{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:13:49Z","timestamp":1791389629789,"version":"4.3.3"},"reference-count":21,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T00:00:00Z","timestamp":1745625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hyogo Medical University Grant for Research Promotion, 2023","award":["25K13533"],"award-info":[{"award-number":["25K13533"]}]},{"name":"Japan Society for the Promotion of Science (KAKENHI)","award":["25K13533"],"award-info":[{"award-number":["25K13533"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>This study aimed to evaluate the humoral and cell-mediated immune responses induced by an inactivated influenza vaccine (IIV4) during the 2019\/2020 influenza season in Japan. We collected blood samples from 25 healthy adults before vaccination, 2 weeks post-vaccination, and 5 months post-vaccination. Humoral and cell-mediated immunities were assessed based on hemagglutination inhibition antibody titers and interferon-\u03b3 (IFN-\u03b3) levels, respectively. The geometric mean titer ratio for A\/H3N2 exceeded 2.5, meeting the criteria outlined by the European Medicines Agency guidelines; other strains did not achieve similar thresholds. IFN-\u03b3 responses indicated significant activation for all strains, with 32\u201336% of participants exhibiting \u2265 1.5-fold increases. Due to the implementation of infection control measures against COVID-19, influenza activity was not observed during the 2020\/2021 and 2021\/2022 seasons, potentially altering influenza immunity. Our findings highlight the importance of both humoral and cell-mediated immunity in evaluating vaccine immunogenicity.<\/jats:p>","DOI":"10.3390\/v17050626","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T08:28:11Z","timestamp":1746174491000},"page":"626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of Humoral and Cell-Mediated Immunity Induced by Quadrivalent Influenza Vaccine in Pre-COVID-19 Japan"],"prefix":"10.3390","volume":"17","author":[{"given":"Naruhito","family":"Otani","sequence":"first","affiliation":[{"name":"Department of Infection Control and Prevention, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"},{"name":"Department of Public Health, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiomi","family":"Okuno","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumiko","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Public Health, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshie","family":"Tsuchida","sequence":"additional","affiliation":[{"name":"Department of Public Health, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9789-4689","authenticated-orcid":false,"given":"Kaori","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Department of Public Health, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Ichiki","sequence":"additional","affiliation":[{"name":"Department of Public Health, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5176-9050","authenticated-orcid":false,"given":"Takashi","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Public Health, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshio","family":"Takesue","sequence":"additional","affiliation":[{"name":"Department of Public Health, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Higasa","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Hematology, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiko","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Public Health, Hyogo Medical University, Nishinomiya 663-8501, Hyogo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,26]]},"reference":[{"key":"ref_1","unstructured":"IASR (2020, November 01). Influenza, 2019\/2020 Season, Available online: https:\/\/www.niid.go.jp\/niid\/en\/865-iasr\/10759-489te.html."},{"key":"ref_2","unstructured":"National Institute of Infectious Diseases (2025, March 25). Weekly Reports of Influenza Virus Isolation\/Detection, 2009\/2010\u20132019\/2020, Available online: https:\/\/www.niid.go.jp\/niid\/images\/iasr\/rapid\/inf3\/2019_36w\/in1j_2021331.gif."},{"key":"ref_3","unstructured":"Centers for Disease Control and Prevention (2025, March 25). Estimated Flu Disease Burden 2019\u20132020 Flu Season, Available online: https:\/\/archive.cdc.gov\/#\/details?url=https:\/\/www.cdc.gov\/flu-burden\/php\/data-vis\/2019-2020.html."},{"key":"ref_4","unstructured":"Centers for Disease Control and Prevention (2025, March 25). CDC Seasonal Flu Vaccine Effectiveness Studies, Available online: https:\/\/www.cdc.gov\/flu-vaccines-work\/php\/effectiveness-studies\/index.html."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e4244","DOI":"10.1093\/cid\/ciaa1884","article-title":"Effect of antigenic drift on influenza vaccine effectiveness in the United States-2019\u20132020","volume":"73","author":"Tenforde","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.15585\/mmwr.mm6907a1","article-title":"Interim estimates of 2019\u201320 seasonal influenza vaccine effectiveness\u2014United States, February 2020","volume":"69","author":"Dawood","year":"2020","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2000153","DOI":"10.2807\/1560-7917.ES.2020.25.10.2000153","article-title":"Interim 2019\/20 influenza vaccine effectiveness: Six European studies, September 2019 to January 2020","volume":"25","author":"Rose","year":"2020","journal-title":"Euro Surveill."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"175","DOI":"10.7883\/yoken.JJID.2020.177","article-title":"Interim 2019\/2020 Influenza Vaccine Effectiveness in Japan from October 2019 to January 2020","volume":"74","author":"Tsuzuki","year":"2021","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Patel, M.M., Grohskopf, L.A., Sambhara, S., Belser, J.A., Katz, J.M., and Fry, A.M. (2023). Inactivated and recombinant influenza vaccines. Plotkin\u2019s Vaccines, Elsevier. [8th ed.].","DOI":"10.1016\/B978-0-323-79058-1.00033-5"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6333","DOI":"10.4049\/jimmunol.176.10.6333","article-title":"T cell responses are better correlates of vaccine protection in the elderly","volume":"176","author":"McElhaney","year":"2006","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nm.2612","article-title":"Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans","volume":"18","author":"Wilkinson","year":"2012","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/nm.3350","article-title":"Cellular immune correlates of protection against symptomatic pandemic influenza","volume":"19","author":"Sridhar","year":"2013","journal-title":"Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.cellimm.2016.09.005","article-title":"Evaluation of influenza vaccine-immunogenicity in cell-mediated immunity","volume":"310","author":"Otani","year":"2016","journal-title":"Cell. Immunol."},{"key":"ref_14","unstructured":"(2025, March 25). European Centre for Disease Prevention and Control (ECDC); World Health Organization Regional Office for Europe. Available online: https:\/\/www.ema.europa.eu\/en\/influenza-vaccines-non-clinical-clinical-module-scientific-guideline."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Otani, N., Nakajima, K., Yamada, K., Ishikawa, K., Ichiki, K., Ueda, T., Takesue, Y., Yamamoto, T., Higasa, S., and Tanimura, S. (2024). Timing of assessment of humoral and cell-mediated immunity after influenza vaccination. Vaccines, 12.","DOI":"10.3390\/vaccines12060584"},{"key":"ref_16","unstructured":"National Institute of Infectious Diseases (2025, March 25). Influenza Antibody Status 2019, Available online: https:\/\/www.niid.go.jp\/niid\/ja\/je-m\/2075-idsc\/yosoku\/sokuhou\/9363-flu-yosoku-rapid2019-2.html."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"ofv067","DOI":"10.1093\/ofid\/ofv067","article-title":"Hemagglutination Inhibition Antibody Titers as a Correlate of Protection Against Seasonal A\/H3N2 Influenza Disease","volume":"2","author":"Benoit","year":"2015","journal-title":"Open Forum Infect. Dis."},{"key":"ref_18","unstructured":"World Health Organization (2025, April 24). Recommended Composition of Influenza Virus Vaccines for Use in the 2023\u20132024 Northern Hemisphere Influenza Season. Available online: https:\/\/www.who.int\/teams\/global-influenza-programme\/vaccines\/who-recommendations\/candidate-vaccine-viruses."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1168","DOI":"10.1093\/cid\/ciac683","article-title":"Effect of repeat vaccination on immunogenicity of quadrivalent cell-culture and recombinant influenza vaccines among healthcare personnel aged 18\u201364 years: A randomized, open-label trial","volume":"76","author":"Gaglani","year":"2023","journal-title":"Clin. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.jiph.2022.12.016","article-title":"Effectiveness of influenza vaccination against SARS-CoV-2 infection among healthcare workers in Qatar","volume":"16","author":"Tayar","year":"2023","journal-title":"J. Infect. Public Health"},{"key":"ref_21","unstructured":"National Institute of Infectious Diseases (2025, March 25). Influenza Cases Reported Per Sentinel Weekly, Available online: https:\/\/www.niid.go.jp\/niid\/ja\/10\/2096-weeklygraph\/1644-01flu.html."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/5\/626\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:22:21Z","timestamp":1760030541000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/5\/626"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,26]]},"references-count":21,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["v17050626"],"URL":"https:\/\/doi.org\/10.3390\/v17050626","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,26]]}}}