Zoonotic Infections
Hepatitis E
Disease Burden
Hepatitis E was first identified as an acute non-A non-B viral hepatitis. It has since been recognized as a major cause of acute hepatitis in young adults throughout much of Asia, Africa and Latin America
[43]
[44]
[45]
[46]
[47]
. The disease is endemic in many parts of the world, including the Indian subcontinent, northwest China, and the Central Asian Republics. In these regions, HEV is transmitted predominantly through the fecal-oral route, especially through the consumption of fecally contaminated drinking water. In India, the lifetime infection risk is more than 60%, which translates into hundreds of thousands of cases annually
[48]
. The highest rates of infection occur in regions with poorest sanitation. A minor mode of transmission could be through blood transfusion
[49].
High prevalence of anti-HEV antibodies has been reported in blood donors from non-endemic regions
[50]
[51]
[52]
, which could be due to zoonotic transmission of the virus. HEV-related viruses have been found in pigs
[53]
[54]
[55]
, deer
[56]
, and wild boar
[57]
as well as in rodents and chickens
[58]
. Direct transmission has been reported from animals to humans through consumption of undercooked deer meat
[59]
or uncooked liver from a wild boar
[60]
. Humans who consume contaminated pork products or are involved in the rearing of pigs are potentially at risk of HEV infection
[59][59]
[61]
[62].
HEV infection occurs mostly in young to middle age adult population, i.e. between the ages of 15 and 40 years. The presence of anti-HEV antibodies has been detected in only less than 5% of children under the age of 10, contrary to what is observed with HAV infection. Clinical symptoms of hepatitis E are typical of acute viral hepatitis including jaundice, abdominal pain, fever and hepatomegaly lasting 1 to 4 weeks. The existence of a chronic form of HEV infection has recently been reported in organ transplant recipients
[63]
. In rare cases, patients may present with severe disease progressing to fatal liver failure. This is mostly observed in chronic liver patients
[64]
and in pregnant women in their third trimester, who often develop encephalopathy with cerebral edema and disseminated intravascular coagulation
[65]
[66]
. The case fatality rate among these women may be as high as 25%, whereas it only is 0.2% to 1% in the general population
[67]
[68]
. The selective suppression of NFkB p65 in pregnant women, causing liver degeneration, severe immunodeficiency and multi-organ failure has been suggested
[69]
but the precise cellular/molecular mechanisms involved are not clear.
Virology
HEV is a small (32-34 nm in diameter), spherical, nonenveloped virus with a 7.2 kb positive-sense, 5'-capped single-stranded RNA genome. It belongs to the genus Hepevirus in the Hepeviridae family. Its molecular organization, deduced from the cloning and sequencing of the genome
[70]
[71]
, shows a high degree of sequence conservation among isolates from different origin. At least four phylogenetically distinct HEV genotypes have been defined
[47][47]
[65][65]
[72]
, although all HEV strains share at least one major serologically cross-reactive epitope, so that they all belong to the same serotype. Genotype 1 includes Asian and African human HEV strains, genotype 2 includes a Mexican and African strains. Genotype 4 is prevalent in Western industrialized countries whereas genotype 3 is mostly found in Far Eastern Asian countries. Outbreaks due to HEV genotype 1 or 2 are the results of efficient human-to-human fecal-oral transmission. In contrast, genotypes 3 and 4 are prevalent in domestic animals such as swine, and only occasionally infect humans, probably due to less efficient cross-species transmission.
The HEV genome includes three partially overlapping open reading frames (ORF). ORF1 encodes a large nonstructural protein with methyltransferase, cysteine protease, RNA helicase and RNA polymerase activities. ORF 2 encodes the 660 amino acid long viral capsid protein, and ORF3 encodes a 123 aminoacid protein which seems to interact with various intracellular pathways to create an environment favorable for virus replication. The capsid protein of HEV (pORF2) is glycosylated. The glycosylation seems to be required for the production of infectious viral particles and replication in macaques
[73].
Vaccine
Since there is no robust system to grow HEV in cell culture, inactivated or live attenuated vaccines were considered as not feasible until recently
[74]
[75]
, when the successful replication of a genotype 3 HEV isolate was obtained in PLC/PRF/5 cells from nonhuman primate origin
[76]
[77]
.
The available HEV vaccine is made of a 56 kD pORF2 segment protein (genotype 1). The truncated protein produced in insect cells using a recombinant baculovirus efficiently self-assembles into virus-like particles (VLPs) that expose the dominant HEV neutralization epitope
[78]
and elicit a protective antibody response in a monkey challenge model
[79]
[80]
. Cynomolgous monkeys were successfully protected against challenge by passive immunization with human convalescent serum or by active immunization with the ORF2 VLP vaccine. These results prompted a randomized clinical trial of the vaccine's efficacy in volunteers from the Nepalese Army, a population at high risk for hepatitis E
[81]
. The VLP vaccine was administered in three doses at months 0, 1 and 6 to 898 subjects who were followed up for a median of over 800 days in parallel with 896 subjects in the placebo group
[82]
. Hepatitis E developed in 66 subjects in the placebo group versus 3 in the vaccine group, which translates into a 95.5% vaccine efficacy. Moreover, the increase by a factor of 10 in anti HEV IgG levels after the administration of the third dose of vaccine was evidence that the first two vaccine doses elicited a strong immune memory.
Another HEV vaccine based on the 50 kD recombinant capsid protein went through Phase III clinical trials at the Xiamen University in China
[83]
. The self-asssembled recombinant virus particle was analyzed at a 22-A resolution basis by cryo-electron microscopy and image reconstruction, yielding the first image of a T=1 particle with 30 morphological units showing protruding dimers at the icosahedral two-fold axes.
The combination of the HEV VLP vaccine with an inactivated HAV vaccine was studied in mice and showed that a dual HAV / HEV vaccination was feasible
[84].