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The global epidemiology of HEV reveals distinct patterns of prevalence, transmission, and disease severity among these populations, necessitating targeted vaccination strategies. The licensing of the Hecolin (HEV 239) vaccine offers promise, but gaps in clinical trial data and varying immune responses in high-risk groups challenge its widespread applicability. Scope: This review synthesizes data on HEV\u2019s epidemiology, discusses the susceptibility of vulnerable populations, evaluates the efficacy and safety of HEV 239, and highlights the urgent need for clinical research tailored to these groups. Key findings underscore the complexity of vaccine response influenced by immunological, physiological, and environmental factors. Additionally, potential advancements in vaccine technology, including the development of broad-spectrum vaccines and innovative delivery systems, are discussed as future directions. Strategies: Addressing regulatory, economic, and logistical barriers remains crucial for effective HEV vaccination programs. A multidisciplinary approach integrating public health policy, rigorous clinical evaluations, and collaborative frameworks is essential to ensure equitable access to HEV vaccination, ultimately improving health outcomes on a global scale.<\/jats:p>","DOI":"10.3390\/vaccines13060621","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T08:22:34Z","timestamp":1749457354000},"page":"621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Vaccination Strategies and Research Gaps in Hepatitis E Virus for Special Populations"],"prefix":"10.3390","volume":"13","author":[{"given":"Meng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing 100069, China"},{"name":"Clinical Center for Liver Cancer, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binwei","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing 100069, China"},{"name":"Clinical Center for Liver Cancer, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengcheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing 100069, China"},{"name":"Clinical Center for Liver Cancer, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing 100069, China"},{"name":"Clinical Center for Liver Cancer, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing 100069, China"},{"name":"Clinical Center for Liver Cancer, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3311-1108","authenticated-orcid":false,"given":"Guangming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing 100069, China"},{"name":"Clinical Center for Liver Cancer, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0349-5213","authenticated-orcid":false,"given":"Yabo","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of General Surgery Center, Beijing YouAn Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing 100069, China"},{"name":"Clinical Center for Liver Cancer, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7030","DOI":"10.3748\/wjg.v22.i31.7030","article-title":"Hepatitis E: Discovery, global impact, control and cure","volume":"22","author":"Khuroo","year":"2016","journal-title":"World J. 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