Hepatitis E virus (HEV) is a positive-sense, single-stranded RNA virus that poses a significant public health risk, yet its study is hindered by the complexity of conventional RNA-based reverse genetics systems. These systems require multiple steps, including genome cloning, in vitro transcription, and capping, making them labor-intensive and susceptible to RNA degradation. In this study, we developed a single-step, plasmid-based HEV expression system that enabled direct intracellular transcription of the full-length HEV genome under a cytomegalovirus immediate-early (CMV-IE) promoter. The viral genome was flanked by hammerhead (HH) and hepatitis delta virus (HDV) ribozymes to ensure precise self-cleavage and the generation of authentic 5' and 3' termini. This system successfully supported HEV genome replication, viral protein expression, and progeny virion production at levels comparable to those obtained using in vitro-transcribed, capped HEV RNA. Additionally, a genetic marker introduced into the plasmid construct was stably retained in progeny virions, demonstrating the feasibility of targeted genetic modifications. However, plasmid-derived HEV exhibited delayed replication kinetics, likely due to the absence of an immediate 5' cap. Attempts to enhance capping efficiency through co-expression of the vaccinia virus capping enzyme failed to improve HEV replication, suggesting that alternative strategies, such as optimizing the promoter design for capping, may be required. This plasmid-based HEV reverse genetics system simplifies the study of HEV replication and pathogenesis and provides a versatile platform for the genetic engineering of the HEV genome.

Viral hepatitis E represents an important global health problem caused by the hepatitis E virus (HEV). Cases of HEV infection are increasingly associated with food-borne transmissions after the consumption of raw or undercooked food products from infected animals in high-income regions. Although most cases of infection are asymptomatic, severe courses of infection have been reported in specific groups of people, predominantly among pregnant women and immunocompromised patients. The viral nucleic acid of HEV is increasingly being reported in food-producing animals and different products of an animal origin. Even though the incubation period for HEV infection is long, several direct epidemiological links between human cases and the consumption of HEV-contaminated meat and meat products have been described. In this article, we review the current knowledge on human HEV infections, HEV in different food-producing animals and products of an animal origin, as well as the accumulation and resistance to HEV in farm and slaughterhouse environments. We also provide preventive measures to help eliminate HEV from animals, the human population, and the environment.

Hepatitis E virus (HEV) poses a significant risk to human health. In Europe, the majority of HEV infection are caused by the zoonotic genotype 3 (HEV-3), which can cause chronic hepatitis E in immunocompromised patients and those with pre-existing liver disease, and may eventually develop into fatal liver cirrhosis. In this study, we examined the effectiveness of a monoclonal antibody (MAb) treatment strategy using a well established HEV-3 pig model with intravenous infection. For this purpose, nine MAbs raised against the viral capsid protein were generated and the neutralizing activities were compared using in vitro assays. The antibody with the highest neutralizing activity, MAb 5F6A1, was selected for an in vivo study in pigs infected with HEV-3. Following the initial infection of pigs with HEV-3, MAb 5F6A1 was administered intravenously one and seven days post-infection. The results suggest MAb 5F6A1 significantly reduced viremia and virus shedding in pigs infected with HEV-3. This study provides significant insight into the dynamics of HEV infection in pigs and highlights the efficacy of MAb based therapy as an option for treating HEV in porcine hosts and, potentially, humans.

Hepatitis E virus (HEV) is one of the leading causes of acute hepatitis, with immunosuppressed individuals, such as oncology patients, being particularly vulnerable to chronic infections that may progress to liver disease or fatal outcomes. Assay variability complicates HEV prevalence assessment in at-risk groups. This study aimed to compare the reliability and concordance of three HEV antibody assays-Wantai, Euroimmun, and Elecsys®-in immunosuppressed oncology patients.

In this prospective pilot study, serum samples were obtained from oncology patients between September 2020 and October 2021. Samples were collected both at baseline (treatment-naive) and during ongoing treatment. A healthy control group was retrospectively included for comparative analysis. Anti-HEV IgM and IgG antibodies were tested in all samples using enzyme-linked immunosorbent assays (Wantai, Euroimmun) and an electrochemiluminescence immunoassay (Elecsys®). Demographic and clinical data, along with information on HEV risk factors, were extracted from medical records and patient questionnaires.

HEV IgM prevalence ranged from 0% (Wantai) to 6% (Elecsys®), while IgG prevalence was 12% (Euroimmun), 38% (Wantai), and 53% (Elecsys®). Concordance was poor, with Cohen's Kappa values indicating slight to moderate agreement (κ = 0.000-0.553). Patients with hematological malignancies exhibited the highest IgG seroprevalence. Risk factor analysis revealed the highest association between HEV exposure and the consumption of undercooked pork or crop-based agriculture.

Significant variability among HEV serological assays highlights the challenges of reliable HEV diagnostics in immunosuppressed oncology patients. Assay selection and improved testing strategies are critical for this high-risk group.

Hepatitis E virus (HEV) is endemic in China, with swine as the most common reservoir. It poses a zoonotic public health risk to swine workers. This study evaluated the cost-effectiveness of hepatitis E vaccination for this high-risk group in China. A decision tree-Markov model was utilized to evaluate the cost-effectiveness of two hepatitis E vaccination strategies, without or following screening, for swine workers aged 16-60 in China from societal perspectives, compared to no vaccination. We calculated HEV-related cases and deaths averted, quality-adjusted life years (QALYs) gained, and incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay (WTP) threshold of GDP per capita. A sensitivity analysis was conducted. Additionally, we stimulated the scenarios of fully receiving 3-dose schedule, partially receiving 3-dose schedule, and fully receiving 2-dose schedule. Both hepatitis E vaccination strategies significantly reduced HEV-related cases and deaths compared to no vaccination. ICERs were estimated to be USD 11,428.16 and 9830.71/QALY averted for vaccination without and following screening, respectively, both lower than GDP per capita (USD 12,325.24, 2023). Furthermore, one-way sensitivity analysis identified the discount rate, utility in asymptomatic cases, and probability of symptomatic infection as crucial factors affecting ICER. Probabilistic sensitivity analysis (PSA) showed a 47.5% cost-effectiveness probability for hepatitis E vaccination following screening, compared to 52.5% for no vaccination. Notably, vaccination following screening was cost-ineffective after age 40 and at a price of USD 138.0/dose. Additionally, fully receiving 2-dose and partially 3-dose schedules were cost-effective, regardless of hepatitis E vaccination without or following screening strategies, while fully receiving 3-dose schedule was cost-ineffective with the vaccination without screening strategy. Hepatitis E vaccination following screening would be optimal for swine workers in China. Vaccination starting at an earlier age and lower vaccine prices can improve the cost-effectiveness. Additionally, 2-dose schedule may be recommended during a hepatitis E outbreak to achieve cost-effectiveness.

Hepatitis E virus (HEV) infection is a frequent cause of acute viral hepatitis. Immunocompromised patients, especially those under anti-CD20 regimens, are prone to chronic or treatment-resistant courses of hepatitis E. We report a case of chronic HEV infection in a 36-year-old man with a history of thrombotic thrombocytopenic purpura treated with rituximab 6 months ago, who presented with new-onset painless jaundice and malaise. Laboratory tests and imaging revealed signs of inflammation and hepatic dysfunction. Due to initial suspicion of autoimmune hepatitis, corticosteroid therapy was started. However, liver biopsy and positive HEV RNA value redefined the diagnosis. Serology tests revealed initially acute infection, which later progressed to chronic hepatitis E infection. Treatment with ribavirin, along with supportive care, achieved significant clinical and laboratory improvement, resolving jaundice, restoring normal transaminase and suppressing HEV RNA values. Further review of the literature highlights the impact of immunosuppression caused by anti-CD20 therapies on HEV infection, as well as the challenges in both treatment and achieving sustained virus clearance in such patients. Moreover, this report underlines the importance of HEV screening in patients with hepatitis who have undergone anti-CD20 therapies, shedding light on a situation that is not well described in the literature and should not be overlooked, even in developed countries.

The hepatitis E virus (HEV) is an emerging infectious disease with zoonotic potential, causing acute hepatitis in humans. Infections in healthy individuals are often acute, self-limiting and asymptomatic, thus leading to the underdiagnosis of HEV infections. Asymptomatic HEV infections pose a problem for blood transfusion safety by increasing the risk for transfusion-transmitted HEV infections. Here, we describe the journey from determining the HEV seroprevalence among blood donors to the implementation of routine HEV RNA testing of all blood products in Switzerland in 2018 and summarise the HEV cases detected since. In total, 290 HEV-positive blood donations were detected by mini-pool nucleic acid testing (NAT) in Switzerland in the period of October 2018-December 2023, equal to an incidence of 20.7 per 100,000 donations. Thanks to the implemented scheme, no transfusion-transmitted infections occurred in this period. Furthermore, blood donation monitoring has proven to be an effective means of detecting HEV outbreaks in the general population. HEV cases in Swiss blood donors are caused by two major genotypes, the Swiss-endemic subtypes 3h3 and 3c. Interestingly, 11 HEV cases (5%) were of genotype 3ra, a variant found in wild and farmed rabbits. Our results indicate that mini-pool NAT is an efficient method to reduce the risk of transfusion-transmitted HEV infections.

Acute hepatitis E was considered rare until reports emerged affirming the existence of hepatitis E virus (HEV) genotypes 3 and 4 infections in Japan in the early 2000s. Extensive studies by Japanese researchers have highlighted the pivotal role of pigs and wild animals, such as wild boars and deer, as reservoirs for HEV, linking them to zoonotic infections in Japan. Currently, when hepatitis occurs subsequent to the consumption of undercooked or grilled pork, wild boar meat, or offal (including pig liver and intestines), HEV infection should be considered. Following the approval of anti-HEV immunoglobulin A antibody as a diagnostic tool for hepatitis E by Japan's Health Insurance System in 2011, the annual number of diagnosed cases of HEV infection has surged. Notably, the occurrence of post-transfusion hepatitis E promoted nationwide screening of blood products for HEV using nucleic acid amplification tests since 2020. Furthermore, chronic hepatitis E has been observed in immunosuppressed individuals. Considering the significance of hepatitis E, heightened preventive measures are essential. The Japan Agency for Medical Research and Development Hepatitis A and E viruses (HAV and HEV) Study Group, which includes special virologists and hepatologists, held a virtual meeting on February 17, 2024. Discussions encompassed pathogenesis, transmission routes, diagnosis, complications, severity factors, and ongoing and prospective vaccination or treatments for hepatitis E. Rigorous assessment of referenced studies culminated in the formulation of recommendations, which are detailed within this review. This comprehensive review presents recent advancements in HEV research and Japanese clinical practice guidelines for HEV infection.

The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.

BackgroundAwareness of transfusion-transmitted hepatitis E raised in recent years led to the mandatory testing of blood donations in some European countries for hepatitis E virus (HEV) RNA. However, little is known about the epidemiology of HEV infections.AimTo and describe and analyse the epidemiology of HEV infections in blood donors in Germany.MethodsData from routine testing of therapeutic blood products donated between January 2015 and December 2022 at the Uni.Blutspendedienst OWL were analysed at the Institute of Laboratory and Transfusion Medicine, Heart and Diabetes Centre North Rhine-Westphalia. A total of 731,630 allogenic blood donations from 119,610 individual blood donors were tested for HEV RNA in minipools of 96 samples. The HEV RNA-positive donations were analysed for the presence of anti-HEV IgM and IgG. The HEV strains were genotyped and various clinical liver-specific parameters were determined.ResultsA total of 497 HEV-positive blood donations were identified, resulting in a yearly incidence of 1:1,474, from which 78.4% of the donations were RNA-only positive. Increased alanine aminotransferase activity was determined in 26.6% of HEV RNA-positive donors and was associated with the detection of IgG antibodies (1.2% anti-HEV IgM-positive, 11.9% anti-HEV IgM- and IgG-positive and 8.5% anti-HEV IgG-positive). An average incidence of 0.084-0.083% HEV RNA-positive donations in June and July in all years was observed, and a higher proportion of HEV RNA-positive men compared with women. All isolated HEV sequences corresponded to genotype 3.ConclusionOur results underline the necessity of HEV RNA screening in blood donations.

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. Up to now, no approved treatment nor a globally licensed vaccine is available. Several recombinant HEV vaccines have been developed to protect against HEV infection in humans, including the commercially available Hecolin vaccine, which are mainly based on HEV genotype 1. However, the efficacy of these vaccines against other HEV genotypes, especially genotype 3 is unknown. In this study, we evaluated the protective efficacy of Hecolin® and a novel genotype 3-based vaccine p239(gt3) against HEV-3 in a pig infection model. Pigs were divided into three groups: one group was vaccinated with Hecolin®, the second group was vaccinated with p239(gt3), and the control group received no vaccine. All pigs were subsequently challenged with HEV genotype 3 to assess the effectiveness of the vaccines. Although all immunised animals developed a high titer of neutralizing antibodies, the results showed that both vaccine applications could not provide complete protection against HEV (gt3) infection: Two out of four animals of the Hecolin® group displayed even virus shedding, and viral RNA could be detected in bile and/or liver of three out of four animals in both vaccination groups. Only one out of four animals in each group was fully protected. Neither Hecolin® nor the novel p239(gt3) vaccine provided sufficient protection against genotype 3 infection. While Hecolin® only partial protected pigs from HEV shedding, the novel p239(gt3) vaccine was at least able to prevent infected pigs from virus shedding. The results highlight the need for further development of HEV vaccines that exhibit broad protection against multiple HEV genotypes and the use of appropriate animal infection models.

Hepatitis E virus (HEV) genotype 3 is the major cause of acute viral hepatitis in several European countries. It is acquired mainly by ingesting contaminated pork, but has also been reported to be transmitted through blood transfusion. Although most HEV infections, including those via blood products, are usually self-limiting, they may become chronic in immunocompromised persons. It is thus essential to identify HEV-infected blood donations to prevent transmission to vulnerable recipients.

Prior to the decision whether to introduce HEV RNA screening for all Swiss blood donations, a 2-year nationwide prevalence study was conducted.

All blood donations were screened in pools of 12-24 samples at five regional blood donation services, and HEV RNA-positive pools were subsequently resolved to the individual donation index donation (X). The viral load, HEV IgG and IgM serology, and HEV genotype were determined. Follow-up investigations were conducted on future control donations (X + 1) and previous archived donations of the donor (X - 1) where available.

Between October 2018 and September 2020, 541,349 blood donations were screened and 125 confirmed positive donations were identified (prevalence 1:4331 donations). At the time of blood donation, the HEV RNA-positive individuals were symptom-free. The median viral load was 554 IU/mL (range: 2.01-2,500,000 IU/mL). Men (88; 70%) were more frequently infected than women (37; 30%), as compared with the sex distribution in the Swiss donor population (57% male/43% female, p < 0.01). Of the 106 genotyped cases (85%), all belonged to genotype 3. Two HEV sub-genotypes predominated; 3h3 (formerly 3s) and 3c. The remaining sub-genotypes are all known to circulate in Europe. Five 3ra genotypes were identified, this being a variant associated with rabbits. In total, 85 (68%) X donations were negative for HEV IgM and IgG. The remaining 40 (32%) were positive for HEV IgG and/or IgM, and consistent with an active infection. We found no markers of previous HEV in 87 of the 89 available and analyzed archive samples (X - 1). Two donors were HEV IgG-positive in the X - 1 donation suggesting insufficient immunity to prevent HEV reinfection. Time of collection of the 90 (72%) analyzed X + 1 donations varied between 2.9 and 101.9 weeks (median of 35 weeks) after X donation. As expected, none of those tested were positive for HEV RNA. Most donors (89; 99%) were positive for anti-HEV lgG/lgM (i.e., seroconversion). HEV lgM-positivity (23; 26%) indicates an often-long persistence of lgM antibodies post-HEV infection.

The data collected during the first year of the study provided the basis for the decision to establish mandatory HEV RNA universal screening of all Swiss blood donations in minipools, a vital step in providing safer blood for all recipients, especially those who are immunosuppressed.

Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis worldwide. HEV associated pregnancy mortality has been reported as up to 30% in humans. Recent findings suggest HEV may elicit effects directly in the reproductive system with HEV protein found in the testis, viral RNA in semen, and viral replication occurring in placental cell types. Using a natural host model for HEV infection, pigs, we demonstrate infectious HEV within the mature spermatozoa and altered sperm viability from HEV infected pigs. HEV isolated from sperm remained infectious suggesting a potential transmission route via sexual partners. Our findings suggest that HEV should be explored as a possible sexually transmittable disease. Our findings propose that infection routes outside of oral and intravenous infection need to be considered for their potential to contribute to higher mortality in HEV infections when pregnancy is involved and in HEV disease in general.

Hepatitis E virus (HEV) is the main cause of acute hepatitis in humans worldwide and is responsible for a large number of outbreaks especially in Africa. Human infections are mainly caused by genotypes 1 and 2 of the genus Paslahepevirus, which are exclusively associated with humans. In contrast, viruses of genotypes 3 and 4 are zoonotic and have their main reservoir in domestic and wild pigs, from which they can be transmitted to humans primarily through the consumption of meat products. Both genotypes 3 and 4 are widespread in Europe, Asia, and North America and lead to sporadic cases of hepatitis E. However, there is little information available on the prevalence of these genotypes and possible transmission routes from animal reservoirs to humans in African countries. We therefore analysed 1086 pig sera collected in 2016/2017 in four districts in Sierra Leone for antibodies against HEV using a newly designed in-house ELISA. In addition, the samples were also analysed for HEV RNA by quantitative real-time RT-PCR. The overall seroprevalence in Sierra Leone was low with only 44 positive sera and a prevalence of 4.0%. Two serum pools were RT-PCR-positive and recovered partial sequences clustered into the genotype 3 (HEV-3) of the order Paslahepevirus, species Paslahepevirus balayani. The results are the first evidence of HEV-3 infection in pigs from Sierra Leone and demonstrate a low circulation of the virus in these animals to date. Further studies should include an examination of humans, especially those with close contact with pigs and porcine products, as well as environmental sampling to evaluate public health effects within the framework of a One Health approach.

While the sexual transmissibility of HAV in MSM has been extensively described, the potential for sexual transmission of HEV has not been definitively established. Although HEV has been detected in the ejaculate of chronically infected men, studies among MSM PrEP users in France did not observe an elevated anti-HEV seroprevalence as an indicator of increased exposure risk by sexual intercourse.

A total of 111 unselected PrEP users and 111 age- and sex-matched blood donors were tested for anti-HEV IgG, IgM and HEV (PCR). Of the participants 79/111 (71 %) responded to a questionnaire covering topics as sexual preferences, previous sexually transmitted diseases, profession, food consumption, and pet ownership.

The anti-HEV IgG seroprevalence in PrEP users (22 %) did not differ significantly from the rate in controls (17 %). While one PrEP user and three controls tested positive for anti-HEV IgM, all PrEP users and controls tested PCR negative.

In immunocompetent individuals with frequent changes of sexual partners, the epidemiology of Hepatitis E Virus does not significantly involve the sexual transmission route.

Hepatitis E virus (HEV) is a small non-enveloped virus that is transmitted via the fecal-oral route. It is a highly common cause of acute hepatitis, particularly in low to middle income regions of Asia, Africa, and Central America. Most cases are self-limited, and symptomatic patients usually present with acute icteric hepatitis. A subset of patients including pregnant women, older men, those with pre-existing liver disease and immunocompromised patients however, may develop severe disease and hepatic failure. Immunocompromised patients are also at risk for chronic infection, and their immunosuppression should be decreased in order to facilitate viral clearance. HEV can also present with a variety of extra-intestinal manifestations including neurological, renal, hematological, and pancreatic derangements. The gold standard of diagnosis is HEV ribonucleic acid detection via nucleic acid amplification testing. Currently, there are no approved treatments for Hepatitis E, though ribavirin is the most commonly used agent to reduce viral load. Studies assessing the safety and efficacy of other antiviral agents for HEV are currently underway. HEV vaccination has been approved in China, and is currently being investigated in other regions as well. This review article aims to discuss the epidemiology, pathogenesis, presentation, diagnosis, complications, and treatment of Hepatitis E infection.

Hepatitis E can potentially progress to HEV-related acute liver failure (HEV-ALF). East and South Asia bear a substantial burden of HEV infection, with Bangladesh, China, and India facing the most severe threat in this region. Therefore, we conducted a systematic review and meta-analysis to evaluate the burden of HEV-ALF in these three high-risk countries.

A systematic literature search was performed utilizing PubMed, the Cochrane Library, Medline, Embase, and Web of Science databases. Studies in English or Chinese that reported data on the burden of HEV-ALF in Bangladesh, China and India were included. Outcomes were pooled with meta-analysis utilizing R software. Estimates were calculated with random-effects models, and subgroup analysis and sensitivity analysis were conducted to address heterogeneity. Egger's test and Begg's test were performed to assess publication bias.

A total of 20 eligible studies were included in this study. The pooled HEV-attributable proportion of viral-related acute liver failure was estimated to be 40.0% (95% CI: 0.28-0.52), 30.0% (95% CI: 0.18-0.44), and 61.0% (95% CI: 0.49-0.72) among non-pregnant individuals in India, China and Bangladesh, while in Indian pregnant females, it was 71.0% (95% CI: 0.62-0.79). The combined prevalence among non-pregnant HEV-infected participants was 28.0% (95% CI: 0.20-0.37) and 10.0% (95% CI: 0.01-0.28) in India and China, and it was 34.0% (95% CI: 0.27-0.42) in Indian pregnant females with HEV infection. The overall mortality of HEV-ALF was estimated to be 32.0% (95% CI: 0.23-0.42) and 64.0% (95% CI: 0.50-0.77) among the non-pregnant and the pregnant participants in India, and it was 23.0% (95% CI: 0.14-0.34) in Chinese non-pregnant participants.

The burden of HEV-ALF in Bangladesh, China, and India is non-negligible despite geographic and population heterogeneity. The prevention of HEV infection and early recognition of HEV-ALF are of great significance, especially in high-risk countries and populations.

PROSPERO registration ID is CRD42022382101.

Hepatitis E virus (HEV) genotype 3 infections in Germany are mainly transmitted zoonotically through the consumption of swine meat. Furthermore, there is evidence that pets might come into contact with HEV, but the relevance of companion animals as possible sources of HEV transmission in Germany still needs to be defined. A monitoring study was therefore carried out on dogs, cats, and horses from Germany. In total 365 serum samples from pets (124 dogs, 119 cats, and 122 horses) were tested for HEV by PCR and for anti-HEV antibodies by a commercial ELISA. The HEV seroprevalence determined by the sero-assay varied significantly between dogs (10%), cats (6%), and horses (2%). Liver injury-related enzymes, alanine transaminase (ALT), and aspartate transaminase (AST) showed no differences between HEV-positive or negative animals. None of the pet serum samples tested positive for PCR. This serological study suggests that dogs and cats are significantly exposed to HEV in Germany, while horses are of minor relevance.

Primary membranous nephropathy (PMN) is a major cause of nephrotic syndrome in adults. Studies have shown that one-third of PMN cases undergo spontaneous remission, among which are some cases of infection-related complete remission. Herein, we report the case of a 57-year-old man who achieved complete remission of PMN shortly after the onset of acute hepatitis E infection. At the age of 55 years, the patient developed a nephrotic syndrome, and renal biopsy revealed membranous nephropathy, Ehrenreich-Churg stage 1. Treatment with prednisolone (PSL) reduced urinary protein from 7.8 g/gCre to approximately 1 g/gCre but did not lead to complete remission. However, 7 months after starting treatment, he developed an acute hepatitis E infection after consuming wild boar meat. Immediately after the onset of acute hepatitis E, the patient's urinary protein levels decreased to < 0.3 g/gCre. The PSL dose was subsequently reduced and discontinued after 2 years and 8 months, and complete remission was maintained thereafter. We considered that an increase in the number of regulatory T cells (Tregs) caused by acute hepatitis E infection was associated with PMN remission in this patient.

From 2014 to 2016, the number of hepatitis E virus (HEV) infections in southern Switzerland increased dramatically and suggested food as a potential infection reservoir. We evaluated the effects of food control measures introduced to limit HEV infections, assessing anti-HEV IgG and IgM rates in blood donors before and after the implementation of food control measures in 2017. From 2012 to 2013, we screened 1283, and from 2017 to 2019, we screened 1447 donors for IgG and IgM antibodies. No statistically significant differences were detected for IgG (32.8% from 2012 to 2013 vs. 31.1% from 2017 to 2019, p = 0.337) or IgM rates (2.0% from 2012 to 2013 vs. 2.8% from 2017 to 2019, p = 0.21). Rural provenience and age > 66 are predictors for positive IgG serology. A total of 5.9% of 303 donors included in both groups lost IgG positivity. We also determined nucleic acid testing (NAT) rates after the introduction of this test in 2018, comparing 49,345 donation results from southern Switzerland with those of 625,559 Swiss donor controls, and only 9 NAT-positive donors were found from 2018 to 2023. The high HEV seroprevalence in southern Switzerland may depend on different food supply chains in rural and urban areas. Local preventive measures probably have a limited impact on blood HEV risk; thus, continuous NAT testing is recommended.

Hepatitis E virus (HEV) is the major cause of acute viral hepatitis worldwide. This virus is responsible for waterborne outbreaks in low-income countries and zoonosis transmission in industrialized regions. Initially, considered self-limiting, HEV may also lead to chronic disease, and evidence supports that infection can be considered a systemic disease. In the late 1980s, Mexico became a hot spot in the study of HEV due to one of the first virus outbreaks in Latin America related to enterically transmitted viral non-A, non-B hepatitis. Viral stool particles recovered from Mexican viral hepatitis outbreaks represented the first identification of HEV genotype (Gt) 2 (Gt2) in the world. No new findings of HEV-Gt2 have been reported in the country, whereas this genotype has been found in countries on the African continent. Recent investigations in Mexico have identified other strains (HEV-Gt1 and -Gt3) and a high frequency of anti-HEV antibodies in animal and human populations. Herein, the potential reasons for the disappearance of HEV-Gt2 in Mexico and the advances in the study of HEV in the country are discussed along with challenges in studying this neglected pathogen. These pieces of information are expected to contribute to disease control in the entire Latin American region.

Viral hepatitis E, a major cause of acute viral hepatitis in adults, is a global public health problem. The zoonotic potential of the virus is currently accepted in developed countries. In developing countries, where transmission is mainly enteric, data on the animal reservoir are very limited. Our objective was to identify a possible risk of zoonotic transmission in our region (eastern Algeria). Four hundred and thirty four sera from blood donors were analysed by an-ti-HEV IgG antibodies detection using a commercial ELISA kit. Study participants were asked about demographics, contact with farm animals, pets, rats, and with live or shot game during a hunting activity. The anti-HEV IgG seroprevalence was 17.05%. Two risk factors were identified; rat contact with a seroprevalence rate at 51.2% (p < 1p.1000), OR = 6.736 [95% CI 3, 42-13.26] and game contact with a seroprevalence at 33% (p = 0.003), OR = 2.76 [95% CI 1.37-5.56]. In summary, zoonotic transmission is possible in our region. Rats and game should be investigated for a probable animal reservoir.

Few cases of transfusion-transmitted hepatitis E virus (HEV) have been published in Spain. Here, we describe a well-characterized lookback investigation of a transfusion-transmitted HEV case at the Community Centre for Blood and Tissues of Asturias (Spain).

A female patient with chronic myeloid leukemia underwent an allogeneic bone marrow transplant in March 2019 and showed alterations in liver function shortly afterwards. This patient received blood components from 30 different donors in the 3 months before the transplant. Frozen plasma samples from these donations were investigated for the presence of HEV-RNA. One frequent donor was identified as asymptomatic HEV RNA-positive at the time of his whole blood donation. The investigation revealed that this donor's plasma unit, originally intended for the fractionation industry, had a viral RNA concentration of 1.9 × 104 copies/mL. HEV RNA was detected initially in the index patient who received the red cell concentrate from this donor 25 days after the transfusion. HEV RNA isolated from both donor and recipient were identified as subtype 3f. The recipient of platelet concentrate (PC), treated with a riboflavin-based pathogen reduction technology (PRT) was not infected, being negative for the presence of HEV IgM, IgG, and HEV RNA before and after the transfusion.

This case study shows that HEV was transmitted through red cell transfusion to a recipient, while the patient who received riboflavin/UV light treated PC did not develop signs of infection. A causal relationship between PRT treatment of the PC and the non-transmission of HEV remains to be established.

Acute-on-chronic liver failure (ACLF) is a potentially reversible syndrome that develops in patients with cirrhosis or with underlying chronic liver disease (CLD) and is characterized by acute decompensation, organ failure, and high short-term mortality. Hepatitis A and hepatitis E are major causes of ACLF. Hepatitis B may also cause ACLF through a flare of hepatitis B, acute infection, or reactivation. Besides supportive care, nucleoside/nucleotide analog therapy should also be initiated in this setting. Nonhepatotropic viruses may rarely also cause ACLF with the severe acute respiratory syndrome coronavirus 2 virus recently being identified with poorer outcomes in those with underlying CLD.

Hepatitis E virus (HEV) is one of the leading causes of acute viral hepatitis. Transmission of HEV mainly occurs via the fecal-oral route (ingesting contaminated water or food) or by contact with infected animals and their raw meat products. Some animals, such as pigs, wild boars, sheep, goats, rabbits, camels, rats, etc., are natural reservoirs of HEV, which places people in close contact with them at increased risk of HEV disease. Although hepatitis E is a self-limiting infection, it could also lead to severe illness, particularly among pregnant women, or chronic infection in immunocompromised people. A growing number of studies point out that HEV can be classified as a re-emerging virus in developed countries. Preventative efforts are needed to reduce the incidence of acute and chronic hepatitis E in non-endemic and endemic countries. There is a recombinant HEV vaccine, but it is approved for use and commercially available only in China and Pakistan. However, further studies are needed to demonstrate the necessity of applying a preventive vaccine and to create conditions for reducing the spread of HEV. This review emphasizes the hepatitis E virus and its importance for public health in Europe, the methods of virus transmission and treatment, and summarizes the latest studies on HEV vaccine development.

Various foodborne viruses have been associated with human health during the last decade, causing gastroenteritis and a huge economic burden worldwide. Furthermore, the emergence of new variants of infectious viruses is growing continuously. Inactivation of foodborne viruses in the food industry is a formidable task because although viruses cannot grow in foods, they can survive in the food matrix during food processing and storage environments. Conventional inactivation methods pose various drawbacks, necessitating more effective and environmentally friendly techniques for controlling foodborne viruses during food production and processing. Various inactivation approaches for controlling foodborne viruses have been attempted in the food industry. However, some traditionally used techniques, such as disinfectant-based or heat treatment, are not always efficient. Nonthermal techniques are considered a new platform for effective and safe treatment to inactivate foodborne viruses. This review focuses on foodborne viruses commonly associated with human gastroenteritis, including newly emerged viruses, such as sapovirus and Aichi virus. It also investigates the use of chemical and nonthermal physical treatments as effective technologies to inactivate foodborne viruses.

Hepatitis E virus (HEV) infection in pregnant women causes adverse pregnancy outcomes, including maternal death, premature delivery, stillbirth, and fetal infection. However, the pathogenesis of maternal and fetal HEV infection is unclear.

Placenta and placental appendixes were collected from HEV-4 infected pregnant women to explore the vertical transmission of HEV from mothers to fetuses.

HEV-4 replicated in the placenta, placental membrane, and umbilical cord and was vertically transmitted from mothers to fetuses. HEV-4 placental infection resulted in serious histopathological damage, such as fibrosis and calcification, and severe inflammatory responses. Adverse maternal outcomes were observed in 38.5% of HEV-4 infected pregnant women. The distinct cytokine/chemokine expression patterns of HEV-infected pregnant women and nonpregnant women may contribute to the adverse pregnancy outcomes. Furthermore, the impaired maternal and fetal innate immune responses against HEV-4 facilitated viral replication during pregnancy.

HEV-4 replicates in the placenta and is vertically transmitted from mothers to fetuses, causing severe histopathological damage.

Hepatitis E virus (HEV)-triggered acute-on-chronic liver failure (ACLF) has unacceptably high short-term mortality. However, it is unclear whether the existing predictive scoring models are applicable to evaluate the prognosis of HEV-triggered ACLF.

We screened datasets of patients with HEV-triggered ACLF from a regional tertiary hospital for infectious diseases in Shanghai, China, between January 2011 and January 2021. Clinical and laboratory parameters were recorded and compared to determine a variety of short-term mortality risk factors, which were used to develop and validate a new prognostic scoring model.

Out of 4952 HEV-infected patients, 817 patients with underlying chronic liver disease were enrolled in this study. Among these, 371 patients with HEV-triggered ACLF were identified and allocated to the training set (n = 254) and test set (n = 117). The analysis revealed that hepatic encephalopathy (HE), ascites, triacylglycerol and apolipoprotein A (apoA) were associated with 90-day mortality (P < 0.05). Based on these significant indicators, we designed and calculated a new prognostic score = 0.632 × (ascites: no, 1 point; mild to moderate, 2 points; severe, 3 points) + 0.865 × (HE: no, 1 point; grade 1-2, 2 points; grade 3-4, 3 points) - 0.413 × triacylglycerol (mmol/L) - 2.171 × apoA (g/L). Compared to four well-known prognostic models (MELD score, CTP score, CLIF-C OFs and CLIF-C ACLFs), the new scoring model is more accurate, with the highest auROCs of 0.878 and 0.896, respectively, to predict 28- and 90-day transplantation-free survival from HEV-triggered ACLF. When our model was compared to COSSH ACLF IIs, there was no significant difference. The test data also demonstrated good concordance.

This study is one of the first to address the correlation between hepatitis E and serum lipids and provides a new simple and efficient prognostic scoring model for HEV-triggered ACLF.

According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are four main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route. Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans via undercooked meat. Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients. The majority of patients with HEV infection are asymptomatic and usually have spontaneous viral clearance without treatment. However, infection in immunocompromised individuals can lead to chronic HEV infection. Both acute and chronic HEV infections can have extrahepatic manifestations. No specific treatment is required for acute HEV infection, no treatment has been approved in chronic infection, and no HEV vaccine has been approved by the (United States) Food and Drug Administration. This review focuses on the molecular virology (HEV life cycle, genotypes, model systems, zoonosis), pathogenesis, clinical manifestation, and treatment of chronic HEV infection, especially in immunocompromised patients, to provide clinicians a better understanding of the global distribution of these infections and the significant effect they can have on immunocompromised patients.

Hepatitis E Virus (HEV) is a major cause of acute and chronic hepatitis. The severity of HEV infection increases manyfold in pregnant women and immunocompromised patients. Despite the extensive research on HEV in the last few decades, there is no widely available vaccine yet. In the current study, immunoinformatic analyses were applied to predict a multi-epitope vaccine candidate against HEV. From the ORF2 region, 41 conserved and immunogenic epitopes were prioritized. These epitopes were further analyzed for their probable antigenic and non-allergenic combinations with several linkers. The stability of the vaccine construct was confirmed by molecular dynamic simulations. The vaccine construct is potentially antigenic and docking analysis revealed stable interactions with TLR3. These results suggest that the proposed vaccine can efficiently stimulate both cellular and humoral immune responses. However, further studies are needed to determine the immunogenicity of the vaccine construct.

Autochthonous hepatitis E (HEV) cases have been increasingly recognized and reported in Europe, caused predominantly by the zoonotic HEV genotype 3. The clinical picture is highly variable, from asymptomatic to acute severe or prolonged hepatitis in immunocompromised patients. The main route of transmission to humans in Europe is the ingestion of undercooked pork meat. Transfusion-transmitted HEV infections have also been reported. The aim of the study was to determine the HEV epidemiology and risk in the Finnish blood donor population. A total of 23,137 samples from Finnish blood donors were screened for HEV RNA from individual samples and 1012 samples for HEV antibodies. Additionally, laboratory-confirmed hepatitis E cases in 2016-2022 were extracted from national surveillance data. The HEV RNA prevalence data was used to estimate the risk of transfusion transmission of HEV in the Finnish blood transfusion setting. Four HEV RNA-positive were found, resulting in 1:5784 (0.02%) RNA prevalence. All HEV RNA-positive samples were IgM-negative, and genotyped samples represented genotype HEV 3c. HEV IgG seroprevalence was 7.4%. From the HEV RNA rate found in this study and data on blood component usage in Finland in 2020, the risk estimate for a severe transfusion-transmitted HEV infection is 1:1,377,000 components or one in every 6-7 years. In conclusion, the results indicate that the risk of transfusion-transmitted HEV (HEV TTI) in Finland is low. However, continuous follow-up of the HEV epidemiology in relation to the transfusion risk landscape in Finland is necessary, as well as promoting awareness in the medical community of the small risk for HEV TTI, especially for immunocompromised patients.

Hepatitis E virus (HEV) is among the most common causes of acute viral hepatitis. It typically causes acute infection, but some cases of chronic infection have also been recorded. These cases were particularly seen in developed countries, in patients who were immunocompromised, organ transplant recipients, or those with underlying hematological malignancy. However, we encountered a case of hepatitis E presenting as a chronic liver disease in an immunocompetent patient from a developing country. Therefore, more underlying risk factors need to be studied, which may lead to such a rare presentation of hepatitis E.

The majority of Hepatitis E Virus (HEV)-related studies are carried out in adults whereas information about HEV seroprevalence, clinical disease manifestation, molecular epidemiology, and transmission patterns in children is limited. To estimate HEV seroprevalence among scholar children living in an urban setting and to analyze risk factors for an infection, we invited children aged 5-18 years from Bogotá (Colombia) for a cross-sectional survey. We collected self-reported data on demographics, social, clinical, and exposure variables in a structured interview. Venous blood samples were analyzed with two commercially available ELISAs for HEV-specific IgG antibodies. Among the 263 participants, we found three HEV IgG-reactive samples (1.1%) using both assays. We additionally characterized the samples for HEV IgM using a commercially available IgM ELISA and for HEV RNA. Here, we found one IgM-reactive sample, which was also reactive for IgG. In contrast, none of the IgM- and IgG-reactive sera samples showed detectable RNA levels indicating HEV exposure had not been recently. All participants reported access to drinking water and sanitary systems in their households and frequent hand washing routines (76-88%). Eighty percent of children reported no direct contact with pigs, but occasional pork consumption was common (90%). In contrast to the majority of studies performed in Colombian adults, we found a low unadjusted HEV seroprevalence of 1.1% (95% CI: 0.3-3.6%) for both HEV IgG ELISAs in our study population. While the majority of participants reported pork consumption, we speculate in the absence of viral RNA for genotyping in the affected individuals, that existing access to drinking water and sanitary systems within our study group contribute to the low HEV seroprevalence.

The factors influencing hepatitis E virus (HEV) circulation remain largely unexplored. We investigated HEV seroprevalence in humans and the prevalence of infection in farm pigs and rabbits in different regions of the Russian Federation, as well as the genetic diversity and population dynamics of the HEV. The anti-HEV IgG antibody detection rates in the general population increase significantly with age, from 1.5% in children and adolescents under 20 years old to 4.8% in adults aged between 20 and 59 years old to 16.7% in people aged 60 years and older. HEV seroprevalence varies between regions, with the highest rate observed in Belgorod Region (16.4% compared with the national average of 4.6%), which also has the country's highest pig population. When compared with the archival data, both increases and declines in HEV seroprevalence have been observed within the last 10 years, depending on the study region. Virus shedding has been detected in 19 out of the 21 pig farms surveyed. On one farm, the circulation of the same viral strain for five years was documented. All the human and animal strains belonged to the HEV-3 genotype, with its clade 2 sequences being predominant in pigs. The sequences are from patients, pigs, and sewage from pig farms clustered together, suggesting a zoonotic infection in humans and possible environmental contamination. The HEV-3 population size that was predicted using SkyGrid reconstruction demonstrated exponential growth in the 1970s-1990s, with a subsequent decline followed by a short rise around the year 2010, the pattern being similar to the dynamics of the pig population in the country. The HEV-3 reproduction number (Re) that was predicted using birth-death skyline analysis has fluctuated around 1 over the past 20 years in Russia but is 10 times higher in Belgorod Region. In conclusion, the HEV-3 circulation varies both geographically and temporally, even within a single country. The possible factors contributing to this variability are largely related to the circulation of the virus among farm pigs.

Hepatitis E virus (HEV) infection usually results in a self-limiting acute disease; however, in infected pregnant women, it is associated with increased mortality and fulminant hepatic failure. Estrogen is known to be elevated during pregnancy, and estrogen signaling via classical estrogen receptor-ERα is known to regulate hepatocyte function and host innate immune response, including the STAT3 pathway. In this study, we investigated whether the estrogen classical signaling pathway via ERαp66 has any effect on STAT3 activation during HEV replication and HEV-induced IFN response. We first demonstrated that Huh7-S10-3 liver cells expressed the nonfunctional estrogen receptor ERαp36 isoform and lack the functional ERαp66 isoform. We further showed persistent phosphorylated-STAT3 levels in genotype 3 human HEV (Kernow P6 strain) RNA-transfected cells at later time points. In Huh7-S10-3 cells, estrogen at first-to-third trimester concentration (7.3 to 73 nM) did not significantly affect HEV replication; however, blocking of STAT3 activation led to a decrease in the HEV ORF2 protein level. Our mechanistic study revealed that STAT3 differentially regulates SOCS3 and type-III interferon (IFN) levels during HEV replication and the presence of estrogen-ERαp66 signaling stabilizes SOCS3 levels in vitro. We also demonstrate that HEV infection in pregnant and nonpregnant rabbits led to a significant increase in IFN response as measured by increased levels of IFN-stimulated-gene-15 (ISG15) mRNA levels irrespective of pregnancy status. Collectively, the results indicate that estrogen signaling and STAT3 regulate SOCS3 and IFN responses in vitro during HEV replication. The results have important implications for understanding HEV replication and HEV-induced innate immune response in pregnant women. IMPORTANCE Hepatitis E is usually a self-resolving acute disease; however, in pregnant women, HEV infection is associated with high mortality and fulminant hepatic failure. During pregnancy, estrogen levels are elevated, and in the liver, the estrogen receptor ERα is predominant and estrogen signaling is known to regulate hepatocyte metabolism and leptin-induced STAT3 levels. Viruses can module host innate immune response via STAT3. Therefore, in this study, we investigated whether STAT3 and estrogen-classical signaling via the ERαp66 pathway modulate HEV replication and HEV-induced innate immune response. We demonstrated that estrogen signaling did not affect HEV replication in human liver cells, but blocking of STAT3 activation reduced HEV capsid protein levels in human liver cells. We also showed that inhibition of STAT3 activation reduced SOCS3 levels, while the presence of the estrogen-ERαp66 signaling pathway stabilized SOCS3 levels. The results from this study will aid our understanding of the mechanism of HEV pathogenesis and immune response during pregnancy.

In immunosuppressed patients, persistent HEV infection is common and may lead to cirrhosis and liver failure. HEV clearance depends on an effective virus-specific CD8+ T-cell response; however, the knowledge gap around HEV-specific CD8+ T-cell epitopes has hindered analysis of the mechanisms of T-cell failure in persistent infection.

We comprehensively studied HEV-specific CD8+ T-cell responses in 46 patients with self-limiting (n = 34) or chronic HEV infection (n = 12), by epitope-specific expansion, functional testing, ex vivo peptide HLA class I tetramer multi-parametric staining, and viral sequence analysis.

We identified 25 HEV-specific CD8+ T-cell epitopes restricted by 9 different HLA class I alleles. In self-limiting HEV infection, HEV-specific CD8+ T cells were vigorous, contracted after resolution of infection, and formed functional memory responses. In contrast, in chronic infection, the HEV-specific CD8+ T-cell response was diminished, declined over time, and displayed phenotypic features of exhaustion. However, improved proliferation of HEV-specific CD8+ T cells, increased interferon-γ production and evolution of a memory-like phenotype were observed upon reduction of immunosuppression and/or ribavirin treatment and were associated with viral clearance. In 1 patient, mutational viral escape in a targeted CD8+ T-cell epitope contributed to CD8+ T-cell failure.

Chronic HEV infection is associated with HEV-specific CD8+ T-cell exhaustion, indicating that T-cell exhaustion driven by persisting antigen recognition also occurs in severely immunosuppressed hosts. Functional reinvigoration of virus-specific T cells is at least partially possible when antigen is cleared. In a minority of patients, viral escape also contributes to HEV-specific CD8+ T-cell failure and thus needs to be considered in personalized immunotherapeutic approaches.

Hepatitis E virus (HEV) infection is usually cleared spontaneously (without treatment) in patients with fully functioning immune systems. In immunosuppressed patients, chronic HEV infection is common and can progress rapidly to cirrhosis and liver failure. Herein, we identified the presence of HEV-specific CD8+ T cells (a specific type of immune cell that can target HEV) in immunosuppressed patients, but we show that these cells do not function properly. This dysfunction appears to play a role in the development of chronic HEV infection in vulnerable patients.