{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T06:09:03Z","timestamp":1784182143984,"version":"3.55.0"},"reference-count":42,"publisher":"Frontiers Media SA","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:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The development of effective and broadly protective vaccines against SARS-CoV-2 remains a global priority. Conserved epitopes from viral structural proteins (E, M, N, and S) represent promising targets less affected by emerging mutations, while\n                    <jats:italic>Bacillus Calmette-Gu\u00e9rin<\/jats:italic>\n                    (BCG) offers unique adjuvant and delivery properties. This study aimed to validate conserved SARS-CoV-2 epitopes in combination with BCG and to design multiepitope vaccine constructs\n                    <jats:italic>in silico<\/jats:italic>\n                    . Dot blot assays confirmed recognition of five synthetic peptides by sera from convalescent patients.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , BCG\u2013peptide formulations activated the MAPK pathway and induced trained immunity signatures in macrophages.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , immunized mice showed modulation of IgG subclasses and increased IL-6, TNF-\u03b1, and IFN-\u03b3 production. Splenocytes from vaccinated animals secreted high cytokine levels upon restimulation, suggesting memory responses.\n                    <jats:italic>In silico<\/jats:italic>\n                    modeling indicated stable, antigenic, and non-allergenic multiepitope constructs with favorable immune simulations. Together, these findings highlight BCG\u2013epitope formulations as promising next-generation vaccine candidates against SARS-CoV-2.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1775087","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:36:26Z","timestamp":1784180186000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bacillus Calmette-Gu\u00e9rin as adjuvant platform enhances immunogenicity of conserved epitopes from structural proteins of SARS-CoV-2"],"prefix":"10.3389","volume":"17","author":[{"given":"Ana de Souza","family":"Santos","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology of Microorganisms, Federal University of Alfenas (UNIFAL-MG)","place":["Alfenas, MG, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo Pereira","family":"de Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Microorganisms, Federal University of Alfenas (UNIFAL-MG)","place":["Alfenas, MG, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego Jose Belato","family":"Orts","sequence":"additional","affiliation":[{"name":"Laboratory of Immunotechnology, Center of Immunology, Institute Adolfo Lutz","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hernan Hermes Monteiro da","family":"Costa","sequence":"additional","affiliation":[{"name":"Laboratory of Immunotechnology, Center of Immunology, Institute Adolfo Lutz","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Interunit Graduate Program in Biotechnology, University of S\u00e3o Paulo","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Multipurpose Laboratory, Butantan Institute","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kely Catarine","family":"Matteucci","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, Ribeir\u00e3o Preto Medical School, University of S\u00e3o Paulo","place":["Ribeir\u00e3o Preto, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evandro Neves","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Microorganisms, Federal University of Alfenas (UNIFAL-MG)","place":["Alfenas, MG, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen Cristina","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Microorganisms, Federal University of Alfenas (UNIFAL-MG)","place":["Alfenas, MG, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovane","family":"Galdino","sequence":"additional","affiliation":[{"name":"Multipurpose Laboratory, Butantan Institute","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Roberto","family":"Prudencio","sequence":"additional","affiliation":[{"name":"Laboratory of Immunotechnology, Center of Immunology, Institute Adolfo Lutz","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Interunit Graduate Program in Biotechnology, University of S\u00e3o Paulo","place":["S\u00e3o Paulo, SP, Brazil"]},{"name":"Multipurpose Laboratory, Butantan Institute","place":["S\u00e3o Paulo, SP, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia Paiva","family":"Corsetti","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Microorganisms, Federal University of Alfenas (UNIFAL-MG)","place":["Alfenas, MG, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo Augusto","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Microorganisms, Federal University of Alfenas (UNIFAL-MG)","place":["Alfenas, MG, Brazil"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1038\/s43856-023-00320-x","article-title":"Evolutionary implications of SARS-CoV-2 vaccination for the future design of vaccination strategies","volume":"3","author":"Rouzine","year":"2023","journal-title":"Commun Med"},{"key":"B2","unstructured":"WHO Coronavirus Dashboard From World Health Organization"},{"key":"B3","unstructured":"COVID-19 Cases, World From World Health Organization"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/s1473-3099(22)00320-6","article-title":"Global impact of the first year of COVID-19 vaccination: a mathematical modelling study","volume":"22","author":"Watson","year":"2022","journal-title":"Lancet Infect Dis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.chom.2020.11.007","article-title":"Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition","volume":"29","author":"Greaney","year":"2021","journal-title":"Cell Host Microbe"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.09.019","article-title":"Transition to endemicity: understanding COVID-19","volume":"54","author":"Antia","year":"2021","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/s41586-021-03792-w","article-title":"After the pandemic: perspectives on the future trajectory of COVID-19","volume":"596","author":"Telenti","year":"2021","journal-title":"Nature"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2021.2002083","article-title":"A comprehensive review of SARS-CoV-2 vaccines: Pfizer, Moderna & Johnson & Johnson","volume":"18","author":"Rikin","year":"2022","journal-title":"Hum Vaccin Immunother"},{"key":"B9","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/s1473-3099(21)00451-5","article-title":"Bell's palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study","volume":"22","author":"Wan","year":"2022","journal-title":"Lancet Infect Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.11.016","article-title":"Antigenic drift: understanding COVID-19","volume":"54","author":"Yewdell","year":"2021","journal-title":"Immunity"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009453","article-title":"A human coronavirus evolves antigenically to escape antibody immunity","volume":"17","author":"Eguia","year":"2021","journal-title":"PloS Pathog"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg3055","article-title":"Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England","volume":"372","author":"Davies","year":"2021","journal-title":"Science"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03470-x","article-title":"Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England","volume":"593","author":"Volz","year":"2021","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuno.2022.100015","article-title":"Epitope identification of SARS-CoV-2 structural proteins using in silico approaches to obtain a conserved rational immunogenic peptide","volume":"7","author":"De Ara\u00fajo","year":"2022","journal-title":"Immunoinformatics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1038\/s41392-025-02257-0","article-title":"Targeting conserved epitopes in structural proteins: a next-generation vaccine strategy against the newly identified HKU5-CoV-2 virus","volume":"10","author":"De Ara\u00fajo","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad443","article-title":"Immunoinformatic approach for rational identification of immunogenic peptides against host entry and\/or exit Mpox proteins and potential multiepitope vaccine construction","volume":"229","author":"De Ara\u00fajo","year":"2024","journal-title":"J Infect Dis"},{"key":"B17","doi-asserted-by":"publisher","first-page":"12503","DOI":"10.1038\/s41598-025-96755-4","article-title":"Multivalent vaccine candidate from conserved immunogenic peptides in entry or exit proteins of Orthopoxvirus genus","volume":"15","author":"De Ara\u00fajo","year":"2025","journal-title":"Sci Rep"},{"key":"B18","doi-asserted-by":"publisher","first-page":"299","DOI":"10.2174\/0109298665364226250328084245","article-title":"Development of a peptide-based multiepitope vaccine from the SARS-CoV-2 spike protein for targeted immune response against COVID-19","volume":"32","author":"Campelo","year":"2025","journal-title":"Protein Pept Lett"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.757858","article-title":"The diverse applications of recombinant BCG-based vaccines to target infectious diseases other than tuberculosis: an overview","volume":"12","author":"Mouhoub","year":"2021","journal-title":"Front Microbiol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2020.05.014","article-title":"BCG vaccination in humans elicits trained immunity via the hematopoietic progenitor compartment","volume":"28","author":"Cirovic","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B21","doi-asserted-by":"publisher","first-page":"17099","DOI":"10.1038\/s41598-025-00553-x","article-title":"A recombinant BCG with surface-displayed antigen induces humoral and cellular immune responses","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41541-021-00406-4","article-title":"A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection","volume":"6","author":"Counoupas","year":"2021","journal-title":"NPJ Vaccines"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/v15020555","article-title":"RBD and spike DNA-based immunization in rabbits elicited igG avidity maturation and high neutralizing antibody responses against SARS-coV-2","volume":"15","author":"da Costa","year":"2023","journal-title":"Viruses"},{"key":"B24","doi-asserted-by":"publisher","first-page":"17642","DOI":"10.1038\/s41598-021-95045-z","article-title":"Assessment of avidity related to IgG subclasses in SARS-CoV-2 Brazilian infected patients","volume":"11","author":"Moura","year":"2021","journal-title":"Sci Rep"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.778475","article-title":"Epitope-based vaccine of a Brucella abortus putative small RNA target induces protection and less tissue damage in mice","volume":"12","author":"Oliveira","year":"2021","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s42770-025-01639-4","article-title":"Sequential macrophage DENV and ZIKV infection shows differential expression of CD86, IFN-\u03b2, and regulation of TNF-\u03b1 and IL-1\u03b2 depending on DENV serotype","volume":"56","author":"Brancaglion","year":"2025","journal-title":"Braz J Microbiol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2105-8-4","article-title":"VaxiJen: a server for prediction of protective antigens, tumour antigens and subunit vaccines","volume":"8","author":"Doytchinova","year":"2007","journal-title":"BMC Bioinf"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac446","article-title":"AllerCatPro 2.0: a web server for predicting protein allergenicity potential","volume":"50","author":"Nguyen","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with alphafold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.169","article-title":"The ClusPro web server for protein-protein docking","volume":"12","author":"Kozakov","year":"2017","journal-title":"Nat Protoc"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0009862","article-title":"Computational immunology meets bioinformatics: the use of prediction tools for molecular binding in the simulation of the immune system","volume":"5","author":"Rapin","year":"2010","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.692729","article-title":"BCG-derived peptides induce SARS-CoV-2 T cell cross-reactivity","volume":"12","author":"Eggenhuizen","year":"2021","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s12967-023-03963-5","article-title":"Immune profiling of SARS-CoV-2 epitopes in asymptomatic and symptomatic pediatric and adult patients","volume":"21","author":"Tornesello","year":"2023","journal-title":"J Transl Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2688","DOI":"10.1084\/jem.20202617","article-title":"Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection","volume":"12","author":"Le Bert","year":"2021","journal-title":"Nat Commun"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.6185","article-title":"Application of built-in adjuvants for epitope-based vaccines","volume":"6","author":"Lei","year":"2019","journal-title":"PeerJ"},{"key":"B37","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.bj.2020.09.005","article-title":"Development of multi-epitope peptide-based vaccines against SARS-CoV-2","volume":"44","author":"Lim","year":"2021","journal-title":"BioMed J"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0302722","article-title":"BCG activation of trained immunity is associated with induction of cross reactive COVID-19 antibodies in a BCG vaccinated population","volume":"19","author":"Iqbal","year":"2024","journal-title":"PloS One"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200731","article-title":"Recombinant bacillus calmette-gu\u00e9rin expressing SARS-coV-2 chimeric protein protects K18-hACE2 mice against viral challenge","volume":"210","author":"Mambelli","year":"2023","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"18908","DOI":"10.1038\/s41598-025-04246-3","article-title":"Evaluation of combined BCG and SARS-CoV-2 vaccination for immune enhancement and lung protection in Syrian hamsters","volume":"15","author":"Ashtari","year":"2025","journal-title":"Sci Rep"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11010047","article-title":"A C57BL\/6 mouse model of SARS-CoV-2 infection recapitulates age- and sex-based differences in human COVID-19 disease and recovery","volume":"11","author":"Davis","year":"2022","journal-title":"Vaccines"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaf277","article-title":"Sex differences in vaccine-induced immunity and protection against Mycobacterium tuberculosis","volume":"232","author":"Parvathy","year":"2025","journal-title":"J Infect Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1775087\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T05:36:27Z","timestamp":1784180187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1775087\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,16]]},"references-count":42,"alternative-id":["10.3389\/fimmu.2026.1775087"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1775087","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,16]]},"article-number":"1775087"}}