{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T18:55:11Z","timestamp":1773860111705,"version":"3.50.1"},"reference-count":50,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"unspecified","delay-in-days":26,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008277","name":"Poul og Erna Sehested Hansens Fond","doi-asserted-by":"publisher","award":["Not Applicable"],"award-info":[{"award-number":["Not Applicable"]}],"id":[{"id":"10.13039\/501100008277","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100031879","name":"Steno Diabetes Center Aarhus","doi-asserted-by":"crossref","award":["Not Applicable"],"award-info":[{"award-number":["Not Applicable"]}],"id":[{"id":"10.13039\/100031879","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100020166","name":"Flu Lab","doi-asserted-by":"publisher","award":["Not Applicable"],"award-info":[{"award-number":["Not Applicable"]}],"id":[{"id":"10.13039\/100020166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2024,6,7]]},"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Children and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving \u03b2-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer \u03b2-cell protection. This study aims to assess the effect of influenza vaccination on preserving \u03b2-cell function in children and adolescents with recent-onset T1D.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>The INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7\u201317 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual \u03b2-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>Ethical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05585983\">NCT05585983<\/jats:ext-link>\n                      and EudraCT Number 2022-500906-17-01.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-084808","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T08:58:17Z","timestamp":1719824297000},"page":"e084808","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["INfluenza VaccInation To mitigate typE 1 Diabetes (INVITED): a study protocol for a randomised, double-blind, placebo-controlled clinical trial in children and adolescents with recent-onset type 1 diabetes"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct05585983","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05585983","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1158-4220","authenticated-orcid":false,"given":"Ida Borreby","family":"Pedersen","sequence":"first","affiliation":[{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark"},{"name":"Department of Clinical Medicine, Aarhus Universitet Faculty of Health, Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mads","family":"Kjolby","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark"},{"name":"Department of Biomedicine, Aarhus Universitet, Aarhus, Denmark"},{"name":"Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus N, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid Johannesson","family":"Hjelholt","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark"},{"name":"Department of Clinical Pharmacology, Aalborg University Hospital, Aalborg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mette","family":"Madsen","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescents Medicine, Aalborg University Hospital, Aalborg, Denmark"},{"name":"Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann-Margrethe R\u00f8nholt","family":"Christensen","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescents Medicine, Aalborg University Hospital, Aalborg, Denmark"},{"name":"Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ditte","family":"Adolfsen","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescents Medicine, Viborg Regional Hospital, Viborg, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesper Sand","family":"Hjelle","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark"},{"name":"Department of Paediatrics and Adolescents Medicine, G\u00f8dstrup Hospital, Herning, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Britta","family":"Kremke","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Adolescents Medicine, Randers Regional Hospital, Randers, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"St\u00f8vring","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark"},{"name":"Department of Biomedicine, Aarhus Universitet, Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"Jessen","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark"},{"name":"Department of Biomedicine, Aarhus Universitet, Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esben Thyssen","family":"Vestergaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Aarhus Universitet Faculty of Health, Aarhus, Denmark"},{"name":"Department of Paediatrics and Adolescents Medicine, Aarhus University Hospital, Aarhus N, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kurt","family":"Kristensen","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus N, Denmark"},{"name":"Department of Clinical Medicine, Aarhus Universitet Faculty of Health, Aarhus, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5846-345X","authenticated-orcid":false,"given":"Ole","family":"Frobert","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus Universitet, Aarhus, Denmark"},{"name":"Department of Cardiology, \u00d6rebro University Hospital, Orebro, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2024,7,1]]},"reference":[{"key":"2025120519294664000_14.6.e084808.1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.01898","article-title":"Type 1 diabetes: a chronic anti-self-inflammatory response","volume":"8","author":"Clark","year":"2017","journal-title":"Front Immunol"},{"key":"2025120519294664000_14.6.e084808.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh1654"},{"key":"2025120519294664000_14.6.e084808.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2020.07.052"},{"key":"2025120519294664000_14.6.e084808.4","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1080\/21645515.2019.1633877","article-title":"Effects of probiotic administration on immune responses of children and adolescents with type 1 diabetes to a quadrivalent inactivated influenza vaccine","volume":"16","author":"Bianchini","year":"2020","journal-title":"Hum Vaccin Immunother"},{"key":"2025120519294664000_14.6.e084808.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2005.09.058"},{"key":"2025120519294664000_14.6.e084808.6","unstructured":"International Diabetes Federation . IDF diabetes atlas. 2021 Available: https:\/\/diabetesatlas.org\/data\/en\/world\/"},{"key":"2025120519294664000_14.6.e084808.7","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.150074","article-title":"IL-6 receptor blockade does not slow \u0392 cell loss in new-onset type 1 diabetes","volume":"6","author":"Greenbaum","year":"2021","journal-title":"JCI Insight"},{"key":"2025120519294664000_14.6.e084808.8","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0418"},{"key":"2025120519294664000_14.6.e084808.9","doi-asserted-by":"crossref","DOI":"10.1136\/bmjdrc-2022-002991","article-title":"Higher risk of severe hypoglycemia in children and adolescents with a rapid loss of C-peptide during the first 6 years after type 1 diabetes diagnosis","volume":"10","author":"Gr\u00f6nberg","year":"2022","journal-title":"BMJ Open Diabetes Res Care"},{"key":"2025120519294664000_14.6.e084808.10","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.26.3.832"},{"key":"2025120519294664000_14.6.e084808.11","doi-asserted-by":"crossref","DOI":"10.1155\/2008\/457912","article-title":"Effect of C-peptide on diabetic neuropathy in patients with type 1 diabetes","volume":"2008","author":"Ekberg","year":"2008","journal-title":"Exp Diabetes Res"},{"key":"2025120519294664000_14.6.e084808.12","doi-asserted-by":"publisher","DOI":"10.2337\/dc08-1241"},{"key":"2025120519294664000_14.6.e084808.13","first-page":"19","article-title":"= Organisation Mondiale de la Sant\u00e9. (\u200e2022)\u200e. weekly Epidemiological record, 2022, vol. 97, 19 [\u200eFull issue]\u200e","volume":"97","year":"2022","journal-title":"Weekly Epidemiological Record = Relev\u00e9 \u00c9pid\u00e9miologique Hebdomadaire"},{"key":"2025120519294664000_14.6.e084808.14","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1009928","article-title":"Induction of trained immunity by influenza vaccination - impact on COVID-19","volume":"17","author":"Debisarun","year":"2021","journal-title":"PLoS Pathog"},{"key":"2025120519294664000_14.6.e084808.15","doi-asserted-by":"crossref","DOI":"10.3390\/vaccines11091419","article-title":"Pleiotropic effects of influenza vaccination","volume":"11","author":"Hjelholt","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"2025120519294664000_14.6.e084808.16","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.2337\/dc23-0675","article-title":"Teplizumab: a disease-modifying therapy for type 1 diabetes that preserves \u0392-cell function","volume":"46","author":"Herold","year":"2023","journal-title":"Diabetes Care"},{"key":"2025120519294664000_14.6.e084808.17","doi-asserted-by":"crossref","first-page":"2902","DOI":"10.1038\/s41591-023-02576-1","article-title":"Pleconaril and ribavirin in new-onset type 1 diabetes: a phase 2 randomized trial","volume":"29","author":"Krogvold","year":"2023","journal-title":"Nat Med"},{"key":"2025120519294664000_14.6.e084808.18","doi-asserted-by":"publisher","DOI":"10.2337\/dc23-S002"},{"key":"2025120519294664000_14.6.e084808.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2019.103208"},{"key":"2025120519294664000_14.6.e084808.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2008.08.010"},{"key":"2025120519294664000_14.6.e084808.21","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.e7586","article-title":"SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials","volume":"346","author":"Chan","year":"2013","journal-title":"BMJ"},{"key":"2025120519294664000_14.6.e084808.22","unstructured":"Personer MED Kronisk Sygdom Tilbydes vaccination Mod influenza [Internet]. 2022. Available: https:\/\/www.sst.dk\/da\/influenza\/Personer-med-kronisk-sygdom"},{"key":"2025120519294664000_14.6.e084808.23","unstructured":"Influenza . Forebyggelse, Diagnostik Og Behandling. 2021."},{"key":"2025120519294664000_14.6.e084808.24","doi-asserted-by":"crossref","unstructured":"Shroff HP , Ricciardelli LA . Physical appearance changes in childhood and adolescence \u2013 boys. In: Cash T , ed. Encyclopedia of body image and human appearance. Oxford: Academic Press, 2012: 608\u201314.","DOI":"10.1016\/B978-0-12-384925-0.00096-1"},{"key":"2025120519294664000_14.6.e084808.25","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.1.250"},{"key":"2025120519294664000_14.6.e084808.26","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-2451"},{"key":"2025120519294664000_14.6.e084808.27","doi-asserted-by":"publisher","DOI":"10.1111\/dme.12159"},{"key":"2025120519294664000_14.6.e084808.28","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.2800"},{"key":"2025120519294664000_14.6.e084808.29","doi-asserted-by":"crossref","DOI":"10.1007\/s11892-018-1083-4","article-title":"The effect of age on the progression and severity of type 1 diabetes: potential effects on disease mechanisms","volume":"18","author":"Leete","year":"2018","journal-title":"Curr Diab Rep"},{"key":"2025120519294664000_14.6.e084808.30","doi-asserted-by":"crossref","unstructured":"Coppieters K , von Herrath M . n.d. The development of immunotherapy strategies for the treatment of type 1 diabetes. Front Med 5:283. doi:10.3389\/fmed.2018.00283","DOI":"10.3389\/fmed.2018.00283"},{"key":"2025120519294664000_14.6.e084808.31","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60886-6"},{"key":"2025120519294664000_14.6.e084808.32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0904452"},{"key":"2025120519294664000_14.6.e084808.33","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0626"},{"key":"2025120519294664000_14.6.e084808.34","doi-asserted-by":"publisher","DOI":"10.2337\/db13-0345"},{"key":"2025120519294664000_14.6.e084808.35","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1016\/S0140-6736(05)62100-9","article-title":"BCG vaccine in insulin-dependent diabetes mellitus","volume":"349","author":"Pozzilli","year":"1997","journal-title":"Lancet"},{"key":"2025120519294664000_14.6.e084808.36","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.22.10.1703"},{"key":"2025120519294664000_14.6.e084808.37","doi-asserted-by":"crossref","DOI":"10.1038\/s41541-018-0062-8","article-title":"Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG Vaccinations","volume":"3","author":"K\u00fchtreiber","year":"2018","journal-title":"NPJ Vaccines"},{"key":"2025120519294664000_14.6.e084808.38","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.21.10.1691"},{"key":"2025120519294664000_14.6.e084808.39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s00125-017-4448-3","article-title":"Pandemrix\u00ae vaccination is not associated with increased risk of islet autoimmunity or type 1 diabetes in the TEDDY study children","volume":"61","author":"Elding Larsson","year":"2018","journal-title":"Diabetologia"},{"key":"2025120519294664000_14.6.e084808.40","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1007\/s00125-018-4662-7","article-title":"Pandemic influenza and subsequent risk of type 1 diabetes: a nationwide cohort study","volume":"61","author":"Ruiz","year":"2018","journal-title":"Diabetologia"},{"key":"2025120519294664000_14.6.e084808.41","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir240"},{"key":"2025120519294664000_14.6.e084808.42","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix525"},{"key":"2025120519294664000_14.6.e084808.43","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.311.7003.481"},{"key":"2025120519294664000_14.6.e084808.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2018.06.002"},{"key":"2025120519294664000_14.6.e084808.45","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0285-6"},{"key":"2025120519294664000_14.6.e084808.46","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.121.057042"},{"key":"2025120519294664000_14.6.e084808.47","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-00443-4"},{"key":"2025120519294664000_14.6.e084808.48","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2009.21"},{"key":"2025120519294664000_14.6.e084808.49","unstructured":"Sundhedsstyrelsen . B\u00f8rn i alderen 2-6 \u00e5r tilbydes vaccination mod influenza, 2022. Available: https:\/\/www.sst.dk\/da\/influenza\/boern"},{"key":"2025120519294664000_14.6.e084808.50","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.43"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2024-084808","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T03:29:56Z","timestamp":1764991796000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2024-084808"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,7,1]]},"published-print":{"date-parts":[[2024,6]]}},"alternative-id":["10.1136\/bmjopen-2024-084808"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2024-084808","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6]]}}}