Hepatitis E (HE), caused by Paslahepevirus balayani (bHEV), is one of the leading causes of acute viral hepatitis worldwide. As a vaccine-preventable disease, HE has been effectively controlled through the use of the world’s first HE vaccine based on the genotype 1 bHEV. This vaccine has been proven to confer long-lasting and robust protection in large-scale clinical trials.
In recent years, the discovery of rat HEV (Rocahepevirus ratti, rHEV) has raised new zoonotic concerns. rHEV was first identified in 2017 as capable of infecting humans and causing hepatitis. rHEV and bHEV share only ~55% sequence identity in their capsid proteins. Previous studies suggested that the major neutralizing epitopes on the rHEV capsid are virus-specific and do not cross-neutralize bHEV; however, an animal model study indicated that bHEV vaccination could partially suppress rHEV infection, presenting conflicting evidence.
A recent study led by Prof. Ningshao Xia, Prof. Zizheng Zheng and Sr. Eng. Qingbing Zheng from Xiamen University, and Clin. Assoc. Prof. Siddharth Sridhar from The University of Hong Kong, revealed cross-genus protection against rat hepatitis E virus elicited by hepatitis E vaccination in humans. The team found that 7.7% (8/104) of vaccine-elicited and 4.2% (2/48) of infection-elicited antibodies cross-reacted with rHEV, but only vaccine-elicited antibodies conferred protection. Cryo-EM structures of six broadly reactive antibodies revealed two cross-reactive sites on the E2s domain: antigenic site 1 and antigenic site 2. Class 1 antibodies targeting antigenic site 1, located on the top lateral side of E2s, conferred in vivo protection by blocking capsid-cell attachment (Figure).
This study suggests that protective efficacy of bHEV vaccination against rHEV is mediated by class 1 antibodies, highlighting the potential value of this site for rHEV vaccine design. Although the immunogens encountered during bHEV infection and vaccination are derived from the open reading frame 2 (ORF2) gene, they differ significantly in glycosylation and structural conformation, possibly explaining why such cross-neutralizing class 1 antibodies were rarely found in natural infection.
Read the full article: Journal of Hepatology. 2025 Jun 24:S0168-8278(25)02283-4.
