HEVscape - Understanding the genetic and antigenic landscape of the hepatitis E virus capsid protein

• Applicant: André Gömer, Ph.D.
• Subject Area: Virology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567188777

Although hepatitis E virus (HEV) is the most common cause of viral hepatitis worldwide, treatment options remain scarce. In addition, high variability and the emergence of resistant variants reduce the efficacy of antiviral drugs. In HEVscape, we aim to gain insights into the genetic diversity of the HEV capsid protein, the underlying mechanisms of its evolution and its adaptability. We will first assess the genetic landscape of the HEV capsid protein in a diverse group of patients with acute or chronic infection. Building on this, we plan to subsequently generate and evaluate the fitness of patient-derived ORF2 chimeras in vitro. In addition, we plan to perform a large high-throughput screen to test all possible genetic variants of the ORF2 P domain for their phenotypic properties. Finally, we will evaluate the antigenic properties of selected variants generated using convalescent plasma from patients with acute or chronic HEV infection. Conducting these experiments will provide us with a better understanding of which sites of the HEV ORF2 protein are highly flexible and, in contrast, which cannot be exchanged and are therefore potentially important for cell binding or protein folding. To achieve this, we propose to pursue the following three complementary work packages: WP1: Characterize the genetic and phenotypic landscape of ORF2 in patients with acute or chronic infection: How does the HEV capsid protein evolve in patients with acute and chronic infection? Do variants occurring in these patients have unique properties? WP2: In-depth analysis of ORF2 properties using high-throughput mutation screens: What are the constraints on HEV capsid variability? Which sites are highly conserved and most likely to be important for the viral replication cycle? Vice versa, which sites are highly variable and may facilitate immune evasion? WP3: Antigenic characterization of ORF2 variants using sera from different patient cohorts and monoclonal antibodies: How can HEV evade humoral immune responses while maintaining infectivity?

• DFG Programme: Research Grants