biostudies-literatureLiu XChina Postdoctoral Science FoundationNatural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)National Natural Science Foundation of China (National Science Foundation of China)11187https://www.ebi.ac.uk/biostudies/studies/S-EPMC12711902biostudies-literatureUnknown16(1)The durability and protective effect of naturally acquired antibodies against hepatitis E virus (HEV) reinfection and clinical progression remain unclear in humans. In a 103-month longitudinal analysis of 7032 adult placebo recipients (aged 16 to 65 years) from a phase 3 HEV vaccine trial in China, we demonstrated that baseline anti-HEV IgG seropositivity (n = 3194) conferred over 50% higher protection against reinfection compared with seronegative individuals (n = 3838), with this protective effect remaining consistent over 8.5 years. A non-linear dose-response relationship was observed, whereby baseline anti-HEV IgG concentrations ≥0.25 WHO units/mL were associated with at least a 50% reduction in infection risk, with higher baseline antibody levels correlated with a lower risk of infection. Natural immunity provided approximately 70% protection against clinically apparent hepatitis E in the cohort, with 10 symptomatic cases identified over a decade of active surveillance. Six were hospitalized, all of whom were baseline seronegative. These findings establish that natural HEV immunity provides durable, though incomplete, protection.Nature communicationsLong-term protection from naturally acquired immunity against hepatitis E virus reinfection.PMC12711902GZB202501952022J0200532370160823B2086Zheng ZChen QZhang JZang XHu XJiang HYang CLiu XHuang SZhuang CZhu KHuang XXia NZhu WWu TWang YLiu DSu YBi ZfalseLong-term protection from naturally acquired immunity against hepatitis E virus reinfection.The durability and protective effect of naturally acquired antibodies against hepatitis E virus (HEV) reinfection and clinical progression remain unclear in humans. In a 103-month longitudinal analysis of 7032 adult placebo recipients (aged 16 to 65 years) from a phase 3 HEV vaccine trial in China, we demonstrated that baseline anti-HEV IgG seropositivity (n = 3194) conferred over 50% higher protection against reinfection compared with seronegative individuals (n = 3838), with this protective effect remaining consistent over 8.5 years. A non-linear dose-response relationship was observed, whereby baseline anti-HEV IgG concentrations ≥0.25 WHO units/mL were associated with at least a 50% reduction in infection risk, with higher baseline antibody levels correlated with a lower risk of infection. Natural immunity provided approximately 70% protection against clinically apparent hepatitis E in the cohort, with 10 symptomatic cases identified over a decade of active surveillance. Six were hospitalized, all of whom were baseline seronegative. These findings establish that natural HEV immunity provides durable, though incomplete, protection.2025-01-01T00:00:00Z2025 Dec2026-06-06T05:07:20.909Z2026-05-26T03:12:07.653ZS-EPMC127119024140768310.1038/s41467-025-66188-8