{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T06:21:29Z","timestamp":1772000489812,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo a Pesquisa do Estado de Minas Gerais, Brazil","award":["APQ-01680-21"],"award-info":[{"award-number":["APQ-01680-21"]}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior, Brazil","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Trained innate immunity refers to the enhanced responsiveness of innate immune cells, particularly macrophages, following exposure to stimuli such as \u03b2-glucan or zymosan, enabling improved defense against unrelated pathogens. This phenomenon has been widely investigated to better understand host\u2013pathogen interactions and to support the development of improved infection control strategies. This study evaluated whether these training stimuli could enhance the protective efficacy of attenuated or inactivated vaccine models against Brucella ovis and Listeria monocytogenes infection. Methods: Trained innate immunity was induced in vivo using \u03b2-glucan or zymosan, and seven days later mice were vaccinated with attenuated or gamma-irradiated formulations and subsequently challenged with B. ovis or L. monocytogenes. Vaccine-induced protection and immune responses were assessed through multiple experimental approaches. Results: \u03b2-glucan significantly reduced bacterial infection in vitro in bone-marrow-derived macrophages and in vivo in target organs compared with zymosan. Although \u03b2-glucan did not enhance the efficacy of the attenuated B. ovis \u0394abcBA vaccine, it markedly reduced bacterial colonization in mice vaccinated with gamma-irradiated B. ovis. \u03b2-glucan also did not improve the efficacy of the gamma-irradiated L. monocytogenes vaccine; however, 50% of the trained and vaccinated mice showed no detectable bacterial recovery. Increasing the number of \u03b2-glucan doses negatively affected infection control, suggesting that overstimulation may impair trained immunity. Conclusion: Trained innate immunity enhances the protective effect of inactivated experimental vaccines against B. ovis and L. monocytogenes, while exerting a detrimental influence on the efficacy of a live attenuated B. ovis vaccine model.<\/jats:p>","DOI":"10.3390\/vaccines14020197","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T14:05:11Z","timestamp":1771855511000},"page":"197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Innate Immunity Trained in the Protective Response of Vaccine Candidates Against Intracellular Pathogens"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8621-9577","authenticated-orcid":false,"given":"Jefferson B. S.","family":"Oliveira","sequence":"first","affiliation":[{"name":"Departamento de Cl\u00ednica e Cirurgia Veterin\u00e1ria, Escola de Veterin\u00e1ria, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2357-5953","authenticated-orcid":false,"given":"Laice A.","family":"Silva","sequence":"additional","affiliation":[{"name":"Departamento de Cl\u00ednica e Cirurgia Veterin\u00e1ria, Escola de Veterin\u00e1ria, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1086-4171","authenticated-orcid":false,"given":"Monique F. S.","family":"Sousa","sequence":"additional","affiliation":[{"name":"Departamento de Patologia Geral, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-9168","authenticated-orcid":false,"given":"Aldcejam M. F.","family":"Junior","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Metabolismo Embrion\u00e1rio e Epigen\u00e9tica, Centro de Ci\u00eancias Naturais e Humanas, Universidade Federal do ABC, Santo Andr\u00e9 09210-580, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camila G.","family":"Almeida","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Inova\u00e7\u00e3o e Nanobiotecnologia e Materiais Avan\u00e7ados para Pecu\u00e1ria, Embrapa Gado de Leite, Juiz de Fora 36038-330, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7052-0154","authenticated-orcid":false,"given":"Robson S.","family":"Barducci","sequence":"additional","affiliation":[{"name":"Pesquisa e Desenvolvimento, Biorigin, Len\u00e7\u00f3is Paulista 18680-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0933-3066","authenticated-orcid":false,"given":"Marcella P.","family":"Milazzotto","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Metabolismo Embrion\u00e1rio e Epigen\u00e9tica, Centro de Ci\u00eancias Naturais e Humanas, Universidade Federal do ABC, Santo Andr\u00e9 09210-580, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7405-3928","authenticated-orcid":false,"given":"Humberto M.","family":"Brand\u00e3o","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Inova\u00e7\u00e3o e Nanobiotecnologia e Materiais Avan\u00e7ados para Pecu\u00e1ria, Embrapa Gado de Leite, Juiz de Fora 36038-330, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renato L.","family":"Santos","sequence":"additional","affiliation":[{"name":"Departamento de Cl\u00ednica e Cirurgia Veterin\u00e1ria, Escola de Veterin\u00e1ria, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8284-9902","authenticated-orcid":false,"given":"Tatiane A.","family":"Paix\u00e3o","sequence":"additional","affiliation":[{"name":"Departamento de Patologia Geral, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.chom.2011.04.006","article-title":"Trained immunity: A memory for innate host defense","volume":"9","author":"Netea","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s12967-023-03944-8","article-title":"BCG-induced trained immunity: History, mechanisms and potential applications","volume":"21","author":"Chen","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.chom.2012.06.006","article-title":"Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes","volume":"12","author":"Quintin","year":"2012","journal-title":"Cell Host Microbe"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1093\/infdis\/jiae112","article-title":"Candida albicans N-linked mannans potentiate the induction of trained immunity via dectin-2","volume":"230","author":"Rosati","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1093\/infdis\/jiz692","article-title":"Trained immunity confers broad-spectrum protection against bacterial infections","volume":"222","author":"Ciarlo","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"107634","DOI":"10.1016\/j.celrep.2020.107634","article-title":"\u03b2-glucan induces protective trained immunity against mycobacterium tuberculosis infection: A key role for IL-1","volume":"31","author":"Moorlag","year":"2020","journal-title":"Cell Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.immuni.2020.10.011","article-title":"The intersection of epigenetics and metabolism in trained immunity","volume":"54","author":"Fanucchi","year":"2021","journal-title":"Immunity"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1250684","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"ref_9","unstructured":"Corbel, M.J. (2006). Brucellosis in Humans and Animals, World Organization for Animal Health."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S1473-3099(06)70382-6","article-title":"The new global map of human brucellosis","volume":"6","author":"Pappas","year":"2006","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1093\/jnen\/nly077","article-title":"Histopathology of Listeria meningitis","volume":"77","author":"Koopmans","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_12","first-page":"e16601","article-title":"Listeria bacteremia presenting with cerebral abscess and endocarditis in an elderly patient with chronic immune thrombocytopenia","volume":"13","author":"Ogunleye","year":"2021","journal-title":"Cureus"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41586-019-1656-7","article-title":"Immunization: Vital progress, unfinished agenda","volume":"575","author":"Piot","year":"2019","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e0166582","DOI":"10.1371\/journal.pone.0166582","article-title":"Meta-analysis and advancement of brucellosis vaccinology","volume":"11","author":"Carvalho","year":"2016","journal-title":"PLoS ONE"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.ijbiomac.2021.02.056","article-title":"Alginate-chitosan microcapsules improve vaccine potential of gamma-irradiated Listeria monocytogenes against listeriosis in murine model","volume":"10","author":"Rocha","year":"2021","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13567-025-01483-2","article-title":"The inactivated and ISA 61 VG adjuvanted vaccine enhances protection against cross-serotype Listeria monocytogenes","volume":"56","author":"Meng","year":"2025","journal-title":"Vet. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"791","DOI":"10.4049\/jimmunol.2200642","article-title":"Bacillus Calmette-Gu\u00e9rin\u2014Trained macrophages elicit a protective inflammatory response against the pathogenic bacteria Brucella abortus","volume":"211","author":"Araujo","year":"2023","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1128\/CVI.00191-15","article-title":"Protection provided by an encapsulated live attenuated \u0394abcBA strain of Brucella ovis against experimental challenge in a murine model","volume":"22","author":"Silva","year":"2015","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_19","first-page":"1","article-title":"Evaluation of polymeric adjuvants associated with candidate vaccine strain Brucella ovis \u2206abcBA in a murine model of Brucella ovis infection","volume":"60","author":"Oliveira","year":"2024","journal-title":"Vet. Ital."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e0298117","DOI":"10.1371\/journal.pone.0298117","article-title":"Comparative Study on Alginate\/chitosan microcapsules and Montanide ISA 61 as vaccine adjuvants in mice","volume":"19","author":"Silva","year":"2024","journal-title":"PLoS ONE"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1128\/IAI.01109-10","article-title":"Putative ATP-binding cassette transporter is essential for Brucella ovis pathogenesis in mice","volume":"79","author":"Silva","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Stone, B.A. (2009). Chemistry of \u03b2-glucans. Chemistry, Biochemistry, and Biology of 1\u20133 Beta Glucans and Related Polysaccharides, Academic Press.","DOI":"10.1016\/B978-0-12-373971-1.00002-9"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Zhang, X., Gon\u00e7alves, R., and Mosser, D.M. (2008). The isolation and characterization of murine macrophages. Curr. Protoc. Immunol., 83.","DOI":"10.1002\/0471142735.im1401s83"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1128\/iai.19.3.763-770.1978","article-title":"Resistance and susceptibility of mice to bacterial infection: Course of listeriosis in resistant or susceptible mice","volume":"19","author":"Cheers","year":"1978","journal-title":"Infect. Immun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Ispada, J., Junior, A.M.F., Lima, C.B., Santos, E.C., Fontes, P.K., Nogueira, M.F.G., Silva, V.L., Almeida, F.N., Leite, C., and Chitwood, J.L. (2020). Tricarboxylic acid cycle metabolites as mediators of DNA methylation reprogramming in bovine preimplantation embryos. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186868"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1128\/IAI.71.2.682-689.2003","article-title":"A\/J mice are susceptible and C57BL\/6 mice are resistant to Listeria monocytogenes infection by intragastric inoculation","volume":"71","author":"Czuprynski","year":"2003","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12950-018-0182-y","article-title":"Zymosan attenuates melanoma growth progression, increases splenocyte proliferation and induces TLR-2\/4 and TNF-\u03b1 expression in mice","volume":"15","author":"Taghavi","year":"2018","journal-title":"J. Inflamm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1093\/mmy\/myaa117","article-title":"Zymosan enhances in vitro phagocyte function and the immune response of mice infected with Paracoccidioides brasiliensis","volume":"59","author":"Silva","year":"2021","journal-title":"Med. Mycol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1016\/j.vaccine.2022.06.044","article-title":"Pathogenesis of Brucella ovis in pregnant mice and protection induced by the candidate vaccine strain B. ovis \u0394abcBA","volume":"40","author":"Braz","year":"2022","journal-title":"Vaccine"},{"key":"ref_30","first-page":"223","article-title":"Effects of exogenous recombinant interleukin-12 on immune responses and protection against Brucella abortus in a murine model","volume":"65","author":"Lee","year":"2001","journal-title":"Can. J. Vet. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1251086","DOI":"10.1126\/science.1251086","article-title":"Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity","volume":"345","author":"Saeed","year":"2014","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cell.2017.12.031","article-title":"BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis","volume":"172","author":"Kaufmann","year":"2018","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"109030","DOI":"10.1016\/j.isci.2024.109030","article-title":"Recognition of yeast \u03b2-glucan particles triggers immunometabolic signaling required for trained immunity","volume":"27","author":"Johnston","year":"2024","journal-title":"iScience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"566893","DOI":"10.3389\/fimmu.2020.566893","article-title":"\u03b2-glucan-induced trained immunity in dogs","volume":"11","author":"Paris","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"689879","DOI":"10.3389\/fimmu.2021.689879","article-title":"Dectin-1-mediated production of pro-inflammatory cytokines induced by yeast \u03b2-glucans in bovine monocytes","volume":"12","author":"Pedro","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1126\/science.127.3301.756.b","article-title":"On the composition of zymosan","volume":"127","author":"Fiore","year":"1958","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kaur, R., Sharma, M., Ji, D., Xu, M., and Agyei, D. (2020). Structural features, modification, and functionalities of beta-glucan. Fibers, 8.","DOI":"10.3390\/fib8010001"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1080\/15476910802019045","article-title":"\u03b2-glucans, history, and the present: Immunomodulatory aspects and mechanisms of action","volume":"5","author":"Novak","year":"2008","journal-title":"J. Immunotoxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5771","DOI":"10.1074\/jbc.M511461200","article-title":"Ligands for the beta-glucan receptor, Dectin-1, assigned using \u201cdesigner\u201d microarrays of oligosaccharide probes (neoglycolipids) generated from glucan polysaccharides","volume":"281","author":"Palma","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.4049\/jimmunol.162.4.2281","article-title":"The \u03b2-glucan-binding lectin site of mouse CR3 (CD11b\/CD18) and its function in generating a primed state of the receptor that mediates cytotoxic activation in response to iC3b-opsonized target cells","volume":"162","author":"Xia","year":"1999","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"25001","DOI":"10.1074\/jbc.M301426200","article-title":"Pneumocystis carinii cell wall \u03b2-glucans initiate macrophage inflammatory responses through NF-\u03baB activation","volume":"278","author":"Lebron","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1371\/journal.pone.0323376","article-title":"\u03b2-glucan induced trained immunity enhances antibody levels in a vaccination model in mice","volume":"20","author":"Ajit","year":"2025","journal-title":"PLoS ONE"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/s41577-020-0307-4","article-title":"Clonal expansion of innate and adaptive lymphocytes","volume":"20","author":"Adams","year":"2020","journal-title":"Nat. Rev. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7146","DOI":"10.4049\/jimmunol.177.10.7146","article-title":"Cytosolic Localization of Listeria monocytogenes Triggers an Early IFN-\u03b3 Response by CD8+ T Cells That Correlates with Innate Resistance to Infection","volume":"177","author":"Troese","year":"2006","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1427443","DOI":"10.3389\/fimmu.2024.1427443","article-title":"Trained immunity inducers in cancer immunotherapy","volume":"15","author":"Sui","year":"2024","journal-title":"Front. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"723393","DOI":"10.3389\/fimmu.2021.723393","article-title":"Trained immunity confers prolonged protection from listeriosis","volume":"12","author":"Reverte","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"34698","DOI":"10.1038\/s41598-025-16350-5","article-title":"The impact of interferon-\u03b3 pathway on trained immunity induction by vaccination with Bacille Calmette-Gu\u00e9rin","volume":"15","author":"Isachesku","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1016\/j.immuni.2023.10.008","article-title":"Sex hormone signaling and regulation of immune function","volume":"56","author":"Hoffmann","year":"2023","journal-title":"Immunity"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/2\/197\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T05:26:49Z","timestamp":1771997209000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/2\/197"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,23]]},"references-count":48,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["vaccines14020197"],"URL":"https:\/\/doi.org\/10.3390\/vaccines14020197","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,23]]}}}