Hepatitis E
Hepatitis E is a disease caused by infection with hepatitis E virus (HEV) and was first recognized in the early 1980s. The virus is member of the Hepeviridae family. It has at least 4 known mammalian genotypes (named 1 to 4), which belong to a single serotype. The viral genome contains three non-overlapping open reading frames (ORF 1-3). Of these, ORF2 codes for the viral capsid protein which is the target of neutralizing antibodies against HEV. To date, genotypes 1 and 2 have been found only in humans, whereas genotypes 3 and 4 have also been found in several mammalian species. The virus is relatively stable in the environment and is sensitive to heat, chlorination and ultraviolet light. New genotypes of HEV (i.e. genotype 5-8), with limited information about their pathogenicity to human and cross-reactivity with human genotypes 1 to 4, have been reported very recently.
HEV is transmitted principally via the fecal-oral route. The virus can cause large water-born epidemics of the disease and sporadic cases as well. A global burden of disease study estimated that HEV genotypes 1 and 2 account for approximately 20.1 million HEV infections, 3.4 million symptomatic cases, 70 000 deaths, and 3000 stillbirths annually. HEV-infected persons exhibit a wide clinical spectrum, ranging from asymptomatic infection through acute icteric hepatitis to fulminant hepatitis. During epidemics, fulminant hepatitis E occurs at a disproportionately high rate among pregnant women. The disease is typically most severe during the third trimester of pregnancy.
Hepatitis E vaccines
A hepatitis E vaccine based on a 239-amino acid recombinant HEV peptide, corresponding to part of the capsid protein of genotype 1 HEV, manufactured in E. coli using recombinant technology is on market at present. The vaccine efficacy after three doses was 100% over a 12-month period after the last dose and was 95.5% over 19 months in all subjects who had received at least one dose. Over 4.5 years the efficacy against disease was 93.3%. Other vaccines based on HEV capsid protein are currently in nonclinical or clinical development.
Hepatitis E vaccine standardization
Written standards
In 2017 WHO organized a series of meetings to review the current status of development and regulation of recombinant hepatitis E vaccines and developed WHO Recommendations to assure the quality, safety and efficacy of recombinant hepatitis E vaccines. This document provides guidance to NRAs and manufacturers on the manufacturing process, and on nonclinical and clinical aspects, to assure the quality, safety and efficacy of recombinant hepatitis E vaccines for prophylactic use based on the ORF2 capsid protein.
Recommendations to assure the quality, safety and efficacy of recombinant hepatitis E vaccines, Annex 2, TRS 1016
Reference materials
Three reference materials have been established by WHO ECBS and available to qualified applicants:
- The first International Reference Reagent for antibodies to hepatitis E virus (95/584), contains 50 units per ampoule, for standardization of diagnostic tests for use in seroprevalence studies and for assessing immunity.
- The first International Standards for hepatitis E virus RNA for nucleic acid amplification technique (NAT)-based assays was established in 2011 and contains 250 000 IU per ampoule.
- The first International Reference Panel for hepatitis E virus NRA genotypes for NAT-based assays (8578/13) contains 11 members and was established in 2015.