Multimodal investigation of rat hepatitis E virus antigenicity: Implications for infection, diagnostics, and vaccine efficacy.

Abstract

BACKGROUND & AIMS:

Rat hepatitis E virus (Orthohepevirus species C; HEV-C1) is an emerging cause of viral hepatitis in humans. HEV-C1 is divergent from other HEV variants infecting humans that belong to Orthohepevirus species A (HEV-A). This study assessed HEV-C1 antigenic divergence from HEV-A and investigated the impact of this divergence on infection susceptibility, serological test sensitivity, and vaccine efficacy.

METHODS:

Immunodominant E2s peptide sequences of HEV-A and HEV-C1 were aligned. Interactions of HEV-C1 E2s and anti-HEV-A monoclonal antibodies (mAbs) were modeled. Recombinant peptides incorporating E2s of HEV-A (HEV-A4 p239) and HEV-C1 (HEV-C1 p241) were expressed. HEV-A and HEV-C1 patient sera were tested using antibody enzymatic immunoassays (EIA), antigen EIAs, and HEV-A4 p239/HEV-C1 p241 immunoblots. Rats immunized with HEV-A1 p239 vaccine (Hecolin), HEV-A4 p239 or HEV-C1 p241 peptides were challenged with a HEV-C1 strain.

RESULTS:

E2s sequence identity between HEV-A and HEV-C1 was only 48%. There was low conservation at E2s residues (23/53; 43.4%) involved in mAb binding. Anti-HEV-A mAbs bound HEV-C1 poorly in homology modeling and antigen EIAs. Divergence resulted in low sensitivity of commercial antigen (0%) and antibody EIAs (10-70%) for HEV-C1 diagnosis. Species-specific HEV-A4 p239/HEV-C1 p241 immunoblots accurately differentiated HEV-A and HEV-C1 serological profiles in immunized rats (18/18; 100%) and infected-patient sera (32/36; 88.9%). Immunization with Hecolin and HEV-A4 p239 was partially protective while HEV-C1 p241 was fully protective against HEV-C1 infection in rats.

CONCLUSIONS:

Antigenic divergence significantly decreases sensitivity of hepatitis E serodiagnostic assays for HEV-C1 infection. Species-specific immunoblots are useful for diagnosing HEV-C1 and for differentiating the serological profiles of HEV-A and HEV-C1. Prior HEV-A exposure is not protective against HEV-C1. HEV-C1 p241 is an immunogenic vaccine candidate against HEV-C1.

LAY SUMMARY:

Rat hepatitis E virus (HEV-C1) is a new cause of hepatitis in humans. Using a combination of methods, we showed that HEV-C1 is highly divergent from the usual cause of human hepatitis (HEV-A). This divergence reduces the capacity of existing tests to diagnose HEV-C1 and also indicates that prior exposure to HEV-A (via infection or vaccination) is not protective against HEV-C1.

• Authors: Siddharth Sridhar, Jianwen Situ, Jian-Piao Cai, Cyril Chik-Yan Yip, Shusheng Wu, Anna Jin-Xia Zhang, Lei Wen, Nicholas Foo-Siong Chew, Wan-Mui Chan, Rosana Wing-Shan Poon, Jasper Fuk-Woo Chan, Dominic Ngai-Chong Tsang, Honglin Chen, Ning-Shao Xia, Kwok-Yung Yuen
• Journal: Journal of hepatology (J Hepatol) Vol. 74 Issue 6 Pg. 1315-1324 (06 2021) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 33845058 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• Epitopes
• Hepatitis Antibodies
• Hepatitis Antigens
• Vaccines, Synthetic
• Viral Hepatitis Vaccines
• hecolin

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Animals
• Antibodies, Monoclonal (immunology)
• Antibodies, Neutralizing (immunology)
• Base Sequence
• Child
• Epitopes (immunology)
• Female
• Genotype
• Hepatitis Antibodies (immunology)
• Hepatitis Antigens (immunology)
• Hepatitis E (blood, prevention & control, veterinary, virology)
• Hepatitis E virus (genetics, immunology)
• Humans
• Immunogenicity, Vaccine (immunology)
• Male
• Middle Aged
• Phylogeny
• Rats
• Rats, Sprague-Dawley
• Treatment Outcome
• Vaccination (methods)
• Vaccine Efficacy
• Vaccines, Synthetic (administration & dosage)
• Viral Hepatitis Vaccines (administration & dosage)
• Young Adult