{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T00:13:58Z","timestamp":1760746438044,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Unpad Doctoral Dissertation Research (RDDU) Padjadjaran University","award":["2203\/NU6.3.1\/PT.00\/2022"],"award-info":[{"award-number":["2203\/NU6.3.1\/PT.00\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: Despite the widespread implementation of Hepatitis B vaccination, some children fail to develop protective immunity. Thus, identifying markers for vaccine unresponsiveness is crucial for optimizing current strategies. As interleukin-12 (IL-12), a central cytokine in Th 1 immune activation, has shown potential as a predictive biomarker, the aim of this study was to determine its role in the Hepatitis B vaccine response, highlighting novel findings regarding the threshold level of IL-12 in the pediatric population in doing so. Methods: A cross-sectional study was conducted on a community in Bandung City. The subjects were 7\u201312-month-old babies who had completed primary Hepatitis B vaccination (0, 2, 3, and 4 months of age). Blood tests for anti-HB examination were performed with a Chemiluminescent Microparticle Immunoassay (CMIA) to determine the response and non-response groups, and an Enzyme Immunosorbent Assay (ELISA) was used for IL-12 detection. Data were analyzed using the Kruskal\u2013Wallis test, Chi-square test, Spearman Correlation, and Receiver Operating Characteristics. Statistical analysis was conducted with SPSS version 18.0. Results: The results of this study indicate that 4.5% of the subjects were unresponsive to the Hepatitis B vaccine. The most important finding was a significant correlation between IL-12 and the presence of anti-HB titers in the responsive and non-responsive groups (p = 0.016). The Receiver Operating Characteristics (ROC) curve for IL-12 identified a cut-off point of \u226510.65 pg\/mL (&gt;100 mIU\/mL in anti-HBs), with a sensitivity of 64.23%, specificity of 68.75%, and accuracy of 65.2%. Conclusions: Interleukin-12 can be considered as an early candidate biomarker for responsiveness to the Hepatitis B vaccine in children.<\/jats:p>","DOI":"10.3390\/children12101400","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T07:33:50Z","timestamp":1760686430000},"page":"1400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-12 as a Predictor for Unresponsiveness to the Hepatitis B Vaccine: A Novel Cut-Off Point in Children"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2510-7379","authenticated-orcid":false,"given":"Yudith Setiati","family":"Ermaya","sequence":"first","affiliation":[{"name":"Department of Child Health, Faculty of Medicine Padjadjaran University, Dr. Hasan Sadikin General Hospital, Bandung 40161, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunia","family":"Sribudiani","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Faculty of Medicine Padjadjaran University, Bandung 40161, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reni","family":"Ghrahani","sequence":"additional","affiliation":[{"name":"Department of Child Health, Faculty of Medicine Padjadjaran University, Dr. Hasan Sadikin General Hospital, Bandung 40161, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quak Seng","family":"Hock","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, National University Hospital, Singapore 119228, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dwi","family":"Prasetyo","sequence":"additional","affiliation":[{"name":"Department of Child Health, Faculty of Medicine Padjadjaran University, Dr. Hasan Sadikin General Hospital, Bandung 40161, Indonesia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2023, March 04). Hepatitis B. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/hepatitis-b."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tahir, A., Shinkafi, S.H., Alshrari, A.S., Yunusa, A., Umar, M.T., Hudu, S.A., and Jimoh, A.O. (2024). A Comprehensive Review of Hepatitis B Vaccine Nonresponse and Associated Risk Factors. Vaccines, 12.","DOI":"10.3390\/vaccines12070710"},{"key":"ref_3","first-page":"710","article-title":"Global HBV Disease Burden and Current Care Gaps","volume":"23","year":"2024","journal-title":"Clin. Liver Dis."},{"key":"ref_4","unstructured":"World Health Organization (2023, May 20). Hepatitis B Is Preventable with Safe and Effective Vaccines. Available online: https:\/\/www.who.int\/southeastasia\/activities\/hepatitis-b-is-preventable-with-safe-and-effective-vaccines."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"World Health Organization (2019). Hepatitis B Vaccines: WHO Position Paper, July 2017\u2014Recommendations. Vaccine, 37, 223\u2013225.","DOI":"10.1016\/j.vaccine.2017.07.046"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.4254\/wjh.v7.i24.2503","article-title":"Recent Advances in Vaccination of Non-Responders to Standard Dose Hepatitis B Virus Vaccine","volume":"7","author":"Walayat","year":"2015","journal-title":"World J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.mehy.2017.05.020","article-title":"Hepatitis B Vaccine Non Response: A Predictor of Latent Autoimmunity?","volume":"104","author":"Mormile","year":"2017","journal-title":"Med. Hypotheses"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.virol.2004.04.042","article-title":"The Nonresponse to Hepatitis B Vaccination Is Associated with Impaired Lymphocyte Activation","volume":"326","author":"Goncalves","year":"2004","journal-title":"Virology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.antiviral.2007.06.012","article-title":"Coimmunization with RANTES Plasmid Polarized Th1 Immune Response against Hepatitis B Virus Envelope via Recruitment of Dendritic Cells","volume":"76","author":"Ma","year":"2007","journal-title":"Antivir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bello, N., Hudu, S.A., Alshrari, A.S., Imam, M.U., and Jimoh, A.O. (2024). Overview of Hepatitis B Vaccine Non-Response and Associated B Cell Amnesia: A Scoping Review. Pathogens, 13.","DOI":"10.3390\/pathogens13070554"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S1359-6101(03)00043-1","article-title":"The Biology of IL-12: Coordinating Innate and Adaptive Immune Responses","volume":"14","author":"Watford","year":"2003","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"63","DOI":"10.5604\/16652681.1226816","article-title":"Effects of Interleukin-4 and Interleukin-12b Gene Polymorphisms on Hepatitis B Virus Vaccination","volume":"16","author":"Roh","year":"2017","journal-title":"Ann. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.12816\/0035540","article-title":"Interleukin-12 Level and Its Relation Ti Hepatits B Virus Vaccine Response in Hemodialysis Patients","volume":"46","author":"Mohamed","year":"2017","journal-title":"Al-Azhar Med. J."},{"key":"ref_14","unstructured":"Siemens (2017). Advia Anti-HBs2 (aHBs2) Assay for the Detection of Antibodies to Hepatitis B Surface Antigen. Advia, 1\u201347. Available online: https:\/\/www.accessdata.fda.gov\/cdrh_docs\/pdf10\/p100039c.pdf."},{"key":"ref_15","unstructured":"(2023, March 08). Elabscience Human IL-12 (Interleukin 12) Elisa Kit. Available online: https:\/\/www.elabscience.com\/p\/human-il-12-interleukin-12-elisa-kit."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Karabay, O., Hamarat, K.F., Guney Eskiler, G., and Aydin, A. (2025). The Association of Systemic Inflammatory Response with Hepatitis B Vaccine Unresponsiveness. Viruses, 17.","DOI":"10.3390\/v17030338"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e175","DOI":"10.5001\/omj.2019.117","article-title":"Humoral Immune Memory to Hepatitis B Vaccine after Primary Vaccination of Children and Adolescents in Assiut, Egypt","volume":"35","author":"Salama","year":"2020","journal-title":"Oman Med. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/S0262-4079(20)30646-1","article-title":"You\u2019re Only as Young as Your Immune System","volume":"245","author":"Lawton","year":"2020","journal-title":"New Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s12887-024-05366-x","article-title":"Immune Response and Associated Factors to Hepatitis B Vaccination among Children under Five Attending Care at Mulago Hospital","volume":"25","author":"Kimera","year":"2025","journal-title":"BMC Pediatr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"805625","DOI":"10.3389\/fmolb.2021.805625","article-title":"Cytokines and Chemokines in HBV Infection","volume":"8","author":"Zhong","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/1348-0421.12947","article-title":"Cytokines Profile in Patients with Acute and Chronic Hepatitis B Infection","volume":"66","author":"Ribeiro","year":"2022","journal-title":"Microbiol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7794890","DOI":"10.1155\/2022\/7794890","article-title":"Serum Interleukins as Potential Prognostic Biomarkers in HBV-Related Acute-on-Chronic Liver Failure","volume":"2022","author":"Zhang","year":"2022","journal-title":"Mediat. Inflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"105184","DOI":"10.1016\/j.micpath.2021.105184","article-title":"Improvement of Hepatitis B Vaccine to Induce IFN-\u03b3 Cytokine Response: A New Formulation","volume":"160","author":"Rahimkhani","year":"2021","journal-title":"Microb. Pathog."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Dimitriadis, K., Katelani, S., Pappa, M., Fragkoulis, G.E., and Androutsakos, T. (2023). The Role of Interleukins in HBV Infection: A Narrative Review. J. Pers. Med., 13.","DOI":"10.3390\/jpm13121675"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/1471-2369-13-75","article-title":"Antibodies to Hepatitis B Virus Surface Antigen and Interleukin 12 and Interleukin 18 Gene Polymorphisms in Hemodialysis Patients","volume":"13","author":"Grzegorzewska","year":"2012","journal-title":"BMC Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6899","DOI":"10.1007\/s11033-013-2809-7","article-title":"Association of the Interleukin-12 Polymorphic Variants with the Development of Antibodies to Surface Antigen of Hepatitis B Virus in Hemodialysis Patients in Response to Vaccination or Infection","volume":"40","author":"Grzegorzewska","year":"2013","journal-title":"Mol. Biol. Rep."}],"container-title":["Children"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9067\/12\/10\/1400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T08:13:34Z","timestamp":1760688814000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9067\/12\/10\/1400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":26,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["children12101400"],"URL":"https:\/\/doi.org\/10.3390\/children12101400","relation":{},"ISSN":["2227-9067"],"issn-type":[{"value":"2227-9067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,17]]}}}