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This study evaluated the comparative efficacy of homologous and heterologous inactivated vaccines against that of the live Bacille Calmette\u2013Gu\u00e9rin (BCG) vaccine on\n                    <jats:italic>M. bovis<\/jats:italic>\n                    isolation, gross TB lesions, and immune responses. Data from four controlled vaccination and challenge trials involving 41 calves were analysed. Animals were vaccinated with live BCG or heat-inactivated\n                    <jats:italic>M. bovis<\/jats:italic>\n                    via oral or parenteral routes, and immunologic and post-mortem analyses were conducted to evaluate vaccine performance. Compared with nonvaccinated controls, all vaccination strategies significantly reduced\n                    <jats:italic>M. bovis<\/jats:italic>\n                    bacterial loads in the lungs (up to 99%). However, bacterial loads in lymphoid tissues increased, confirming that tuberculosis is primarily a lymphatic disease. Diagnostic interference varied by vaccine type and administration route, with oral administration resulting in lower interference. Gross lesion scores were inconsistent across groups, suggesting limited utility as a measure of vaccine efficacy. Immune responses revealed increased detection of infection, particularly with inactivated vaccines. The lung bacterial load appeared to be decoupled from cellular immune responses, lymph node lesions and bacterial load, which were negatively correlated. Inactivated vaccines can offer a safe and effective means of reducing the bovine TB reproductive rate (R\u2080) even without total bacterial clearance. These findings highlight the need for revised evaluation criteria and support the integration of inactivated vaccines into TB control strategies.\n                  <\/jats:p>","DOI":"10.1186\/s13567-025-01637-2","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T14:31:42Z","timestamp":1761316302000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tuberculosis vaccination: microbiological and immunological summary of a series of experimental challenge studies"],"prefix":"10.1186","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6037-5873","authenticated-orcid":false,"given":"Ramon A.","family":"Juste","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iker A.","family":"Sevilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmeralda","family":"Minguijon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Fuertes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Elguezabal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariv\u00ed","family":"Geijo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Vazquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arrazuria","family":"Rakel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Gortazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaia","family":"Etxezarreta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseba M.","family":"Garrido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"1637_CR1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/S13620-023-00241-0","volume":"76","author":"J Bezos","year":"2023","unstructured":"Bezos J, S\u00e1ez-Llorente JL, \u00c1lvarez J, Romero B, D\u00edez-Guerrier A, Dom\u00ednguez L, de Juan L (2023) Bovine tuberculosis in Spain, is it really the final countdown? 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The experimental design was reviewed and approved by NEIKER\u2019s Animal Care and Use Committee (OEBA-NEIKER-2015\u2013010) and the Department of Agriculture of Diputaci\u00f3n Foral de Bizkaia (MYCOINVAC-39\/2015-BFA).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"202"}}