Highlights
- •Rat HEV (HEV-C1) is antigenically distinct from human HEV genotypes.
- •Human HEV-based antigen and antibody assays may not diagnose HEV-C1 infection.
- •Prior exposure to human HEV genotypes is not protective against HEV-C1 infection.
- •An HEV-C1 peptide can be used for specific HEV-C1 serodiagnosis and vaccination.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: April 09, 2021
Accepted:
December 17,
2020
Received in revised form:
November 30,
2020
Received:
August 5,
2020
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
