Hepatitis E: An Emerging Global Disease

From Discovery Towards Control and Cure

Mehnaaz S. Khuroo; Mohammad S. Khuroo


J Viral Hepat. 2016;23(2):68-79. 

Hepatitis E is a systemic disease affecting the liver predominantly and caused by infection with the hepatitis E virus (HEV). HEV has marked genetic heterogeneity and is known to infect several animal species including pigs, boar, deer, mongoose, rabbit, camel, chicken, rats, ferret, bats and cutthroat trout. HEV is the sole member of the family Hepeviridae and has been divided into 2 genera: Orthohepevirus (mammalian and avian HEV) and Piscihepevirus (trout HEV). Human HEVs included within the genus Orthohepevirus are designated Orthohepevirus A (isolates from human, pig, wild boar, deer, mongoose, rabbit and camel). Hepatitis E is an important public health concern, and an estimated one-third of the world population has been infected with HEV. In recent years, autochthonous hepatitis E is recognized as a clinical problem in industrialized countries. Several animal species especially domestic swine, wild boar and wild deer are reservoirs of genotype HEV-3 and HEV-4 in these countries. Human infections occur through intake of uncooked or undercooked meat of the infected animals and pig livers or sausages made from these livers and sold in supermarkets. HEV can be transmitted through blood and blood component transfusions, and donor screening for HEV is under serious consideration. Chronic hepatitis E resulting in rapidly progressive liver cirrhosis and end-stage liver disease has been described in organ transplant patients. Ribavirin monotherapy attains sustained virological response in most patients. HEV 239 vaccine has been marketed in China and its long-term efficacy over four and a half years reported.

Hepatitis E is a systemic disease affecting the liver predominantly and caused by infection with the hepatitis E virus (HEV).[1] Hepatitis E has a major global impact. It is estimated that one-third of the world population has been exposed to the agent. In India alone, around 2.2 million cases of hepatitis E are thought to occur. In 2005, around 20 million cases of incident HEV infections were estimated to occur in nine endemic zones causing estimated 3.4 million cases, 70 000 deaths and 3000 stillbirths.[2] These calculated numbers are a gross underestimate of the actual disease load in developing countries and need to be revised based on the following: (i) occurrence of repeated epidemics of hepatitis E in the same population on periodic intervals, (ii) disease load with estimated HEV incidence of 6%, (iii) dynamics of antibody response to HEV infection and (iv) occurrence of reinfections with altered immune response.[3–6] Hepatitis E is being recognized as an important clinical problem in many industrialized countries (Fig. 1;[7]). Most of these infections are autochthonous rather than travelling to endemic zones. Data acquired from seroprevalence studies point to the fact that these numbers constitute only a tip of the iceberg and most infections occur as asymptomatic events or are not recognized or reported alternatively as drug-induced liver injury.[8]

Figure 1.

Reported cases of hepatitis E virus infection from industrialized countries. Data source: references 7, 8 and 39.

Discovery of hepatitis E is a remarkable human-interest story related to the complexities, the missteps, the near misses and the ups and downs as with many similar events in history, ([9] www.drkhuroo.com). The story is fascinating as it originated from one of most remote region of the world with very hard weather conditions and primitive healthcare and investigative facilities (Fig. 2). Thus, the story also focuses on the fact that discoveries do not necessarily require high-tech laboratories or institutions with cutting-edge research facilities but can be accomplished in very primitive situations as well, an example in focus. The 1978 epidemic had caused colossal human suffering and loss of life, and an estimated 52 000 patients had icteric disease with around 1700 deaths.[10,11] Through an ingenious house-to-house survey protocol extending for over 14 years, we identified an enterically transmitted non-A, non-B hepatitis with many unique features, namely (i) repeated occurrence of large-scale waterborne epidemics in same geographic region; (ii) disease affecting young adults and selectively sparing children; (iii) exceptional increased incidence and severity in pregnant women; (iv) propensity towards vertical transmission with high foetal and perinatal mortality; (vi) self-limiting disease; and (vii) loss of antibodies in a substantial proportion of infected subjects over time.[5,12–14] A similar disease was reported constituting over half of endemic hepatitis in the same environment.[15] While the hepatitis E story has moved forward over 35 years, it is a matter of concern that we have not been able to furnish answers for many of the unique epidemiological and clinical features of this remarkable pathogen.

Figure 2.

Epidemic region Kashmir 1978. Drinking water is collected from a canal in which public latrine sewage flows, garbage of the whole locality is dumped, utensils and linen are washed, children swim and locals buy fish. The hard weather conditions and primitive healthcare and investigative facilities are depicted.

Is hepatitis E an emerging disease that has appeared in a population for the first time, or did it exist previously and now rapidly increased in incidence or geographic range? Recently, the evolutionary history of mammalian HEV was reported.[16] The times to the most recent common ancestors (tMRCAs) for all four HEV genotypes were calculated using sequences from the nonoverlapped region of ORF2 in a Bayesian analysis. This finding showed that the most common recent ancestor for modern mammalian HEV existed between 536 and 1344 years ago. This progenitor appears to have given rise to anthropotropic and enzootic variants of HEV, which evolved into genotypes HEV-1 and HEV-2 and genotypes HEV-3 and HEV-4, respectively. The discovery of a genetically distinct avian HEV indicates a very long evolutionary history for the HEV group of viruses. In other studies, indigenization and spread of HEV in Japan and China were associated with the popularization of eating pork.

Hepatitis E virion is a 27- to 32-nm, spherical particle, is icosahedral in symmetry and has spikes on the surface.[17] Virus is resistant to heating at 56 °C for 1 h; however, it is susceptible to boiling and frying for 5 min and to chlorination. The HEV genome is a single-stranded RNA of ~7.2 kb that is positive-sense, with a 7-methylguanine cap (m7G) at its 5′ end and a poly (A) at its 3′ end. HEV RNA replicons express genomic RNA and only one bicistronic 2.2-kb subgenomic RNA. The genome contains three partially overlapping open reading frames. ORF1 encodes a nonstructural polyprotein of 1693 amino acids. ORF2 encodes the major viral capsid protein of 660 amino acids. ORF3 is a small phosphoprotein of 114 amino acids (Fig. 3).

Figure 3.

(a) The hepatitis E virus genome, (b) genomic RNA and bicistronic subgenomic RNA, (c) open reading frames (ORFs) and (d) 3 encoded proteins (pORF1, pORF2 and pORF3). For details, see text about hepatitis E virus.

The life cycle of HEV is poorly understood, largely because of the nonavailability of efficient in vitro culture methods or small animal models of infection.[18] The viral particles are concentrated on the surface of hepatocytes, bind a specific yet uncharacterized receptor and are internalized. The virus then uncoats to release genomic RNA that is translated in the cytoplasm into nonstructural proteins. RNA-dependent RNA polymerases replicate the positive-sense genomic RNA into negative-sense transcripts; the latter then act as templates for the synthesis of a 2.2-kb subgenomic RNA as well as full-length positive-sense transcripts. The positive-sense subgenomic RNA is translated into ORF2 and ORF3 proteins. The ORF2 protein packages the genomic RNA to assemble new virions, while the ORF3 protein may optimize the host cell environment for viral replication. The ORF3 protein is also associated with endomembranes or plasma membranes and may aid in viral egress. Recent studies suggest that mature virions excreted from the liver into the circulation are enveloped by the ORF3 protein and lipids, which are subsequently removed through a process that is not understood at present, to resume a fresh infection cycle (Fig. 4).

Figure 4.

Proposed replication of hepatitis E virus. For details, see text about hepatitis E replication.

HEV has remarkable heterogeneity with many groups and genotypes and subtypes but with one serotype. Classifying this agent has been a huge hassle, and as of today, a recent consensus has classified the agent in one family of Hepeviridae which has been broadly divided into 2 genera namely Orthohepevirus and Piscihepevirus ( Table 1 ;[19]). Orthohepevirus is further divided into 4 species, namely A to D. Orthohepevirus A is the species infecting humans and swine and other animals with possible human spread/transmission,Orthohepevirus B includes all 3 avian HEV strains, Orthohepevirus C includes 2 species one from rat (HEV C1) and another one from ferret (HEV C2) and Orthohepevirus D includes bat HEV. Piscihepevirus includes 2 trout HEV strains within a single species.Orthohepevirus A comprises of isolates from human, pigs, boar, deer, mongoose, rabbit and camel. These include two genotypes isolated from humans alone (HEV-1 and HEV-2), two genotypes reported in both humans and different animal species and associated with the zoonotic cases (HEV-3 and HEV-4), two isolates from wild boar in Japan (genotype HEV-5 & HEV-6) and a single isolate from dromedary camel in Dubai (genotype HEV-7). Rabbit HEV and closely related human isolate has been placed as a distant member in HEV-3. The moose virus appears to cluster closely to genotype HEV-3, HEV isolates from mink to ferret virus (HEV C2) and HEV isolates from fox to rat virus (HEV C1). These viruses have not been placed in any specific genotype and need complete genomic sequences for a definite taxonomic classification.

The course of acute hepatitis E infection has been well studied (Fig. 5;[20]). Incubation period is roughly 4–6 weeks; however, it may range from 9 days to 2 months. Disease is present if there were symptoms such as fever, anorexia, vomiting and jaundice. The symptoms coincide with a sharp rise in serum alanine transaminase (ALT) levels. Symptoms may persist for few weeks to a month or more. ALT levels return to normal during convalescence. HEV RNA may be detected in both serum and stool early in the course of infection, but serum viraemia may be difficult to detect by the time cases come to clinical attention. Anti-HEV IgM titres increase rapidly and then wane over the weeks following infection, while anti-HEV IgG antibody titres continue to rise more gradually during the convalescence period, and detectable anti-HEV IgG may persist for months to years.

Figure 5.

Clinical, biochemical and serological profile of hepatitis E virus infection. Based on data from Pinglina epidemic, Kashmir 1992.

HEV disease has significant morbidity and mortality in developing countries.[11] The disease is multifaceted and in its manifestations keeps multiple medical specialists on their toes to face and fight this python ( Table 2 ). Repeated large-scale epidemics hit each region on periodic intervals, causing panic and tsunami-like phenomenon ( Table 3 ;[1,3,10]). Most of these epidemics are not reported for political pressures or not studied for lack of medical infrastructure. Endemic HEV disease is the commonest cause of acute sporadic hepatitis and has been estimated to cause around whooping 2.2 million infections per year in India alone.[15] Acute liver failure is a common occurrence in developing countries although there are no actual estimates. HEV is the dominant aetiological cause of acute liver failure.[21] One of the most intriguing manifestations of hepatitis E in developing countries is increased incidence and severity in pregnant women. HEV strikes pregnant women so much that it is difficult to find a pregnant mother in a community recently hit by the epidemic.[12,22] HEV in developing countries is a major threat to patients with stable chronic liver disease. Around 21% of patients with cirrhosis get HEV superinfection and develop rapidly progressive liver disease with around 34% short-term mortality.[23] Continuing the catastrophes caused by HEV in developing countries, foetal and neonatal deaths are estimated to cause 3000 deaths per year and post-transfusion HEV infections lead to undefined disease load in such communities.[14,24]

How does HEV cause such major catastrophes in such regions? Gross faecal contamination of drinking water supplies occurs through a panorama of mechanisms.[25,26] Around 2.4 billion people, one-third of the world population, will remain without access to improved sanitation by 2015. Globally, an estimated 1.8 billion shall drink polluted/faecally contaminated water. Over 300 million Indians still defecate in the open. India accounts for about 60% of the world population without toilets, with human excrement that goes into a field polluting groundwater, crops and waterways. That is at a time when more people shall have a mobile phone in hand to make a call than a toilet to defecate. The situation in India shall continue to remain a matter of great concern.

Sanitation and sewage disposal in India and other developing countries is the ultimate among so many practices which shall infuse major impact to economy; stabilize health care; give dignity, respect and safety to women; and improve children health statistics.[25] In addition, a common Indian shall have a safe glass of water to drink and help prevent many waterborne diseases including HEV infection. It is heartening to know that Govt of India has started 'Clean India Campaign' in October 2014. An estimated US$ 10 billion will be spent on the mission over the next 5 years. Targets identified include cleaning the environment, construction of public and school latrines and implementing hygienic practices especially hand hygiene. By 2019, around 1.2 billion residents shall have access to toilets. With all this, I yet believe it shall take a long time for a common Indian to have access to portable clean water. It is painful to know that many regions hit by the epidemics lack basic healthcare facilities and need an emergency makeshift health delivery system for surveillance, health education and identifying high-risk patients for referral to tertiary healthcare centres. Mass chlorination of water resources and its use at domestic level is regularly being practised to control spread of disease. All what is done is equal to a drop in the ocean for what is needed to face and fight this dangerous python. All of us have eyes on the availability of a cheap, effective and safe HEV vaccine. Earlier it is made available is better than never.

Why large-scale epidemics occur on a periodic basis in such regions and what triggers an epidemic while there is constant pressure from faecally contaminated water supplies? Is it a phenomenon of reinfections in population with HEV antibodies, or loss of HEV antibodies over time in a substantial proportion of people weakening herd immunity and susceptibility to new epidemic, or is it an influenza-like phenomenon where new strains of HEV are introduced in the community causing repeat epidemics? Over the last 3 decades, we have repeatedly estimated IgG anti-HEV prevalence in our population following epidemics and second epidemics and defined a temporal pattern of seroprevalence in our community. IgG anti-HEV prevalence is around 4% reaching a plateau of around 10% in 3rd and 4th decades. Following an epidemic, around 20% population of all ages test seropositive to HEV. Subsequent to this, there is a gradual decline in seropositivity of IgG anti-HEV over the next 2 decades and poor sero-exposure in the new cohort population during the interepidemic period. Repeat outbreaks occur when overall seropositivity reaches around 4%, low in first 2 decades (new cohort) and around 10% in 3rd and 4th decades of life.[1,3,5] We believe gross faecal contamination is constantly present due to poor sanitation and improper sewage disposal system in such hyperendemic zones.[25]

HEV-related acute liver failure (ALF) in pregnancy is an explosive disease with rapid progression of symptoms: high occurrence of cerebral oedema, sepsis and disseminated intravascular coagulation.[12,22] Why should pregnant women with hepatitis E have such a devastating clinical course? We and several other groups have compared demographic, nutritional, and obstetric and biochemical features of mothers with ALF to those with nonfulminant disease and found no significant difference between the two groups. All these patients are infected with HEV-1 and viral load, and duration of viraemia has been similar in these two groups. Thus, there seems to be no obvious risk factor in host or agent which could enhance liver injury in pregnancy. A shift of the TH1-TH2 balance towards a shift to TH2 response in pregnant women with HEV infection but not in nonpregnant women with HEV infection has been documented and may point towards a primary immunologic cause of sever disease in pregnancy. However, as the mechanisms of liver cell injury in hepatitis E remain unknown, it is difficult to ascribe the severity of liver injury in these patients to this immune phenomenon. Also hormones of pregnancy especially estrogens and progesterone might impair cellular immunity by triggering adapter protein (ORF3) which could facilitate viral replication and lead to release of cytokines and liver cell apoptosis.[27]

Recently, we wanted to study a provocative hypothesis 'Could Severe fetal HEV infection be the possible cause of increased severity of HEV infection in the mother', which may represent another example of mirror syndrome.[28] First, we found a close relationship between severity of HEV infection in the mother and HEV infection in babies. Second, we and others found that mothers who delivered babies early on expectant basis survived and had rapid clinical recovery from ALF. This pointed to dangers of long gestational period after onset of coma. In addition, DIC was limited to mothers who delivered babies with ALF and not in those who delivered normal or babies with nonfulminant HEV infection. This led us to believe that foetuses with severe hepatitis caused by vertically transmitted HEV infection may be related to outcome of ALF in the mothers. This relationship may be akin to what happens in mirror syndrome in which mother develops generalized anasarca subsequent to foetal and/or placental oedema. The possible mechanism of increased severity of liver disease in the mother may be due to the production of toxic metabolites in the foetus with ALF. Such toxins can cross over to maternal blood and precipitate the onset of hepatic encephalopathy and possibly DIC in the mother with HEV infection. Such a mechanism has been established for the pathogenesis of acute fatty liver of pregnancy (AFLP) in which foetus is homozygous for long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and produces large amounts of toxic omega fatty acids, which cross over to the maternal blood. This hypothesis needs further studies.

In 2004, we were the first to report on transfusion-associated hepatitis E from Kashmir, India.[29] Thirteen of the 145 multiply transfused subjects had HEV infection as detected by IgM anti-HEV and HEV RNA as against 2 of the 250 control subjects. In a prospective study, we traced 3 transfusion-associated HEV infections to 4 HEV RNA-positive donors. All infections were caused by HEV-1. Around same time, a Japanese patient on transfusion-associated HEV infection with complete donor–patient sequence identity was reported.[30] Several cases of transfusion-associated HEV infection have come to light over the years.[31] Data from England showed 18 (42%) of the 42 HEV-positive transfusion recipients developed HEV-3 infection. Three cleared infection with ribavirin. Ten developed prolonged or persistent infection.[32]

Several groups including ours from India had shown that a significant percentage of healthy donors have short-lasting circulating HEV RNA of HEV-1 and HEV-positive donation rate is substantially high reaching 1:27 in hyperendemic zones.[29,33] Now, data on HEV RNA in healthy blood donors are available from several countries ( Table 4 ;[33–36]). HEV RNA was uniformly detected in variable proportion in all countries. It varied from 0.01 to 0.14%. Accordingly, HEV RNA-positive donation rate varied from 1:672 as in Germany to 1:8416 as in Austria. Two observations that infectious dose required for HEV infection was as low as to the limit of detection by RT-PCR and duration of viraemia can extend up to 45 days are of concern. How do these data explode into load of HEV infections in these countries? Based on HEV infection rate of 0.04% and duration of viraemia of 8 weeks, around 80 000–100 000 HEV infections are likely to have occurred in England during the year 2013. A total of 7.4 million blood products were administered in Germany in 2013, and between 1600 and 5900 HEV RNA-positive blood donations could be occurring in Germany per year. In the Netherlands, one HEV-positive donation per day has been reported, implying that transmission by transfusion is a likely event in this country. HEV infection in pregnant women, patients with underlying liver disease, solid organ transplant patients and immunosuppressed and those with haematological neoplasm can run a severe course and/or lead to rapidly progressive chronic liver disease. Such patients often need blood or blood products. Based on magnitude of problem and possible severe consequences especially in high-risk groups, screening for HEV RNA is an urgent need especially in countries with high HEV prevalence.[37]

It is now well accepted that HEV-3 infection can induce chronic hepatitis, and cirrhosis in solid organ transplant (SOT) patients, in patients with HIV positive and in those with haematological diseases.[38,39] Diagnosis of chronic hepatitis is acceptable if HEV RNA persists for 3 months or longer. The prevalence of HEV RNA in SOT varies from 0.9 to 3.5% in Europe.[40] Most of the chronic HEV infections in SOT are asymptomatic. Others have constitutional symptoms and modest enzyme elevation. Extrahepatic disease can occur. Liver fibrosis progresses rapidly in a subgroup of patients ending up in cirrhosis in 2–3 years. One large follow-up study of 85 SOT patients with HEV infection showed that 29 cleared the virus, 56 had chronic HEV infection and 9 patients ended up to develop cirrhosis. Predictors for the development of chronic hepatitis in SOT patients include the use of tacrolimus as an immunosuppressant and low platelet in SOT patients and low CD4 in HIV-infected patients.[41]

While industrialized countries have controlled spread of hepatitis E by ensuring clean portable water, HEV-3 and HEV-4 spread through ingenious foodborne transmission.[42] Domestic pigs, wild boar and sika deer show cross-transmission of hepatitis E, and consuming raw or undercooked meat or liver (a luxury in such countries) can cause outbreaks of hepatitis E. More serious is the practice of visiting supermarkets and buying raw liver or Corsican Figatelli sausage and eating it undercooked or raw. Significant percentages of such livers and sausages contain live HEV. Sewage from pig in such countries can flow to waterways, and visiting sea beaches or consuming infected molluscs has led to outbreaks of HEV.

Chronic HEV infection in SOT patients is a substantial clinical problem in many European countries and needs to be controlled.[43] Apart from advice against intake of possible infected swine meat, liver or sausage, antiviral therapy for HEV RNA patients prior to transplant has been recommended for fear of chronic HEV infection. Some have recommended expanding explant testing for HEV RNA to prevent explant-related HEV infection. As SOT patients are at high risk for contracting HEV in HEV-3 endemic zones, HEV vaccine in such patients is an option in future if vaccine is found safe and efficacious. Treatment algorithm for HEV RNA-positive patients in SOT patients is being developed. It is advisable to reduce immunosuppression which helps to clear the virus in a large proportion of patients. If HEV RNA persists for 3 months and beyond, ribavirin therapy 600 mg per day is advisable. Persistent HEV infection can be managed with pegylated IFN selectively in liver transplant patients. A subgroup of patients may have rapidly progressive liver failure and may be considered for liver transplant or retransplant.

The development of accurate diagnostic assays for the detection of serological markers of HEV infection remains challenging ( Table 5 ;[44]). The antigen structure of HEV protein has been characterized, and highly immunoreactive diagnostic antigens have been engineered and efficient diagnostic tests devised. However, many outstanding issues related to sensitivity and specificity of these assays in clinical and epidemiological settings remain to be resolved. Some of these assays have shown issues of genotype applicability and poor performance in immune disorders and are cross-reactive with other viral infections. There are two major factors that potentially affect the detection of anti-HEV in human sera samples. These include diagnostic properties of the antigen and, secondly, variable nature of the specific HEV-antibody responses. It is essential that assays should be developed and evaluated for analytical sensitivity against WHO reference reagent for hepatitis E and not against sera obtained from patients with recent infection. Broadly, 2 formats, namely 'indirect' ELISA and class capture ELISA, have been employed to develop these assays. In the latter, immobilized antibodies against mu chain of IgM to capture this class of antibodies are employed.

IgM anti-HEV is a marker of recent or current HEV infection.[45] Overall, >90% of patients infected with HEV have detectable IgM anti-HEV in the first 2 weeks after the onset of illness and lasts for up to 5 months. IgM anti-HEV is recommended as the first-line diagnostic assay for acute infection in immunocompetent host. In immunocompromised host, additional HEV RNA testing may be needed due to impaired immune responses and poor performance of IgM assays for this population. Many in-house and commercial assays are available. A recent evaluation of performance of these assays has shown considerable variability in their sensitivity and specificity. A commercially available assay based on improved mu capture (based on mu chain of IgM) has been developed and marketed by Beijing Wantai Biological Pharmacy. An immunochromatographic method (rapid test) for the detection of IgM anti-HEV has been developed by Genelabs Diagnostics, Singapore (ASSURE™). The test has sensitivity of 93% and specificity of 99.7%. IgG anti-HEV assays have utility in seroprevalence studies and in diagnosis of acute HEV infection. The determination of the anti-HEV IgG concentration could be useful for determining the level of antibodies that reliably prevents infection after natural infection or vaccine administration in vaccine trials. A vaccine study suggests that an antibody concentration of 2.5 WHO units/ml was protective. HEV RNA detection in serum and stools can be applied to the diagnosis of acute HEV infection especially in patients with immune disorders and to document chronicity and evaluate antiviral response in chronic hepatitis E. HEV RNA testing may be extended for screening of blood donors in future. Viraemia during acute HEV infection is short-lasting and peaks during the incubation period and early symptomatic phase. There have been issues with some in-house assays, and recently, a WHO standard (genotype HEV-3a) has been established for HEV RNA detection and accurate quantification. Detection and quantification of HEV RNA in blood and other components are based on real-time PCR with primers targeting conserved regions between HEV genotypes. Recently, another nucleic acid amplification technique, the loop-mediated isothermal amplification (LAMP) assay, has been developed based on a set of six primers that recognize eight distinct regions of the target sequence. This is a one-step, single-tube isothermal amplification of HEV RNA. The assay is quicker, needs no special equipment and is suitable for resource limited areas.

When expressed in insect cells by baculovirus expression system, full-length and truncated ORF2 genes can generate a number of capsid proteins with various molecular weights (Fig. 6;[46]). However, only two HEV capsid proteins self-assemble into virus-like particles (VLPs), namely VLP/T = 1 (a 23-nm empty particle) and VLP/T3 (a 42-nm particle with a 2-kb RNA). When recombinant ORF2 was expressed in E. coli, three proteins of HEV capsid protein are expressed. These occur as homodimers which model dominant antigenic determinants of HEV. p239 has the capacity to form a 23-nm empty particle. VLPs expressed in Baculovirus and E coli display similar properties to native particles in terms of antigenity and surface structure and have been exploited to study a three-dimensional structure of the native virus. Also 2 of these VLPs have markedly enhancing immunogenic properties and form the basic units for 2 HEV vaccines, which have completed phase III trials. p239 vaccine is commercially available as Hecolin in Chinese market.

Figure 6.

Hepatitis E virus ORF2 proteins expressed in Baculovirus expression system and Escherichia coli. For details, see details about hepatitis E ORF2 expression.

HEV 239 is a particulate vaccine expressed in E. coli, consisting of 368–606 aa of ORF2 from HEV-1 Chinese strain. HEV 239 has 2 epitopes between 533 and 552 aa and induces a vigorous T cell-dependent antibody response. HEV 239 has successfully completed phase II and phase III trials in China and is commercially available in China (Hecolin) in 30-μg doses to be administered at 0-, 1- and 6-month regimens.[47] At 4.5 years, vaccine efficacy was 86.8%; 87% of vaccine group maintained antibodies and 9% control group developed antibodies.[48] HEV 239 gave cross-protective efficacy as HEV-4 is the predominant genotype in the region of study. Despite several limitations as of today on global use, the successful phase III trial of HEV 239 vaccine is a major leap forward in the path to control hepatitis E.

Hepatitis E vaccine is available at present only in Chinese market. To make it available, there are several important issues to be sorted out for its global launch. First, available safety data on this vaccine from phase 1, II and III clinical trials in healthy subjects' age group 16 to 65 years are reassuring. However, there are no safety data in paediatric and elderly, persons with underlying diseases namely chronic liver diseases, solid organ transplant, HIV-infected and other immunosuppressed conditions. Safety of p239 vaccine given concomitantly with other vaccines also needs to be studied. There are limited data on safety of this vaccine with regard to maternal and foetal outcomes following administration during pregnancy, and these need to be extended.[49] Postmarketing phase IV study can be conducted once vaccine is available globally. The cost-effectiveness of the vaccine programme to control massive epidemics needs to be measured. A preliminary study using Uganda epidemic data found the cost of US$ 875 per disability-adjusted life years, although this estimate is sensitive to changes in the assumptions used. HEV 239 vaccine was found efficacious in a context of lesser endemicity (background HEV attack rate 0.03%) and virulence, and it is important to determine whether this vaccine shall maintain efficacy in Indian subcontinent where the disease is hyperendemic, with high background attack rate of around ~7.36% and highly virulent pathogen. Also vaccine efficacy needs to be determined in the setting of indigenous HEV-3 disease in industrialized countries.[50]

Let us summarize what are our challenges in control and cure of this global human pathogen. We need better and more accurate diagnostic tools which should be available and extendable to regions of the world with primitive healthcare facilities and even those with political unstable and disturbed regions. We need to get a better understanding of many perplexing issues about the epidemiology of hepatitis E both in resource poor countries and in industrialized world. We need to develop treatment strategies for HEV infection and management plans for those with severe infections especially liver failure. Finally, we need to develop and implement effective preventive strategies, especially HEV vaccine.[1]

Hepatitis E story started 35 years back with my extreme belief that epidemics of jaundice and resultant mortality in pregnant women in our community had a hidden saga and to uncover it needed hard work, persistence, belief in oneself and honesty of purpose. It needed courage to stand on feet to fight the sceptics and listen to the wise. It meant spending days in snowbound roads of those villages and feeling the pain and anguish of the sufferers. I needed nights to spend awake with pen and paper to write what one believed is true and to uncover. While this journey was treacherous, hard, full of failures and some successes, the end has been pleasant and rewarding. For discoveries do not come without price to be paid.