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Hepatitis E Vaccines
Hepatitis E was not recognized as a distinct disease until 1980, when waterborne epidemics of hepatitis in India, previously thought to have been caused by hepatitis A virus (HAV), were shown to have occurred in persons who were already immune to HAV. , Three years later, the etiologic agent (tentatively designated as “epidemic non-A non-B hepatitis,” or “enterically transmitted non-A non-B hepatitis”) was transmitted to a volunteer and to cynomolgus monkeys. The viral genome was cloned and sequenced in 1990, and the virus was renamed hepatitis E virus (HEV) with four genotypes (genotypes 1 to 4, HEV1 to HEV4). In retrospect, it is probable that most waterborne clinical hepatitis occurring in developing countries in the first half of the 20th century or earlier was hepatitis E and not hepatitis A.
For many years, hepatitis E was thought to be largely restricted to endemic developing countries, and only of clinical relevance in developed countries in returning travelers. Over the last few years this notion was shown to be mistaken, as hepatitis E is endemic in many developed countries. In such settings, it is largely a porcine zoonosis caused by HEV genotypes 3 and 4 (HEV3 and HEV4), and human infection is surprisingly common.
CLINICAL DESCRIPTION
Acute Hepatitis E
In developing countries hepatitis E is caused by HEV1 and HEV2, and mainly affects young adults. Infections are sporadic, with occasional large outbreaks involving hundreds or thousands of cases. The incubation period is approximately 40 days, and infections may range from inapparent to fulminant hepatitis, with an overall reported mortality of approximately 1%. Clinical signs and symptoms may include malaise, anorexia, abdominal pain and tenderness, nausea, vomiting, fever, and jaundice. Biochemical evidence of hepatitis includes elevated serum levels of liver enzymes and bilirubinemia, which generally return to normal within 6 weeks of onset. The clinical features of hepatitis E in developed countries are similar to those seen in endemic developing nations and are indistinguishable from those observed in any form of acute viral hepatitis. However, there are some important differences ( Table 29.1 ), the most notable of which is that acute hepatitis E in developed countries is commonly asymptomatic and clinical illness is mostly observed in middle aged and elderly males.
TABLE 29.1
Comparison of Hepatitis E Virus Genotypes 1 and 2 With Genotypes 3 and 4
| HEV 1 and 2 | HEV 3 and 4 | |
|---|---|---|
| Geographical distribution | Asia (HEV1) Africa (HEV1 and HEV2) Mexico (HEV2) |
Worldwide, including developed countries (HEV3) Japan, China, Europe (HEV4) |
| Source of infection | Obligate human pathogen | Zoonotic Blood supply |
| Route of infection | Oral-fecal via infected water | Oral via consumption of infected pork Parenteral, iatrogenic (blood supply) |
| Risk of infection from blood supply | Low | High |
| Outbreaks | Yes | No |
| Intrafamilial spread | No | No |
| Clinical attack rate | 1 : 2 | <1 : 10 |
| Demographics | Mainly affects young adults | Mainly affects older men (median age, 63 years; M : F = 3 : 1) |
| Chronic infection | No | Yes, in the immunocompromised Rapidly progressive liver disease if untreated: 10% are cirrhotic within 2 years Viral clearance is usually achieved with a 3-mo course of ribavirin monotherapy |
| Can second HEV infections occur? | Yes; not well documented | Yes Not well documented for HEV3 Well documented in HEV4; more likely in women who have a milder hepatitis than that seen in primary infections |
| Clinical course | Self-limiting hepatitis in most | Self-limiting hepatitis in most |
| Pregnancy | Mortality rate of 25% | Increased mortality rate not seen |
| Underlying chronic liver disease | Increased mortality rate | Increased mortality rate |
| Neurological sequelae | Yes; poorly documented | Yes |
HEV, hepatitis E virus.
Chronic Hepatitis E
Chronic infection with HEV occurs in the immunosuppressed, including transplant recipients, patients with hematological malignancy, and individuals with HIV. To date, chronic infection has only been documented with HEV3 and HEV4. The best-characterized population is transplant recipients in developed countries, where up to 60% of such patients develop chronic infection after exposure to HEV. Chronically infected patients usually have no symptoms, are not icteric, and have modestly elevated serum alanine aminotransferase (ALT) (100–200 IU/L). Untreated, rapidly progressive chronic liver disease ensues, with 10% becoming cirrhotic within 2 years.
Hepatic Complications
In developing countries, the mortality of acute hepatitis E is approximately 1%. This is largely from acute hepatic failure in pregnant women with associated fetal loss. Acute liver failure is commonly seen in patients with underlying chronic liver disease, with an associated mortality of up to 70%. In developed countries, the mortality rate ranges from 3% to 10%. Most deaths occur from acute liver failure in older males with underlying chronic liver disease. These data are an overestimate of the population-based mortality, as asymptomatic cases (>90% of cases) were mostly not included in these hospital-based case series. Of transplant patients with untreated chronic infection, 10% are cirrhotic within 2 years. In such patient’s chronic liver failure requiring (re)transplantation commonly develops, and a number of such cases have died.
Extrahepatic Complications
A number of extrahepatic manifestations have been described in association with hepatitis E, including acute pancreatitis, thrombocytopenia, cryoglobulinemia, autoimmune thyroiditis, acute myocarditis, and a range of neurologic injuries. Such complications have been described in both acute and chronic infections and in developing and developed countries. Neurologic complications are the most commonly described, with 8% of patients presenting with a neurological illness in one case series.
The most commonly described neurologic syndromes are Guillain-Barré syndrome (GBS), neuralgic amyotrophy (NA), and meningoencephalitis. Recent studies from Europe of cohorts of GBS and NA patients showed that 5% and 10%, respectively, had evidence of acute hepatitis E (HEV3) at the start of their neurological illness. , In such patients the hepatitis was mild or asymptomatic and the neurologic symptoms and signs dominated the clinical picture. The mechanisms of neurologic injury are unknown. In some cases, HEV RNA has been recovered from the cerebrospinal fluid. In one patient, HEV quasispecies compartmentalization was documented, with differences in HEV RNA found in the virus isolated from the blood and HEV isolated from the cerebrospinal fluid. This suggests that, at least in some cases, HEV may be directly neurotropic.
VIROLOGY AND PATHOGENESIS
HEV is a spherical nonenveloped virus that is 27–34 nm in diameter. The virus circulating in the blood during acute or chronic infection is associated with lipids and is distinct from the nonenveloped virions shed in feces. , The HEV genome is a positive-stranded RNA of approximately 7.2 kb. The genome consists of a short 5′ noncoding region that is capped with 7-methylguanosine, three open reading frames (ORFs), and a short 3′ noncoding region that is terminated by a stretch of adenosines.
ORF1
ORF1 encodes a nonstructural protein of approximately 1700 amino acids containing several functional domains. These include a methyltransferase/guanyltransferase responsible for capping the viral genome, a papain-like cysteine protease, a macrodomain, a helicase exhibiting RNA 5′ triphosphatase (NTPase), RNA unwinding activity, and an RNA-dependent RNA polymerase. A variable region containing a proline-rich hinge, called the polyproline region (PPR), is located between the protease and the macrodomain. The PPR is an intrinsically disordered region where segments of human gene have been identified in vitro and in vivo . This region could be involved in virus adaptation to the host. , A greater heterogeneity of PPR quasispecies at the acute phase of HEV infection was found in immunocompromised patients who develop chronic infection than in individuals with resolving infection.
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