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Background\/Objectives: Our aim was to optimize the composition of the candidate vaccine against HCV by combining recombinant non-structural proteins and a DNA construct with a complex adjuvant. Methods: C57BL\/6 and DBA\/2J mice were immunized three times at 2-week intervals using different schemes. The viral antigens consisted of a mixture of NS3, NS5A, and NS5B proteins and\/or recombinant DNA expressing NS3-NS5B polyprotein. As adjuvants, a complex adjuvant, a mixture of Polymuramil\u00ae and Pyrogenalum\u00ae (NOD1\/NOD2 and TLR-4 agonists), or a CpG ODN adjuvant (TLR-9 agonist) were used. Results: The most efficient regimen was three subcutaneous administrations of the combined DNA, recombinant protein components, and a new complex adjuvant. This scheme elicited a robust immune response, characterized by high antibody titers, enhanced antigen-specific lymphocyte proliferation, and significant interferon-gamma (IFN-\u03b3) secretion in both mouse lines. Furthermore, the complex adjuvant outperformed CpG ODN in stimulating both humoral and cellular immunity against the HCV antigens. The vaccine composition stimulated the formation of CD4+ memory T cells and decreased the relative frequences of suppressive Treg and MDSCs. Conclusions: The presented candidate vaccine induces a strong immune response to HCV proteins. The next step would be to validate the protective effect in cell culture and animal models. This would one the path to preclinical studies of this vaccine composition.<\/jats:p>","DOI":"10.3390\/vaccines14070640","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T08:14:27Z","timestamp":1784621667000},"page":"640","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immunogenicity of a Candidate Hepatitis C Vaccine Based on Non-Structural DNA-Protein Sequences and a Novel Complex Adjuvant"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5571-5669","authenticated-orcid":false,"given":"Olga V.","family":"Masalova","sequence":"first","affiliation":[{"name":"Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2801-6843","authenticated-orcid":false,"given":"Ekaterina I.","family":"Lesnova","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vyacheslav V.","family":"Kozlov","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir T.","family":"Valuev-Elliston","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3579-4416","authenticated-orcid":false,"given":"Kristina Yu.","family":"Permyakova","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"},{"name":"Federal State Budgetary Educational Institution of Higher Education \u201cMoscow State Academy of Veterinary Medicine and Biotechnology\u2014MVA by K.I. Skryabin\u201d, 109472 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8466-7993","authenticated-orcid":false,"given":"Natalya E.","family":"Fedorova","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana N.","family":"Nikolaeva","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-9783","authenticated-orcid":false,"given":"Alexander V.","family":"Pronin","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5659-9679","authenticated-orcid":false,"given":"Alexander V.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3396-5533","authenticated-orcid":false,"given":"Alla A.","family":"Kushch","sequence":"additional","affiliation":[{"name":"Gamaleya National Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","unstructured":"Hepatitis, C. 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