{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T15:41:05Z","timestamp":1776440465515,"version":"3.51.2"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CLS Seqirus","award":["93913243"],"award-info":[{"award-number":["93913243"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Influenza remains a primary cause of severe illness and death in adults over 60. In this group, immunosenescence and existing health conditions make infections more dangerous and traditional vaccines less effective. The MF59-adjuvanted vaccine was specifically designed to overcome these limitations by enhancing the body\u2019s immune activation and antigen presentation. While the vaccine shows clear benefits, some recent concerns regarding vaccine safety have been raised without supporting scientific evidence. Therefore, this systematic review focuses on providing a comprehensive evaluation of its safety outcomes compared to standard vaccines. Methods: Following the PRISMA guidelines, a systematic review and meta-analysis were conducted; two researchers independently assessed the eligibility of the studies, and the risk of bias was assessed using RoB2 and ROBINS tools for randomized clinical trials and observational studies, respectively. Pooled risk estimates were calculated using a random-effects model. Results: Ten RCTs and three non-RCTs meeting the inclusion criteria were included. No significant differences were found for severe systemic outcomes: Guillain\u2013Barr\u00e9 syndrome (RR 1.01, 95% CI 0.64\u20131.80) and encephalitis (RR 1.23, 95% CI 0.85\u20131.78). For other systemic adverse effects, there were no significant differences between adjuvanted and non-adjuvanted vaccines; only myalgia showed a small but significant increase with adjuvanted vaccines (RR 1.35, 95% CI 1.02\u20131.78) compared with non-adjuvanted vaccines. Conclusions: MF59-adjuvanted influenza vaccines have a favorable and well-characterized safety profile in adults aged 60 years and older. Adverse events are predominantly mild and transient, with no evidence of increased risk of serious or immune-mediated outcomes compared with non-adjuvanted vaccines.<\/jats:p>","DOI":"10.3390\/vaccines14040360","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:24:51Z","timestamp":1776435891000},"page":"360","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systematic Review of Safety of MF59-Adjuvanted Influenza Vaccine in Older Adults"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8934-7013","authenticated-orcid":false,"given":"Matias Edgardo","family":"Manzotti","sequence":"first","affiliation":[{"name":"Geriatrics Section, Department of Internal Medicine, German Hospital, Buenos Aires C1118AAT, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5741-5221","authenticated-orcid":false,"given":"Agustin","family":"Bengolea","sequence":"additional","affiliation":[{"name":"Geriatrics Section, Department of Internal Medicine, German Hospital, Buenos Aires C1118AAT, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7728-9543","authenticated-orcid":false,"given":"Hebe","family":"Vazquez","sequence":"additional","affiliation":[{"name":"Stamboulian Foundation, Buenos Aires C1012AAI, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1001\/jama.292.11.1333","article-title":"Influenza-associated hospitalizations in the United States","volume":"292","author":"Thompson","year":"2004","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.smim.2018.10.010","article-title":"Vaccination in the elderly: The challenge of immune changes with aging","volume":"40","author":"Ciabattini","year":"2018","journal-title":"Semin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.vaccine.2005.04.019","article-title":"The unmet need in the elderly: Designing new influenza vaccines for older adults","volume":"23","author":"McElhaney","year":"2005","journal-title":"Vaccine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"A6","DOI":"10.1016\/j.vaccine.2020.09.048","article-title":"The disease burden of influenza beyond respiratory illness","volume":"39","author":"Macias","year":"2021","journal-title":"Vaccine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S1473-3099(16)00129-8","article-title":"Variable influenza vaccine effectiveness by subtype: A systematic review and meta-analysis of test-negative design studies","volume":"16","author":"Belongia","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"B3","DOI":"10.1016\/j.vaccine.2014.11.062","article-title":"Safety and effectiveness of MF-59 adjuvanted influenza vaccines in children and adults","volume":"33","author":"Black","year":"2015","journal-title":"Vaccine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1016\/S0264-410X(00)00499-0","article-title":"The adjuvanted influenza vaccines with novel adjuvants: Experience with the MF59-adjuvanted vaccine","volume":"19","author":"Podda","year":"2001","journal-title":"Vaccine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1586\/erv.12.140","article-title":"The history of MF59\u00ae adjuvant: A phoenix that arose from the ashes","volume":"12","author":"Ott","year":"2013","journal-title":"Expert Rev. Vaccines"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6959","DOI":"10.1016\/j.vaccine.2009.08.101","article-title":"MF59-adjuvanted versus non-adjuvanted influenza vaccines: Integrated analysis from a large safety database","volume":"27","author":"Pellegrini","year":"2009","journal-title":"Vaccine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1248\/yakushi.131.1733","article-title":"MF59 adjuvanted seasonal and pandemic influenza vaccines","volume":"131","author":"Tsai","year":"2011","journal-title":"Yakugaku Zasshi"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1093\/aje\/kwt078","article-title":"Safety of MF59-adjuvanted influenza vaccination in the elderly: Results of a comparative study of MF59-adjuvanted vaccine versus nonadjuvanted influenza vaccine in northern Italy","volume":"178","author":"Villa","year":"2013","journal-title":"Am. J. Epidemiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.vaccine.2016.12.011","article-title":"Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: A systematic review and meta-analysis","volume":"35","author":"Domnich","year":"2017","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1093\/infdis\/jiy716","article-title":"Relative Effectiveness of Cell-Cultured and Egg-Based Influenza Vaccines Among Elderly Persons in the United States, 2017\u20132018","volume":"220","author":"Izurieta","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"334","DOI":"10.37201\/req\/145.2022","article-title":"Efficacy, effectiveness and safety of the adjuvanted influenza vaccine in the population aged 65 or over","volume":"36","year":"2023","journal-title":"Rev. Esp. Quimioter."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e70020","DOI":"10.1002\/rmv.70020","article-title":"Relative Efficacy, Effectiveness and Safety of Newer and\/or Enhanced Seasonal Influenza Vaccines for the Prevention of Laboratory-Confirmed Influenza in Individuals Aged 18 Years and Over: Update of a Systematic Review","volume":"35","author":"Askar","year":"2025","journal-title":"Rev. Med. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e64016","DOI":"10.2196\/64016","article-title":"MetaAnalysisOnline.com: Web-Based Tool for the Rapid Meta-Analysis of Clinical and Epidemiological Studies","volume":"27","author":"Fekete","year":"2025","journal-title":"J. Med. Internet Res."},{"key":"ref_20","unstructured":"(2025, September 27). Chapter 10: Analysing Data and Undertaking Metaanalyses. Available online: https:\/\/training.cochrane.org\/handbook\/current\/chapter-10."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E901","DOI":"10.1503\/cmaj.200077","article-title":"Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses","volume":"192","author":"Schandelmaier","year":"2020","journal-title":"CMAJ"},{"key":"ref_22","unstructured":"(2025, October 01). ICEMAN. Available online: https:\/\/www.iceman.help\/."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"112","DOI":"10.4172\/2167-0870.1000112","article-title":"Immunogenicity and Safety of an MF59\u00ae-Adjuvanted and a Non-Adjuvanted Inactivated Subunit Influenza Vaccine in Adults Affected by Chronic Diseases","volume":"2","author":"Baldo","year":"2012","journal-title":"J. Clin. Trials"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1093\/infdis\/jiaa255","article-title":"Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults","volume":"222","author":"Cowling","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3094","DOI":"10.1016\/S0264-410X(99)00138-3","article-title":"Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly","volume":"17","author":"Granoff","year":"1999","journal-title":"Vaccine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5027","DOI":"10.1016\/j.vaccine.2014.07.013","article-title":"Comparison of the safety and immunogenicity of an MF59\u00ae-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects","volume":"32","author":"Frey","year":"2014","journal-title":"Vaccine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1023\/A:1017919305501","article-title":"Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects","volume":"17","author":"Gasparini","year":"2001","journal-title":"Eur. J. Epidemiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1742-4933-5-2","article-title":"Safety and immunogenicity of an MF59-adjuvanted subunit influenza vaccine in elderly Chinese subjects","volume":"5","author":"Li","year":"2008","journal-title":"Immun. Ageing"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3856","DOI":"10.1016\/j.vaccine.2019.05.041","article-title":"Surveillance for Guillain-Barr\u00e9 syndrome after influenza vaccination among U.S. Medicare beneficiaries during the 2017\u20132018 season","volume":"37","author":"Wernecke","year":"2019","journal-title":"Vaccine"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e204079","DOI":"10.1001\/jamanetworkopen.2020.4079","article-title":"Comparative Postmarket Safety Profile of Adjuvanted and High-Dose Influenza Vaccines in Individuals 65 Years or Older","volume":"3","author":"Pillsbury","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.4161\/hv.25580","article-title":"Safety, immunogenicity, and tolerability of three influenza vaccines in older adults: Results of a randomized, controlled comparison","volume":"9","author":"Scheifele","year":"2013","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2031266","DOI":"10.1001\/jamanetworkopen.2020.31266","article-title":"Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults: A Randomized Clinical Trial","volume":"4","author":"Schmader","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3486","DOI":"10.1016\/j.vaccine.2024.04.051","article-title":"Assessment of potential adverse events following the 2022\u20132023 seasonal influenza vaccines among U.S. adults aged 65 years and older","volume":"42","author":"Shi","year":"2024","journal-title":"Vaccine"},{"key":"ref_34","first-page":"121","article-title":"Comparison between a conventional subunit vaccine and the MF59-adjuvanted subunit influenza vaccine in the elderly: An evaluation of the safety, tolerability and immunogenicity","volume":"50","author":"Sindoni","year":"2009","journal-title":"J. Prev. Med. Hyg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/S0264-410X(02)00401-2","article-title":"Comparison of the reactogenicity and immunogenicity of a split and a subunit-adjuvanted influenza vaccine in elderly subjects","volume":"21","author":"Squarcione","year":"2003","journal-title":"Vaccine"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/4\/360\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T14:39:55Z","timestamp":1776436795000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/4\/360"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["vaccines14040360"],"URL":"https:\/\/doi.org\/10.3390\/vaccines14040360","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,17]]}}}