal recall in mice and non-human primates","volume":"15","year":"2024","journal-title":"Nat Commun"},{"issue":"7","key":"2026072007000947000_2026.07.10.737547v1.22","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/S1473-3099(24)00814-4","article-title":"Immunogenicity, safety, and efficacy of the vaccine H56:IC31 in reducing the rate of tuberculosis disease recurrence in HIV-negative adults successfully treated for drug-susceptible pulmonary tuberculosis: a double-blind, randomised, placebo-controlled, phase 2b trial","volume":"25","year":"2025","journal-title":"Lancet Infect Dis"},{"issue":"33","key":"2026072007000947000_2026.07.10.737547v1.23","doi-asserted-by":"crossref","first-page":"4130","DOI":"10.1016\/j.vaccine.2015.06.051","article-title":"First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults","volume":"33","year":"2015","journal-title":"Vaccine"},{"key":"2026072007000947000_2026.07.10.737547v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2016.11.023"},{"issue":"50","key":"2026072007000947000_2026.07.10.737547v1.25","doi-asserted-by":"crossref","first-page":"6285","DOI":"10.1016\/j.vaccine.2016.10.060","article-title":"The TB vaccine H56+IC31 dose-response curve is peaked not saturating: Data generation for new mathematical modelling methods to inform vaccine dose decisions","volume":"34","year":"2016","journal-title":"Vaccine"},{"issue":"2","key":"2026072007000947000_2026.07.10.737547v1.26","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1164\/rccm.201802-0366OC","article-title":"Dose Optimization of H56:IC31 Vaccine for Tuberculosis-Endemic Populations. A Double-Blind, Placebo-controlled, Dose-Selection Trial","volume":"199","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"issue":"5","key":"2026072007000947000_2026.07.10.737547v1.27","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1093\/infdis\/jiae170","article-title":"Safety and Immunogenicity of the H56:IC31 Tuberculosis Vaccine Candidate in Adults Successfully Treated for Drug-Susceptible Pulmonary Tuberculosis: A Phase 1 Randomized Trial","volume":"230","year":"2024","journal-title":"J Infect Dis"},{"key":"2026072007000947000_2026.07.10.737547v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2006.03.071"},{"key":"2026072007000947000_2026.07.10.737547v1.29","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.1513"},{"key":"2026072007000947000_2026.07.10.737547v1.30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007643"},{"key":"2026072007000947000_2026.07.10.737547v1.31","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41541-018-0075-3","article-title":"Using vaccine Immunostimulation\/Immunodynamic modelling methods to inform vaccine dose decision-making","volume":"3","year":"2018","journal-title":"NPJ Vaccines"},{"issue":"1","key":"2026072007000947000_2026.07.10.737547v1.32","doi-asserted-by":"crossref","first-page":"6658","DOI":"10.1038\/s41467-021-26934-0","article-title":"A Mycobacterium tuberculosis-specific subunit vaccine that provides synergistic immunity upon co-administration with Bacillus Calmette-Guerin","volume":"12","year":"2021","journal-title":"Nat Commun"},{"key":"2026072007000947000_2026.07.10.737547v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2014.10.003"},{"key":"2026072007000947000_2026.07.10.737547v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2009.06.004"},{"key":"2026072007000947000_2026.07.10.737547v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2016.70"},{"key":"2026072007000947000_2026.07.10.737547v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.05.012"},{"key":"2026072007000947000_2026.07.10.737547v1.37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1427846"},{"key":"2026072007000947000_2026.07.10.737547v1.38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400019"},{"key":"2026072007000947000_2026.07.10.737547v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.02.010"},{"key":"2026072007000947000_2026.07.10.737547v1.40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101122"},{"key":"2026072007000947000_2026.07.10.737547v1.41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006687"},{"key":"2026072007000947000_2026.07.10.737547v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01897-8"},{"key":"2026072007000947000_2026.07.10.737547v1.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0088149"},{"key":"2026072007000947000_2026.07.10.737547v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0319-9"},{"issue":"4","key":"2026072007000947000_2026.07.10.737547v1.45","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S2213-2600(18)30077-8","article-title":"Safety and immunogenicity of the novel tuberculosis vaccine ID93 + GLA-SE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial","volume":"6","year":"2018","journal-title":"Lancet Respir Med"},{"key":"2026072007000947000_2026.07.10.737547v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2015.05.088"},{"key":"2026072007000947000_2026.07.10.737547v1.47","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201208-1385OC"},{"key":"2026072007000947000_2026.07.10.737547v1.48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01262"},{"key":"2026072007000947000_2026.07.10.737547v1.49","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.11.7759-7764.2005"},{"key":"2026072007000947000_2026.07.10.737547v1.50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00324"},{"key":"2026072007000947000_2026.07.10.737547v1.51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007060"},{"key":"2026072007000947000_2026.07.10.737547v1.52","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900947"},{"key":"2026072007000947000_2026.07.10.737547v1.53","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005490"},{"key":"2026072007000947000_2026.07.10.737547v1.54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijid.2018.06.011","article-title":"The exhausted CD4(+)CXCR5(+) T cells involve the pathogenesis of human tuberculosis disease","volume":"74","year":"2018","journal-title":"Int J Infect Dis"},{"key":"2026072007000947000_2026.07.10.737547v1.55","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141518"},{"key":"2026072007000947000_2026.07.10.737547v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2023.05.006"},{"key":"2026072007000947000_2026.07.10.737547v1.57","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adq8229"},{"key":"2026072007000947000_2026.07.10.737547v1.58","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy046"},{"issue":"1","key":"2026072007000947000_2026.07.10.737547v1.59","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1093\/infdis\/jiz056","article-title":"KLRG1-Expressing CD4 T Cells Are Reduced in Tuberculosis Patients Compared to Healthy Mycobacterium tuberculosis-Infected Subjects, but Increase With Treatment","volume":"220","year":"2019","journal-title":"J Infect Dis"},{"key":"2026072007000947000_2026.07.10.737547v1.60","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.60"},{"key":"2026072007000947000_2026.07.10.737547v1.61","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2412381"},{"key":"2026072007000947000_2026.07.10.737547v1.62","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1909953"},{"key":"2026072007000947000_2026.07.10.737547v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.07.007"},{"key":"2026072007000947000_2026.07.10.737547v1.64","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty441"},{"key":"2026072007000947000_2026.07.10.737547v1.65","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.07.10.737547","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:00:29Z","timestamp":1784556029000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.07.10.737547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":65,"URL":"https:\/\/doi.org\/10.64898\/2026.07.10.737547","relation":{},"subject":[],"published":{"date-parts":[[2026,7,16]]},"subtype":"preprint"}}