{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:26:05Z","timestamp":1760145965741,"version":"build-2065373602"},"reference-count":22,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:00:00Z","timestamp":1725494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CJSC Biotechnology Developments"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Objectives: This study aimed to determine the safety, tolerability and immunogenicity of TetraFluBet, an inactivated subunit influenza vaccine that contains a corpuscular immuno-adjuvant derived from natural betulin. Methods: We conducted a prospective, randomized, open-labeled, single-center, phase I trial. The study was conducted in two stages: 5 volunteers in stage I and 25 volunteers in stage II. Eligible participants received one single dose (20 \u03bcg\/0.5 mL) of TetraFluBet intramuscularly. Participants were followed for adverse events and reactogenicity. Seroconversion rate, seroprotection level, geometric mean titers (GMTs) of virus-neutralizing antibodies, IFN-\u03b3 induction and cell-mediated immunity were assessed. Results: A total of 30 participants were enrolled. No vaccine-related serious adverse events were observed. The proportions of study participants with 4-fold seroconversions assessed by the HI assay (with 95% CIs) were 80.0% (62.7; 90.5), 70.0% (52.1; 83.3), 63.3% (45.5; 78.1) and 73.3% (55.6; 85.8) for influenza virus subtypes A (H1N1), A (H3N2), B1 and B2, respectively. Seroprotection levels (with 95% CIs) were 83.3% (66.4; 92.7), 83.3% (66.4; 92.7), 73.3% (55.6; 85.8) and 66.7% (48.8; 80.8), respectively. The fold increases in the GMTs of virus-neutralizing antibodies for subtype H1N1 was 6.50, for subtype H3N2 was 3.03, for subtype B1 was 3.56 and for subtype B2 was 6.07. The population of cytotoxic T-cells increased significantly in the post-vaccination period, indicating a strong CD3+CD8+ response. Conclusions: TetraFluBet tetravalent inactivated subunit vaccine with adjuvant demonstrated pronounced immunogenic properties, leading to the formation of both specific humoral and cellular immunity at a 20 \u03bcg dose.<\/jats:p>","DOI":"10.3390\/vaccines12091017","type":"journal-article","created":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T11:23:19Z","timestamp":1725535399000},"page":"1017","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phase I Clinical Study of the Subunit Betulin-Adjuvanted Tetravalent Candidate Influenza Vaccine TetraFluBet"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5048-7828","authenticated-orcid":false,"given":"Igor","family":"Krasilnikov","sequence":"first","affiliation":[{"name":"CJSC Biotechnology Developments, 119136 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4479-3848","authenticated-orcid":false,"given":"Irina","family":"Tcymbarevich","sequence":"additional","affiliation":[{"name":"CJSC Biotechnology Developments, 119136 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7985-9314","authenticated-orcid":false,"given":"Anna","family":"Krasheninnikova","sequence":"additional","affiliation":[{"name":"CJSC Biotechnology Developments, 119136 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4572-1878","authenticated-orcid":false,"given":"Maria","family":"Sukhova","sequence":"additional","affiliation":[{"name":"CJSC Biotechnology Developments, 119136 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7608-1914","authenticated-orcid":false,"given":"Aleksandr","family":"Ivanov","sequence":"additional","affiliation":[{"name":"CJSC Biotechnology Developments, 119136 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Stukova","sequence":"additional","affiliation":[{"name":"Smorodintsev Research Institute of Influenza of the Ministry of Health of the Russian Federation, 197376 Saint Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekaterina","family":"Romanovskaya-Romanko","sequence":"additional","affiliation":[{"name":"Smorodintsev Research Institute of Influenza of the Ministry of Health of the Russian Federation, 197376 Saint Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Zubkova","sequence":"additional","affiliation":[{"name":"Smorodintsev Research Institute of Influenza of the Ministry of Health of the Russian Federation, 197376 Saint Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandr","family":"Mironov","sequence":"additional","affiliation":[{"name":"CRO \u201cCTR-Pharma\u201d, 119311 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitriy","family":"Lioznov","sequence":"additional","affiliation":[{"name":"Smorodintsev Research Institute of Influenza of the Ministry of Health of the Russian Federation, 197376 Saint Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,5]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2024, June 21). Available online: https:\/\/web.archive.org\/web\/20170828235000\/http:\/\/www.who.int\/mediacentre\/factsheets\/fs211\/en\/."},{"key":"ref_2","first-page":"7","article-title":"Efficacy and safety of influenza vaccination of different contingents","volume":"2","author":"Kostinov","year":"2011","journal-title":"Terra Medica"},{"key":"ref_3","first-page":"48","article-title":"The Impact Annual Immunization against Flu on Morbidity of Flu in the Russian Federation","volume":"15","author":"Popova","year":"2016","journal-title":"\u00c8pidemiol. Vakcinoprofil."},{"key":"ref_4","unstructured":"(2024, August 22). Federal State Budgetary Institution \u201cResearch Institute of Influenza\u201d of the Ministry of Health of the Russian Federation. Available online: https:\/\/www.influenza.spb.ru\/system\/epidemic_situation\/laboratory_diagnostics\/?year=2018&week=03."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1136\/bmjebm-2020-111549","article-title":"Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil","volume":"26","author":"Fink","year":"2020","journal-title":"BMJ Evid. Based Med."},{"key":"ref_6","unstructured":"(2024, June 21). The Australian Immunisation Handbook, Available online: https:\/\/immunisationhandbook.health.gov.au\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.vaccine.2010.08.028","article-title":"The need for quadrivalent vaccine against seasonal influenza","volume":"28","author":"Belshe","year":"2010","journal-title":"Vaccine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.vaccine.2015.01.025","article-title":"Safety and immunogenicity of a quadrivalent intradermal influenza vaccine in adults","volume":"33","author":"Gorse","year":"2015","journal-title":"Vaccine"},{"key":"ref_9","first-page":"CD001269","article-title":"Vaccines for preventing influenza in healthy adults","volume":"18","author":"Demicheli","year":"2007","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1017\/S095026880800126X","article-title":"Long time trends in influenza-like illness and associated determinants in The Netherlands","volume":"137","author":"Dijkstra","year":"2009","journal-title":"Epidemiol. Infect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1016\/j.vaccine.2015.03.065","article-title":"Safety, immunogenicity, and lot-to-lot consistency of a quadrivalent inactivated influenza vaccine in children, adolescents, and adults: A randomized, controlled, phase III trial","volume":"33","author":"Nolan","year":"2015","journal-title":"Vaccine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1080\/21645515.2017.1381808","article-title":"Immunogenicity and safety of a split-virion quadrivalent influenza vaccine in adults 18\u201360 years of age in the Republic of Korea","volume":"14","author":"Choi","year":"2018","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1097\/00006454-200404000-00005","article-title":"Comparison of immunogenicity and tolerability of a virosome-adjuvanted and a split influenza vaccine in children","volume":"20","author":"Kanra","year":"2004","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.trivac.2016.02.002","article-title":"Immunogenicity and safety of a quadrivalent influenza vaccine in children and adolescents in Taiwan: A phase III open-label trial","volume":"5","author":"Lu","year":"2016","journal-title":"Trials Vaccinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3072","DOI":"10.1080\/21645515.2016.1212143","article-title":"Safety and immunogenicity of an intramuscular quadrivalent influenza vaccine in children 3 to 8 y of age: A phase III randomized controlled study","volume":"12","author":"Pepin","year":"2016","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1093\/infdis\/jit091","article-title":"A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3\u201317 years","volume":"207","author":"Domachowske","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1093\/infdis\/jit263","article-title":"Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: A phase III randomized controlled trial in children","volume":"208","author":"Langley","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_18","first-page":"1000371","article-title":"TetraFluBet: A Tetravalent Influenza Vaccine Enhanced with Natural Betulin Adjuvant","volume":"12","author":"Tcymbarevich","year":"2024","journal-title":"Infect. Dis. Prev. Med."},{"key":"ref_19","unstructured":"Isaev, A.A., Krasilnikov, I.V., Frolova, M.E., Kudryavtsev, A.V., Vakhrusheva, A.V., and Ivanov, A.V. (2020). Method for preparation of betulin for use as adjuvant in vaccine against SARS-CoV-2 coronavirus. (RU 2749193 C1)."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1055\/s-0043-123472","article-title":"New pharmacological opportunities for betulinic acid","volume":"84","year":"2018","journal-title":"Planta Medica"},{"key":"ref_21","unstructured":"Pogodin, P.I., and Efimov, O.I. (2019). Instructions for use of the medicinal product for medical use TetraFluBET, inactivated subunit tetravalent influenza vaccine, adjuvanted (Unpublished work)."},{"key":"ref_22","unstructured":"Krasilnikov, I.V., Ivanov, A.V., Belyakova, O.V., Nikolaeva, A.M., and Pogodin, P.I. (2021). Method for producing tetravalent subunit influenza vaccine. Standard No. RU 2740751 C1."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/9\/1017\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:49:24Z","timestamp":1760111364000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/9\/1017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,5]]},"references-count":22,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["vaccines12091017"],"URL":"https:\/\/doi.org\/10.3390\/vaccines12091017","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2024,9,5]]}}}