Design and Analysis of Novel HEV Vaccine Variants and Evaluation of Two Selected Candidates in a Porcine Infection Model

Background and Aims Hepatitis E virus (HEV) poses a significant global health concern, with millions of annual infections and a notable impact on public health. Although HEV is the leading cause of acute viral hepatitis worldwide, there is a substantial lack of approved and licensed vaccines. In this study, we evaluated the efficacy of several protein‐ and DNA‐based vaccine candidates against HEV using a combined in vitro/in vivo workflow. Methods Corresponding vaccine candidates were produced, biochemically analysed and characterised. The general immunogenicity of suitable vaccine candidates was initially evaluated in a rabbit model. Resulting antibodies were assessed for their reactivity and neutralising efficiency. Finally, the most effective candidates were tested in a pig infection model using a prime‐boost vaccination regimen. Results Using this approach, we analysed a total of seven vaccine candidates and demonstrated that the two most promising candidates significantly reduced virus shedding in swine faecal samples after infection. However, no sterile immunity was achieved. Conclusions This study conducted a comprehensive analysis to establish a rational approach for post‐vaccination immune responses in pigs. The insights gained from this research are expected to significantly contribute to the development and evaluation of future vaccine candidates for pig herds, ultimately reducing viral dissemination among pigs and preventing HEV transmission from pigs to humans. These findings hold important translational value, offering a foundation for both improving animal health and safeguarding public health.