Abstract
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.