{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T07:04:14Z","timestamp":1774422254049,"version":"3.50.1"},"reference-count":75,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017638","name":"Ministry of Health of the Russian Federation","doi-asserted-by":"crossref","award":["125021101877-7"],"award-info":[{"award-number":["125021101877-7"]}],"id":[{"id":"10.13039\/501100017638","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Epitope-based mRNA vaccines represent a promising strategy for eliciting protective T-cell immunity against SARS-CoV-2 and as well as for non-infectious mRNA-based vaccines. However, how the structural architecture of vaccine constructs (including epitope arrangement, linker composition, signal peptide presence, and the combination of MHC class I and II epitopes) shapes the quality of T-cell responses remains poorly understood. Methods: Ten tandem minigene mRNA constructs (Cons1\u201310) encoding different combinations of MHC class I and class II epitopes from SARS-CoV-2 proteins (S, N, M, ORF3a) were designed, encapsulated in lipid nanoparticles, and administered to C57BL\/6 mice. Immunogenicity was assessed by cytokine profiling (IFN-\u03b3, IL-2, IL-4, IL-10) and T-cell proliferation assays. Protective efficacy was evaluated in K18-hACE2 transgenic mice challenged with SARS-CoV-2. Results: Constructs lacking a signal peptide and enriched in MHC class I-restricted epitopes induced robust Th1 responses and strong CD8+ T-cell proliferation, achieving up to 66% survival following lethal challenge. In contrast, constructs associated with elevated IL-10 and IL-4 production conferred limited protection (11\u201333%), consistent with functional skewing towards regulatory or Th2-associated immune profiles. Conclusions: These findings establish a direct link between construct design parameters and T-cell polarization quality, and provide a rational framework for next-generation epitope-based mRNA vaccine development.<\/jats:p>","DOI":"10.3390\/vaccines14030281","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"281","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Design of T-Cell Epitope-Based mRNA Vaccine Constructs Determines the Quality of T-Cell Immunity and Protective Efficacy Against SARS-CoV-2 in Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9397-3762","authenticated-orcid":false,"given":"Vladimir A.","family":"Gushchin","sequence":"first","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"},{"name":"Department of Medical Genetics and Postgenomic Technologies, Sechenov First Moscow State Medical University, 119991 Moscow, Russia"},{"name":"Department of Virology, Lomonosov Moscow State University, 119234 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7576-2059","authenticated-orcid":false,"given":"Andrei E.","family":"Siniavin","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1107-9351","authenticated-orcid":false,"given":"Andrei A.","family":"Pochtovyi","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"},{"name":"Department of Medical Genetics and Postgenomic Technologies, Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1743-0798","authenticated-orcid":false,"given":"Alina S.","family":"Dzharullaeva","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8518-1669","authenticated-orcid":false,"given":"Dmitriy N.","family":"Shcherbinin","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3187-8572","authenticated-orcid":false,"given":"Anastasia S.","family":"Ungur","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8506-2339","authenticated-orcid":false,"given":"Amir I.","family":"Tukhvatulin","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inna V.","family":"Shuliakova","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9422-7238","authenticated-orcid":false,"given":"Denis A.","family":"Kleymenov","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0701-5152","authenticated-orcid":false,"given":"Elena P.","family":"Mazunina","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2269-1469","authenticated-orcid":false,"given":"Evgeniia N.","family":"Bykonia","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6196-8262","authenticated-orcid":false,"given":"Sofia R.","family":"Kozlova","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5197-2465","authenticated-orcid":false,"given":"Evgeny V.","family":"Usachev","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. Gamaleya\u201d, The Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilya D.","family":"Zorkov","sequence":"additional","affiliation":[{"name":"Federal State Budget Institution \u201cNational Research Center for Epidemiology and Microbiology Named After the Honorary Academician N.F. 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