{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:17:25Z","timestamp":1786123045478,"version":"build-2736575974"},"reference-count":58,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["No. 806776"],"award-info":[{"award-number":["No. 806776"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"award":["No. 806776"],"award-info":[{"award-number":["No. 806776"]}],"id":[{"id":"https:\/\/ror.org\/019af4n30","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: Seasonal influenza vaccination shows highly variable effectiveness across individuals, particularly in older adults, in whom age-related immune decline compromises protective responses. Methods: This study evaluated immune responses to the 2019\/2020 quadrivalent influenza vaccine in 75 individuals aged 25\u201389 years. Influenza-specific antibody titers and virus-neutralizing activity were measured before and four weeks after vaccination, and participants were stratified as high or low responders. Results: We observed that older individuals exhibited increased frequencies of myeloid-derived suppressor cells (MDSCs) and activated regulatory T cells (Treg) expressing HLA-DR and CD38, consistent with enhanced immunosuppressive activity. Importantly, higher levels of these immunoregulatory populations correlated with poor vaccine responsiveness in both adult and older participants. Additionally, circulating T follicular regulatory (Tfr) cells were elevated in older participants and in low responders, whereas T follicular helper (Tfh) cells remained unchanged, resulting in an increased Tfr\/Tfh ratio associated with impaired antibody production. However, when adjusting for possible confounders, most immunoregulatory subsets did not remain independently associated with responder status, except CD38+ Treg cells. Conclusions: These findings suggest that immunoregulatory networks, while essential for controlling chronic inflammation during aging, may limit vaccine-induced immunity. Identifying biomarkers such as MDSC frequency, activated Treg phenotype, and Tfr\/Tfh balance may contribute to the identification of individuals with different levels of vaccine responsiveness and could help inform future personalized vaccination strategies.<\/jats:p>","DOI":"10.3390\/vaccines14080680","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T13:20:16Z","timestamp":1786108816000},"page":"680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association Between Immunosuppressive Cell Populations and Immune Response to Influenza Vaccination in Younger and Older Adults"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2274-9039","authenticated-orcid":false,"given":"Daniela","family":"Di Placido","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9888-8156","authenticated-orcid":false,"given":"Antonio","family":"Ciaramella","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Riccomi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7229-9919","authenticated-orcid":false,"given":"Claudia Maria","family":"Trombetta","sequence":"additional","affiliation":[{"name":"Department of Molecular and Development Medicine, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Dorrucci","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Farchi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9958-164X","authenticated-orcid":false,"given":"Roberto","family":"Giuseppetti","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6817-2461","authenticated-orcid":false,"given":"Serena","family":"Marchi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Development Medicine, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nunzia","family":"Sanarico","sequence":"additional","affiliation":[{"name":"Center for Control and Evaluation of Medicines, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0805-2927","authenticated-orcid":false,"given":"Patrizio","family":"Pezzotti","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Rita","family":"Ciccaglione","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Montomoli","sequence":"additional","affiliation":[{"name":"Department of Molecular and Development Medicine, University of Siena, 53100 Siena, Italy"},{"name":"VisMederi Research srl, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catia","family":"Valdarchi","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Vendetti","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Istituto Superiore di Sanit\u00e0, 00169 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e00084-18","DOI":"10.1128\/CMR.00084-18","article-title":"Factors That Influence the Immune Response to Vaccination","volume":"32","author":"Zimmermann","year":"2019","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.it.2020.04.001","article-title":"Improving Vaccine-Induced Immunity: Can Baseline Predict Outcome?","volume":"41","author":"Tsang","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1086\/529197","article-title":"Biology of Immune Responses to Vaccines in Elderly Persons","volume":"46","author":"Weinberger","year":"2008","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Goyani, P., Christodoulou, R., and Vassiliou, E. (2024). Immunosenescence: Aging and Immune System Decline. Vaccines, 12.","DOI":"10.3390\/vaccines12121314"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.coi.2009.05.023","article-title":"Immunosenescence: What Does It Mean to Health Outcomes in Older Adults?","volume":"21","author":"McElhaney","year":"2009","journal-title":"Curr. Opin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6894","DOI":"10.1038\/s41467-022-34487-z","article-title":"Distinct Immunological and Molecular Signatures Underpinning Influenza Vaccine Responsiveness in the Elderly","volume":"13","author":"Riese","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/j.ajic.2020.05.011","article-title":"Impact of Repeated Yearly Vaccination on Immune Responses to Influenza Vaccine in an Elderly Population","volume":"48","author":"Kitamura","year":"2020","journal-title":"Am. J. Infect. Control"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12979-023-00352-w","article-title":"Aging and Chronic Inflammation: Highlights from a Multidisciplinary Workshop","volume":"20","author":"Saavedra","year":"2023","journal-title":"Immun. Ageing"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41569-018-0064-2","article-title":"Inflammageing: Chronic Inflammation in Ageing, Cardiovascular Disease, and Frailty","volume":"15","author":"Ferrucci","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_10","first-page":"325","article-title":"Myeloid-Derived Suppressor Cells (MDSC): An Important Partner in Cellular\/Tissue Senescence","volume":"19","author":"Salminen","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.4049\/jimmunol.2200914","article-title":"Here, There, and Everywhere: Myeloid-Derived Suppressor Cells in Immunology","volume":"210","author":"Lamb","year":"2023","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pawelec, G., Verschoor, C.P., and Ostrand-Rosenberg, S. (2019). Myeloid-Derived Suppressor Cells: Not Only in Tumor Immunity. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01099"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.arr.2018.09.001","article-title":"The Role of Myeloid-Derived Suppressor Cells (MDSC) in the Inflammaging Process","volume":"48","author":"Salminen","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13448","DOI":"10.18632\/oncotarget.3626","article-title":"Expansion of Myeloid-Derived Suppressor Cells with Arginase Activity Lasts Longer in Aged than in Young Mice after CpG-ODN plus IFA Treatment","volume":"6","author":"Harman","year":"2015","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.mad.2007.10.003","article-title":"Age-Related Increase of Tumor Susceptibility Is Associated with Myeloid-Derived Suppressor Cell Mediated Suppression of T Cell Cytotoxicity in Recombinant Inbred BXD12 Mice","volume":"128","author":"Grizzle","year":"2007","journal-title":"Mech. Ageing Dev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1007\/s00018-019-03048-x","article-title":"Immunosenescence: The Potential Role of Myeloid-Derived Suppressor Cells in Age-Related Immune Deficiency","volume":"76","author":"Salminen","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9729","DOI":"10.1007\/s11357-014-9729-x","article-title":"Ageing and Myeloid-Derived Suppressor Cells: Possible Involvement in Immunosenescence and Age-Related Disease","volume":"36","author":"Bueno","year":"2014","journal-title":"Age"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Schroeter, A., Roesel, M.J., Matsunaga, T., Xiao, Y., Zhou, H., and Tullius, S.G. (2022). Aging Affects the Role of Myeloid-Derived Suppressor Cells in Alloimmunity. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.917972"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1189\/jlb.0912461","article-title":"Blood CD33(+)HLA-DR(\u2212) Myeloid-Derived Suppressor Cells Are Increased with Age and a History of Cancer","volume":"93","author":"Verschoor","year":"2013","journal-title":"J. Leukoc. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12979-025-00524-w","article-title":"Aging Modulates the Immunosuppressive, Polarizing and Metabolic Functions of Blood-Derived Myeloid-Derived Suppressor Cells (MDSCs)","volume":"22","author":"Keltsch","year":"2025","journal-title":"Immun. Ageing"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e13703","DOI":"10.1111\/acel.13703","article-title":"Identification of Aging-Associated Immunotypes and Immune Stability as Indicators of Post-Vaccination Immune Activation","volume":"21","author":"Cevirgel","year":"2022","journal-title":"Aging Cell"},{"key":"ref_22","unstructured":"World Health Organization (WHO) (2026, January 07). Recommended Composition of Influenza Virus Vaccines for Use in the 2019\u20132020 Northern Hemisphere Influenza Season. Available online: https:\/\/www.who.int\/publications\/m\/item\/recommended-composition-of-influenza-virus-vaccines-for-use-in-the-2019-2020-northern-hemisphere-influenza-season."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1503\/cmaj.050051","article-title":"A Global Clinical Measure of Fitness and Frailty in Elderly People","volume":"173","author":"Rockwood","year":"2005","journal-title":"Can. Med. Assoc. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.2147\/CIA.S194543","article-title":"Grip Strength: An Indispensable Biomarker For Older Adults","volume":"14","author":"Bohannon","year":"2019","journal-title":"Clin. Interv. Aging"},{"key":"ref_25","unstructured":"World Health Organization (2011). Manual for the Laboratory Diagnosis and Virological Surveillance of Influenza, World Health Organization."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sacchi, A., Tumino, N., Grassi, G., Casetti, R., Cimini, E., Bordoni, V., Ammassari, A., Antinori, A., and Agrati, C. (2018). A New Procedure to Analyze Polymorphonuclear Myeloid Derived Suppressor Cells in Cryopreserved Samples Cells by Flow Cytometry. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0202920"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic Self-Tolerance Maintained by Activated T Cells Expressing IL-2 Receptor Alpha-Chains (CD25). Breakdown of a Single Mechanism of Self-Tolerance Causes Various Autoimmune Diseases","volume":"155","author":"Sakaguchi","year":"1995","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4622","DOI":"10.4049\/jimmunol.176.8.4622","article-title":"MHC Class II Expression Identifies Functionally Distinct Human Regulatory T Cells","volume":"176","author":"Wolf","year":"2006","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1182\/blood-2015-12-687749","article-title":"Daratumumab Depletes CD38+ Immune Regulatory Cells, Promotes T-Cell Expansion, and Skews T-Cell Repertoire in Multiple Myeloma","volume":"128","author":"Krejcik","year":"2016","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Riccomi, A., Trombetta, C.M., Dorrucci, M., Di Placido, D., Sanarico, N., Farchi, F., Giuseppetti, R., Villano, U., Marcantonio, C., and Marchi, S. (2024). Effects of Influenza Vaccine on the Immune Responses to SARS-CoV-2 Vaccination. Vaccines, 12.","DOI":"10.20944\/preprints202403.1414.v1"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.1172\/JCI76861","article-title":"Circulating T Follicular Regulatory and Helper Cells Have Memory-like Properties","volume":"124","author":"Sage","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/nm.2425","article-title":"Foxp3+ Follicular Regulatory T Cells Control the Germinal Center Response","volume":"17","author":"Linterman","year":"2011","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Spensieri, F., Siena, E., Borgogni, E., Zedda, L., Cantisani, R., Chiappini, N., Schiavetti, F., Rosa, D., Castellino, F., and Montomoli, E. (2016). Early Rise of Blood T Follicular Helper Cell Subsets and Baseline Immunity as Predictors of Persisting Late Functional Antibody Responses to Vaccination in Humans. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0157066"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1129","DOI":"10.1002\/cti2.1129","article-title":"Dynamic Changes in Circulating T Follicular Helper Cell Composition Predict Neutralising Antibody Responses after Yellow Fever Vaccination","volume":"9","author":"Huber","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wrona, M.V., Ghosh, R., Coll, K., Chun, C., and Yousefzadeh, M.J. (2024). The 3 I\u2019s of Immunity and Aging: Immunosenescence, Inflammaging, and Immune Resilience. Front. Aging, 5.","DOI":"10.3389\/fragi.2024.1490302"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e162978","DOI":"10.1172\/jci.insight.162978","article-title":"Human HLA-DR+CD27+ Regulatory T Cells Show Enhanced Antigen-Specific Suppressive Function","volume":"8","author":"Ma","year":"2023","journal-title":"JCI Insight"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1182\/blood-2013-02-482539","article-title":"Multiparameter Single-Cell Profiling of Human CD4+FOXP3+ Regulatory T-Cell Populations in Homeostatic Conditions and during Graft-versus-Host Disease","volume":"122","author":"Dong","year":"2013","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Lara, J.C., Espinosa, E., Santos-Argumedo, L., Romero-Ram\u00edrez, H., L\u00f3pez-Herrera, G., Garc\u00eda-Garc\u00eda, F., Sandoval-Montes, C., Ortiz-Navarrete, V., Flores-Mu\u00f1oz, M., and Rodr\u00edguez-Alba, J.C. (2021). CD38 Correlates with an Immunosuppressive Treg Phenotype in Lupus-Prone Mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111977"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Rocamora-Reverte, L., Melzer, F.L., W\u00fcrzner, R., and Weinberger, B. (2021). The Complex Role of Regulatory T Cells in Immunity and Aging. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.616949"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/j.1365-2249.2005.02798.x","article-title":"The Number of Human Peripheral Blood CD4+ CD25high Regulatory T Cells Increases with Age","volume":"140","author":"Gregg","year":"2005","journal-title":"Clin. Exp. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"944","DOI":"10.4049\/jimmunol.1500443","article-title":"IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age","volume":"195","author":"Raynor","year":"2015","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"148","DOI":"10.33696\/immunology.6.201","article-title":"T Lymphocytes in Aging: CD38 as a Novel Contributor between Inflammaging and Immunosenescence","volume":"6","year":"2024","journal-title":"J. Cell. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.mad.2009.06.003","article-title":"Aging and Human CD4+ Regulatory T Cells","volume":"130","author":"Hwang","year":"2009","journal-title":"Mech. Ageing Dev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/j.exger.2013.09.003","article-title":"The Th17\/Treg Balance Is Disturbed during Aging","volume":"48","author":"Schmitt","year":"2013","journal-title":"Exp. Gerontol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zhou, L., Ge, M., Zhang, Y., Wu, X., Leng, M., Gan, C., Mou, Y., Zhou, J., Valencia, C.A., and Hao, Q. (2022). Centenarians Alleviate Inflammaging by Changing the Ratio and Secretory Phenotypes of T Helper 17 and Regulatory T Cells. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.877709"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e13591","DOI":"10.1111\/aji.13591","article-title":"HLA-DR+ CD45RA\u2212 Tregs and CD28\u2212 Treg-like Cells: Potential Immunologic Biomarkers for Reproductive Aging","volume":"89","author":"Muyayalo","year":"2023","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Trombetta, C.M., Kistner, O., Montomoli, E., Viviani, S., and Marchi, S. (2022). Influenza Viruses and Vaccines: The Role of Vaccine Effectiveness Studies for Evaluation of the Benefits of Influenza Vaccines. Vaccines, 10.","DOI":"10.3390\/vaccines10050714"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Wiggins, K.B., Smith, M.A., and Schultz-Cherry, S. (2021). The Nature of Immune Responses to Influenza Vaccination in High-Risk Populations. Viruses, 13.","DOI":"10.3390\/v13061109"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Ellebedy, A.H. (2018). Immunizing the Immune: Can We Overcome Influenza\u2019s Most Formidable Challenge?. Vaccines, 6.","DOI":"10.3390\/vaccines6040068"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Lewnard, J.A., and Cobey, S. (2018). Immune History and Influenza Vaccine Effectiveness. Vaccines, 6.","DOI":"10.3390\/vaccines6020028"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1080\/14760584.2017.1334554","article-title":"Repeated Annual Influenza Vaccination and Vaccine Effectiveness: Review of Evidence","volume":"16","author":"Belongia","year":"2017","journal-title":"Expert Rev. Vaccines"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3759","DOI":"10.1016\/j.vaccine.2020.03.025","article-title":"Negative Effect on Immune Response of Repeated Influenza Vaccination and Waning Effectiveness in Interseason for Elderly People","volume":"38","author":"Sugishita","year":"2020","journal-title":"Vaccine"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/cid\/ciaa706","article-title":"Effects of Prior Season Vaccination on Current Season Vaccine Effectiveness in the United States Flu Vaccine Effectiveness Network, 2012\u20132013 Through 2017\u20132018","volume":"73","author":"Kim","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e189300","DOI":"10.1172\/JCI189300","article-title":"Integrative Mapping of Preexisting Influenza Immune Landscapes Predicts Vaccine Response","volume":"135","author":"Hao","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e01795-18","DOI":"10.1128\/JVI.01795-18","article-title":"High Tfh:Tfr Ratios Drive Induction of Potent Neutralizing Antibody Responses","volume":"93","author":"Eldi","year":"2019","journal-title":"J. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.celrep.2015.06.015","article-title":"Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging","volume":"12","author":"Sage","year":"2015","journal-title":"Cell Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1038\/s41598-018-20740-3","article-title":"Activated T Follicular Helper-like Cells Are Released into Blood after Oral Vaccination and Correlate with Vaccine Specific Mucosal B-Cell Memory","volume":"8","author":"Magnusson","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.4049\/jimmunol.2001381","article-title":"Activation and Kinetics of Circulating T Follicular Helper Cells, Specific Plasmablast Response, and Development of Neutralizing Antibodies Following Yellow Fever Virus Vaccination","volume":"207","author":"Sandberg","year":"2021","journal-title":"J. Immunol."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/8\/680\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T13:26:34Z","timestamp":1786109194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/8\/680"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":58,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["vaccines14080680"],"URL":"https:\/\/doi.org\/10.3390\/vaccines14080680","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,7]]}}}