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Experimental models are pivotal for unraveling the infection and pathogenesis mechanisms, life cycle regulation, as well as development and evaluation of antiviral vaccines and therapeutics. Traditional two\u2010dimensional (2D) cell lines (e.g., lymphoblastoid cell lines [LCLs] and NPC43) have provided foundational insights into viral latency and oncogenesis, but lack physiological complexity. Emerging three\u2010dimensional (3D) models, such as air\u2013liquid interface (ALI) cultures, spheroids, and patient\u2010derived organoids (PDOs), better mimic tissue architecture and tumor microenvironments and yet face challenges in scalability, dynamic microenvironments, and immune component integration. Animal models, such as humanized mice, rabbits, and tree shrews, have been developed that overcome\n                    <jats:italic>in vitro<\/jats:italic>\n                    limitations by recapitulating systemic interactions, immune responses, and disease progression. Despite these advances, persistent challenges remain, including species\u2010specific constraints, incomplete modeling of the tumor microenvironment, partial immune system representation, and limited disease heterogeneity. This review systematically summarizes the technical features, applicability, and limitations of current models, provides guidance for selecting experimental models in further studies, and emphasizes the need for innovative, patient\u2010tailored platforms to unravel EBV's lifelong pathogenesis and facilitate the translation of EBV vaccines and therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/mlf2.70081","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:45:26Z","timestamp":1786441526000},"page":"401-416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Advances and challenges in experimental models for Epstein\u2013Barr virus research"],"prefix":"10.1002","volume":"5","author":[{"given":"Gulimire","family":"Wufuer","sequence":"first","affiliation":[{"name":"State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health Xiamen University Xiamen China"},{"name":"National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry\u2010Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology Xiamen University Xiamen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiabao","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health Xiamen University Xiamen China"},{"name":"National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry\u2010Education Integration in Vaccine Research, NMPA Key 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengxiang","family":"Ge","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health Xiamen University Xiamen China"},{"name":"National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry\u2010Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology Xiamen University Xiamen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9907-3282","authenticated-orcid":false,"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health Xiamen University Xiamen China"},{"name":"National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry\u2010Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology Xiamen University Xiamen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningshao","family":"Xia","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health Xiamen University Xiamen China"},{"name":"National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry\u2010Education Integration in Vaccine 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