{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T11:42:32Z","timestamp":1779277352413,"version":"3.51.4"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["643381"],"award-info":[{"award-number":["643381"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Schweizer Staatssekretariat f\u00fcr Bildung, Forschung und Innovation (SBFI)","award":["15.0033-3"],"award-info":[{"award-number":["15.0033-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and\/or adult vaccination efforts against pulmonary tuberculosis.<\/jats:p>","DOI":"10.3390\/ijms23052700","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T20:11:14Z","timestamp":1646079074000},"page":"2700","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis"],"prefix":"10.3390","volume":"23","author":[{"given":"Elodie","family":"Belnoue","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland"},{"name":"W.H.O. Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva 4, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Vogelzang","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5749-2462","authenticated-orcid":false,"given":"Natalie E.","family":"Nieuwenhuizen","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena A.","family":"Krzyzaniak","sequence":"additional","affiliation":[{"name":"Division of Experimental Virology, Department of Biomedicine, University of Basel, 4003 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Darbre","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland"},{"name":"W.H.O. Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva 4, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Kreutzfeldt","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland"},{"name":"Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva 4, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doron","family":"Merkler","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland"},{"name":"Division of Clinical Pathology, Geneva University Hospital, 1211 Geneva 4, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul-Henri","family":"Lambert","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland"},{"name":"W.H.O. Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva 4, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan H. E.","family":"Kaufmann","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire-Anne","family":"Siegrist","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland"},{"name":"W.H.O. Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva 4, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1594-3189","authenticated-orcid":false,"given":"Daniel D.","family":"Pinschewer","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland"},{"name":"W.H.O. Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva 4, Switzerland"},{"name":"Division of Experimental Virology, Department of Biomedicine, University of Basel, 4003 Basel, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021, May 03). WHO Global Tuberculosis Report 2020. Available online: https:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/336069\/9789240013131-eng.pdf."},{"key":"ref_2","unstructured":"Calmette, A., Gu\u00e9rin, C., Boquet, A., and N\u00e9gre, L. (1927). La Vaccination Pr\u00e9ventive Contre La Tuberculose Par Le \u201cBCG\u201d, Masson et Cie."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"g4643","DOI":"10.1136\/bmj.g4643","article-title":"Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: Systematic review and meta-analysis","volume":"349","author":"Roy","year":"2014","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.3389\/fimmu.2017.01203","article-title":"TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development","volume":"8","author":"Kaufmann","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1056\/NEJMoa1909953","article-title":"Final Analysis of a Trial of M72\/AS01E Vaccine to Prevent Tuberculosis","volume":"381","author":"Tait","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_6","first-page":"138","article-title":"Prevention of M","volume":"379","author":"Nemes","year":"2018","journal-title":"tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12013","DOI":"10.1073\/pnas.89.24.12013","article-title":"Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection","volume":"89","author":"Flynn","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4204","DOI":"10.1073\/pnas.97.8.4204","article-title":"Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice","volume":"97","author":"Sousa","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1128\/iai.55.9.2037-2041.1987","article-title":"Impaired resistance to Mycobacterium tuberculosis infection after selective in vivo depletion of L3T4+ and Lyt-2+ T cells","volume":"55","author":"Cobbold","year":"1987","journal-title":"Infect. Immun."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chen, C.Y., Huang, D., Wang, R.C., Shen, L., Zeng, G., Yao, S., Shen, Y., Halliday, L., Fortman, J., and McAllister, M. (2009). A critical role for CD8 T cells in a nonhuman primate model of tuberculosis. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000392"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7608","DOI":"10.1016\/j.vaccine.2012.10.031","article-title":"The recombinant tuberculosis vaccine rBCG DeltaureC::hly(+) induces apoptotic vesicles for improved priming of CD4(+) and CD8(+) T cells","volume":"30","author":"Farinacci","year":"2012","journal-title":"Vaccine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41586-019-1817-8","article-title":"Prevention of tuberculosis in macaques after intravenous BCG immunization","volume":"577","author":"Darrah","year":"2020","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/248701a0","article-title":"Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system","volume":"248","author":"Zinkernagel","year":"1974","journal-title":"Nature"},{"key":"ref_14","first-page":"1","article-title":"Lymphocytic choriomeningitis virus and immunology","volume":"Volume 263","author":"Zinkernagel","year":"2002","journal-title":"Arenaviruses II. Current Topics in Microbiology and Immunology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/369648a0","article-title":"Cytotoxic T-cell memory without antigen","volume":"369","author":"Lau","year":"1994","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/90950","article-title":"Oldstone, Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory","volume":"7","author":"Homann","year":"2001","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4663","DOI":"10.1073\/pnas.0600652103","article-title":"Recovery of an arenavirus entirely from RNA polymerase I\/II-driven cDNA","volume":"103","author":"Flatz","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.virol.2006.01.012","article-title":"Rescue of the prototypic Arenavirus LCMV entirely from plasmid","volume":"350","author":"Sanchez","year":"2006","journal-title":"Virology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7895","DOI":"10.1073\/pnas.1332709100","article-title":"Recombinant lymphocytic choriomeningitis virus expressing vesicular stomatitis virus glycoprotein","volume":"100","author":"Pinschewer","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/nm.2104","article-title":"Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8(+) T cell immunity","volume":"16","author":"Flatz","year":"2010","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7760","DOI":"10.1128\/JVI.00599-12","article-title":"Gene-based vaccination with a mismatched envelope protects against simian immunodeficiency virus infection in nonhuman primates","volume":"86","author":"Flatz","year":"2012","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e00300-16","DOI":"10.1128\/CVI.00300-16","article-title":"Additive Protection against Congenital Cytomegalovirus Conferred by Combined Glycoprotein B\/pp65 Vaccination Using a Lymphocytic Choriomeningitis Virus Vector","volume":"24","author":"Schleiss","year":"2017","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vaccine.2016.11.063","article-title":"Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens","volume":"35","author":"Shields","year":"2017","journal-title":"Vaccine"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Schwendinger, M., Thiry, G., De Vos, B., Leroux-Roels, G., Bruhwyler, J., Huygens, A., Ganeff, C., Buchinger, H., Orlinger, K.K., and Pinschewer, D.D. A Randomized Dose-Escalating Phase I Trial of a Replication-Deficient Lymphocytic Choriomeningitis Virus Vector-Based Vaccine Against Human Cytomegalovirus. J. Infect. Dis., 2020.","DOI":"10.1093\/infdis\/jiaa121"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sommerstein, R., Flatz, L., Remy, M.M., Malinge, P., Magistrelli, G., Fischer, N., Sahin, M., Bergthaler, A., Igonet, S., and Ter Meulen, J. (2015). Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005276"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1073\/pnas.1314973111","article-title":"Tuberculosis vaccine with high predicted population coverage and compatibility with modern diagnostics","volume":"111","author":"Knudsen","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.micpath.2017.08.040","article-title":"Antigen 85 complex as a powerful Mycobacterium tuberculosis immunogene: Biology, immune-pathogenicity, applications in diagnosis, and vaccine design","volume":"112","author":"Babaki","year":"2017","journal-title":"Microb. Pathog."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1093\/trstmh\/trw016","article-title":"TB vaccine development and the End TB Strategy: Importance and current status","volume":"110","author":"Fletcher","year":"2016","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e00611-19","DOI":"10.1128\/mBio.00611-19","article-title":"Dynamics of Mycobacterium tuberculosis Ag85B Revealed by a Sensitive Enzyme-Linked Immunosorbent Assay","volume":"10","author":"Ernst","year":"2019","journal-title":"mBio"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1126\/science.276.5317.1420","article-title":"Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis","volume":"276","author":"Belisle","year":"1997","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6332","DOI":"10.4049\/jimmunol.174.10.6332","article-title":"Exchanging ESAT6 with TB10.4 in an Ag85B fusion molecule-based tuberculosis subunit vaccine: Efficient protection and ESAT6-based sensitive monitoring of vaccine efficacy","volume":"174","author":"Dietrich","year":"2005","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3109\/08830180009088505","article-title":"Vaccination in the Neonatal Period and Early Infancy","volume":"19","author":"Siegrist","year":"2000","journal-title":"Int. Rev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"88ra56","DOI":"10.1126\/scitranslmed.3002461","article-title":"Immunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infants","volume":"3","author":"Ota","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12434","DOI":"10.1073\/pnas.0703510104","article-title":"Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis","volume":"104","author":"Steinhoff","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yang, J.D., Mott, D., Sutiwisesak, R., Lu, Y.-J., Raso, F., Stowell, B., Babunovic, G.H., Lee, J., Carpenter, S.M., and Way, S.S. (2018). Mycobacterium tuberculosis-specific CD4+ and CD8+ T cells differ in their capacity to recognize infected macrophages. PLoS Pathog., 14.","DOI":"10.1101\/262493"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1172\/JCI24617","article-title":"Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin","volume":"115","author":"Grode","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1128\/IAI.66.4.1527-1533.1998","article-title":"Vaccination with plasmid DNA encoding mycobacterial antigen 85A stimulates a CD4+ and CD8+ T-cell epitopic repertoire broader than that stimulated by Mycobacterium tuberculosis H37Rv infection","volume":"66","author":"Denis","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.4049\/jimmunol.1401771","article-title":"Protective efficacy of individual CD8+ T cell specificities in chronic viral infection","volume":"194","author":"Johnson","year":"2015","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"100209","DOI":"10.1016\/j.xcrm.2021.100209","article-title":"Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack","volume":"2","author":"Bonilla","year":"2021","journal-title":"Cell Rep. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.3389\/fimmu.2019.01520","article-title":"Reactivating Immunity Primed by Acellular Pertussis Vaccines in the Absence of Circulating Antibodies: Enhanced Bacterial Control by TLR9 Rather Than TLR4 Agonist-Including Formulation","volume":"10","author":"Auderset","year":"2019","journal-title":"Front. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2700\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:29:45Z","timestamp":1760135385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2700"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,28]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23052700"],"URL":"https:\/\/doi.org\/10.3390\/ijms23052700","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,28]]}}}