The 2023 South Sudanese outbreak of Hepatitis E emphasizes ongoing circulation of genotype 1 in North, Central, and East Africa.

In April 2023, an outbreak of acute hepatitis was reported amongst internally displaced persons in the Nazareth community of South Sudan. IgM serology-based screening suggested the likely etiologic agent to be Hepatitis E virus (HEV). In this study, plasma specimens collected from anti-HEV IgM-positive cases were subjected to additional RT-qPCR testing and sequencing of extracted nucleic acids, resulting in the recovery of five full and eight partial HEV genomes. Maximum likelihood phylogenetic reconstruction confirmed the genomes belong to HEV genotype 1. Using distance-based methods, we show that genotype 1 is best split into three sub-genotypes instead of the previously proposed seven, and that these sub-genotypes are geographically restricted. The South Sudanese sequences confidently cluster within sub-genotype 1e, endemic to northeast, central, and east Africa. Bayesian Inference of phylogeny incorporating sampling dates shows that this new outbreak is not directly descended from other recent local outbreaks for which sequence data is available. However, the analysis suggests that sub-genotype 1e has been consistently and cryptically circulating locally for at least the past half century and that the known outbreaks are often not directly descended from one another. The ongoing presence of HEV, combined with poor sanitation and hygiene in the conflict-affected areas in the region, place vulnerable populations at risk for infection and its more serious effects, including progression to fulminant hepatitis.

Hepatitis E virus immunosuppressed animal models.

Hepatitis E virus (HEV) is an important emerging pathogen producing significant morbidity in immunosuppressed patients. HEV has been detrimental to solid organ transplant (SOT) patients, cancer patients, and HIV-positive patients, where chronic HEV infections occur. Blood-borne transfusions and multiple cases of chronic HEV infection in transplant patients have been reported in the past few decades, necessitating research on HEV pathogenesis using immunosuppressed animal models. Numerous animal species with unique naturally occurring HEV strains have been found, several of which have the potential to spread to humans and to serve as pathogenesis models. Host immunosuppression leads to viral persistence and chronic HEV infection allows for genetic adaptation to the human host creating new strains with worse disease outcomes. Procedures necessary for SOT often entail blood transfusions placing immunosuppressive patients into a "high risk group" for HEV infection. This scenario requires an appropriate immunosuppressive animal model to understand disease patterns in these patients. Hence, this article reviews the recent advances in the immunosuppressed animal models for chronic HEV infection with emphasis on pathogenesis, immune correlates, and the liver pathology associated with the chronic HEV infections.

Detection of Hepatitis E Virus (HEV) Among Ruminant Animals.

BACKGROUND: HEV is endemic in several Middle Eastern countries including Saudi Arabia, which hosts the annual pilgrimage for Muslims from around the world. One of the Hajj rituals is the sacrifice of animals, including camels, cows, goats, and sheep. HEV Zoonosis is established in swine and other suspected species, including deer, rabbits, dromedary, and Bactrian camels. HEV was identified in small, domesticized animals like goats, cows, sheep, and horses. We previously investigated HEV seroprevalence in Camels. This study aimed to evaluate HEV seroprevalence in other highly consumed ruminants in Saudi Arabia, namely cows, sheep, and goats. METHODS: Sera from cows (n = 47), goats (n = 56), and sheep (n = 67) were analyzed for the presence of HEV-IgG by using in-house developed ELISA assays. RESULTS: The highest seroprevalence was found in sheep (62.7%), followed by cows (38.3%), and then goats (14.3%), with a p-value of < 0.001. No other demographic characteristics of the animals were significantly correlated with the HEV seroprevalence. CONCLUSIONS: This study provides baseline data as the first study on the seroprevalence of HEV in ruminant animals in Saudi Arabia. The high seroprevalence found in sheep and cows must be further investigated for the potential zoonotic HEV transmission to humans. Further studies are needed to investigate the active viremia in these animal species through nucleic acid detection and sequencing to provide data on the circulating HEV genotypes among the targeted animal species. The detection of HEV in different animal products, such as milk, liver, and others, also remains an important study area to consider.

Serological and molecular survey of rat hepatitis E virus (Rocahepevirus ratti) in drug users.

ABSTRACTRat hepatitis E virus (ratHEV) is an emerging cause of acute hepatitis of zoonotic origin. Since seroprevalence studies are scarce, at-risk groups are almost unknown. Because blood-borne infections frequently occur in people with drug use, who are particularly vulnerable to infection due to lack of housing and homelessness, this population constitutes a priority in which ratHEV infection should be evaluated. Therefore, the aim of this study was to evaluate the ratHEV seroprevalence and RNA detection rate in drug users as a potential at-risk population. We designed a retrospective study involving individuals that attended drug rehabilitation centres. Exposure to ratHEV was assessed by specific antibody detection using ELISA and dot blot (DB) assay and the presence of active infection by ratHEV RNA detection using RT-qPCR. Three-hundred and forty-one individuals were included, the most of them being men (67.7%) with an average age of 45 years. A total of 17 individuals showed specific IgG antibodies against ratHEV (4.6%; 95% CI; 3.1%-7.9%). One case of active ratHEV infection was identified (0.3%; 95% CI: 0.1%-1.8%). This was a 57-year-old homeless woman with limited financial resources, who had active cocaine and heroin use via parenteral route. In conclusion, we identified a potential exposure to ratHEV among drug users. Targeted studies in drug users with proper control groups are necessary to evaluate high-risk populations and transmission routes more accurately.

The AP-1 adaptor complex is essential for intracellular trafficking of the ORF2 capsid protein and assembly of Hepatitis E virus.

Although the Hepatitis E virus (HEV) is an emerging global health burden, little is known about its interaction with the host cell. HEV genome encodes three proteins including the ORF2 capsid protein that is produced in different forms, the ORF2i protein which is the structural component of viral particles, and the ORF2g/c proteins which are massively secreted but are not associated with infectious material. We recently demonstrated that the endocytic recycling compartment (ERC) is hijacked by HEV to serve as a viral factory. However, host determinants involved in the subcellular shuttling of viral proteins to viral factories are unknown. Here, we demonstrate that the AP-1 adaptor complex plays a pivotal role in the targeting of ORF2i protein to viral factories. This complex belongs to the family of adaptor proteins that are involved in vesicular transport between the trans-Golgi network and early/recycling endosomes. An interplay between the AP-1 complex and viral protein(s) has been described for several viral lifecycles. In the present study, we demonstrated that the ORF2i protein colocalizes and interacts with the AP-1 adaptor complex in HEV-producing or infected cells. We showed that silencing or drug-inhibition of the AP-1 complex prevents ORF2i protein localization in viral factories and reduces viral production in hepatocytes. Modeling of the ORF2i/AP-1 complex also revealed that the S domain of ORF2i likely interacts with the σ1 subunit of AP-1 complex. Hence, our study identified for the first time a host factor involved in addressing HEV proteins (i.e. ORF2i protein) to viral factories.

Global temporal trends and projections of acute hepatitis E incidence among women of childbearing age: Age-period-cohort analysis 2021.

BACKGROUND & AIMS: Acute hepatitis E (AHE) poses a significant threat to global public health, particularly among women of childbearing age (WCBA), who are at heightened risk for severe pregnancy-related complications. This study aimed to delineate the temporal trends and project future incidence of AHE in WCBA, providing insights crucial for targeted prevention and control strategies. METHODS: Data on AHE incidence from the Global Health data 2021. The age-period-cohort (APC) model was applied to analyze trends across different age groups, periods, and birth cohorts, and the Bayesian APC model was utilized for forecasting future epidemiological trajectories. RESULTS: Globally, AHE incidence numbers among WCBA rose from 2,831,075 in 1992 to 3,420,786 in 2021, while the age-standardized incidence rate (ASIR) declined from 194.66 to 179.54 per 100,000 with a global net drift of -0.28%. However, high SDI regions showed a contrasting trend with a positive net drift of 0.02%. The age effect was consistent across SDI regions and globally, showing a decrease with advancing age, while unfavorable period and cohort effects were exhibited in high-SDI region. At the national level, locations exhibited varying trends of change. The BAPC model predicted a total of 3,759,384 AHE global cases in WCBA by 2030, with an expected mild increase in the ASIR. The outlook for the management and containment of AHE is grim in certain countries, including India. CONCLUSIONS: The study revealed a complex epidemiological landscape of AHE in WCBA, with increasing global incidence numbers juxtaposed against a declining ASIR. The AHE burden by 2030 remain severe among WCBA. Young WCBA and high SDI region merit particular attention. The findings underscore the need for region-specific strategies to curb the projected rise in AHE incidence and align with the 2030 WHO goals.

Understanding hepatitis E vaccination intention among women of childbearing-age: A theory-based cross-sectional study.

OBJECTIVES: The purpose of this study was to investigate the HEV vaccination intention, its determinants, and overall influence mechanisms among childbearing-age women. METHOD: The current study was cross-sectional and conducted online from June 25, 2023 to September 25, 2023 in Nanjing, China. Logistic regression models were constructed to identify the intention-associated background factors. Technology Acceptance Model (TAM) and Theory of Planned Behavior (TPB) were integrated and expanded as TAM-TPB model to further investigate the determinants and overall influence mechanism of HEV vaccination intention among this population using structural equation modeling. RESULTS: A total of 423 eligible participants were included in this study. High general HEV knowledge was independently associated with an increased intention to get HEV vaccination (OR = 1.97, 95 % CI: 1.11-3.58, P = 0.023). All the hypotheses proposed in the theoretical TAM-TPB model were supported, with perceived ease of use, perceived usefulness, attitude, subjective norm, and perceived behavioral control positively affecting the intention of HEV vaccination (all P values <0.05), while perceived risk (P = 0.003) exhibited an inverse association with HEV vaccination intention. The model achieved an acceptable fit, and the total explained variance of HEV vaccination intention was as high as 86.20 %. Moreover, no significant common method bias was observed. CONCLUSION: This is the first theory-based study that explored the HEV vaccination intention, its determinants, and overall influence mechanism among childbearing-age women. The results of the current study are of great importance for improving the understanding of the HEV vaccination intention among females of childbearing age.

Hepatitis E virus in the Kathmandu Valley: Insights from a representative longitudinal serosurvey.

BACKGROUND: Hepatitis-E virus (HEV), an etiologic agent of acute inflammatory liver disease, is a significant cause of morbidity and mortality in South Asia. HEV is considered endemic in Nepal; but data on population-level infection transmission is sparse. METHODS: We conducted a longitudinal serosurvey in central Nepal to assess HEV exposure. At each visit, capillary blood samples were collected and analyzed for the presence of anti-HEV IgG antibodies. The study took place between February 2019 and April 2021, with up to 4 visits per participant approximately 6 months apart. RESULTS: We collected 2513 samples from 923 participants aged 0-25 years, finding a seroprevalence of 4.8% and a seroincidence rate of 10.9 per 1000 person-years. Young adults and individuals consuming surface water faced the highest incidence of infection. Geospatial analysis identified potential HEV clusters, suggesting a need for targeted interventions. SIGNIFICANCE: Our findings demonstrate that HEV is endemic in Nepal and that the risk of infection increases with age.

Serological indication of chronic inflammatory demyelinating polyneuropathy as an extrahepatic manifestation of hepatitis E virus infection.

Guillain-Barré syndrome and neuralgic amyotrophy have been associated with hepatitis E virus (HEV) genotype 3 infections, while myasthenia gravis (MG) has been associated with HEV genotype 4 infections. However, whether chronic inflammatory demyelinating polyneuropathy (CIDP) is associated with HEV infections has not been conclusively clarified yet. 102 CIDP patients, 102 age- and sex-matched blood donors, 61 peripheral neuropathy patients (non-CIDP patients), and 26 MG patients were tested for HEV and anti-HEV IgM and IgG. Sixty-five of the 102 (64%) CIDP patients tested positive for anti-HEV IgG and one (1%) for anti-HEV IgM. No other patient tested positive for ati-HEV IgM. In the subgroup of CIDP patients with initial diagnosis (without previous IVIG treatment), 30/54 (56%) tested positive for anti-HEV IgG. Anti-HEV rates were significantly lower in blood donors (28%), non-CIDP peripheral neuropathy patients (20%), and MG patients (12%). No subject tested positive for HEV viremia. CSF tested negative for in 61 CIDP patients (54 patients with primary diagnosis). The development of CIDP but not non-CIDP polyneuropathy may be triggered by HEV exposure in an HEV genotype 3 endemic region. The increased anti-HEV seroprevalence in CIDP patients is not a consequence of IVIG therapy.

Chronic hepatitis E virus-induced spinal cord atrophy in a patient with chronic lymphatic leukemia: a case report and interdisciplinary management proposal.

Background: The hepatitis E virus (HEV) can cause acute viral hepatitis with or without neurological manifestations, and occasionally progresses to chronic infection in immunocompromised individuals. The management of chronic HEV infection in cancer patients may be challenging due to the complex immunological constellation. Furthermore, the diagnostic workflow and the impact on quality of life of neurological HEV manifestations in immunocompromised patients have not been sufficiently delineated previously. Case description: A 61-year-old male with systemically treated chronic lymphocytic leukemia (CLL) experienced a slowly progressive atrophy of the spinal cord due to a chronic HEV infection. Despite continuous antiviral treatment with ribavirin, the patient's neurological condition continued to deteriorate, particularly following subsequent attempts to treat CLL. Treatment with obinutuzumab resulted in acute bowel and urinary retention and a further deterioration of motor skills, prompting the discontinuation of obinutuzumab. The patient's neurological status improved after the administration of intravenous immunoglobulins. Conclusion: This case study provides a comprehensive long-term follow-up of a cancer patient with chronic HEV infection and associated CNS involvement, which resulted in progressive neurological disability over several years. The challenges faced in diagnosing new neurological symptoms in patients undergoing immunosuppressive cancer treatment underscore the need for an interdisciplinary diagnostic approach that includes HEV testing. We propose a diagnostic pathway for future validation in immunocompromised cohorts presenting with neurological symptoms, emphasizing its potential to enhance clinical outcomes.

Misdiagnosed Antibiotic-Induced Liver Injury: Unveiling Acute Hepatitis E in a 65-Year-Old Patient.

BACKGROUND Common causes of severely elevated transaminases, especially alanine transaminase, due to liver diseases include drug-induced liver injury and acute viral hepatitis, especially hepatitis E, which can present similarly in clinical practice. Broad differential diagnostic workup in patients with elevated transaminases is required to not overlook the possibility of hepatitis E infection. CASE REPORT We report on a 65-year-old asymptomatic man who was referred to the Emergency Department from the rehabilitation center due to markedly elevated liver transaminases. Physical examination revealed no jaundice or abdominal pain. Laboratory findings included severely elevated aspartate transaminase, alanine transaminase, and bilirubin levels. He was previously treated with imipenem/cilastatin and clindamycin for a surgical site infection of his jaw after the removal of a squamous cell carcinoma 2 weeks earlier. An ultrasound of the liver was unremarkable. Drug-induced liver injury was suspected, and all potentially hepatotoxic drugs, including antibiotics, were stopped. Due to the rapid and marked increase in liver transaminases, further tests were performed, including testing for hepatitis E. Serum anti-hepatitis E virus immunoglobulin M, immunoglobulin G antibodies, and hepatitis E virus-ribonucleic acid-polymerase chain reaction turned positive, and the diagnosis of hepatitis E was confirmed. Supportive care was applied. Liver transaminases decreased spontaneously. CONCLUSIONS The diagnostic workup in patients with markedly elevated liver transaminases and suspected drug-induced liver injury should include the screening for hepatitis E. Making the correct diagnosis is crucial given the differing treatment approaches, the implications on further therapy, and the risk of contagion of hepatitis E.

From discovery to treatment: tracing the path of hepatitis E virus.

The hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. HEV is classified into eight genotypes, labeled HEV-1 through HEV-8. Genotypes 1 and 2 exclusively infect humans, while genotypes 3, 4, and 7 can infect both humans and animals. In contrast, genotypes 5, 6, and 8 are restricted to infecting animals. While most individuals with a strong immune system experience a self-limiting infection, those who are immunosuppressed may develop chronic hepatitis. Pregnant women are particularly vulnerable to severe illness and mortality due to HEV infection. In addition to liver-related complications, HEV can also cause extrahepatic manifestations, including neurological disorders. The immune response is vital in determining the outcome of HEV infection. Deficiencies in T cells, NK cells, and antibody responses are linked to poor prognosis. Interestingly, HEV itself contains microRNAs that regulate its replication and modify the host's antiviral response. Diagnosis of HEV infection involves the detection of HEV RNA and anti-HEV IgM/IgG antibodies. Supportive care is the mainstay of treatment for acute infection, while chronic HEV infection may be cleared with the use of ribavirin and pegylated interferon. Prevention remains the best approach against HEV, focusing on sanitation infrastructure improvements and vaccination, with one vaccine already licensed in China. This comprehensive review provides insights into the spread, genotypes, prevalence, and clinical effects of HEV. Furthermore, it emphasizes the need for further research and attention to HEV, particularly in cases of acute hepatitis, especially among solid-organ transplant recipients.

Prevalence of hepatitis A and E viruses in wastewater in Asian countries.

Hepatitis A and E viruses (HAV and HEV, respectively) remain a significant global health concern despite advancements in healthcare and vaccination programs. Regular monitoring and vaccine efficacy of HAV are still lacking in different countries. This study aimed to investigate HAV and HEV prevalence in developed, developing, and least-developed Asian countries using wastewater as a surveillance tool. A total of 232 untreated wastewater samples were collected from six wastewater treatment plants, a sewage treatment plant, or an open drainage in six countries [Nepal (n = 51), Indonesia (n = 37), Thailand (n = 30), Vietnam (n = 27), the Philippines (n = 17), and Japan (n = 70)] between April and October 2022. Viruses in wastewater were concentrated by simple centrifugation or polyethylene glycol precipitation method, followed by viral RNA extraction and reverse transcription-quantitative polymerase chain reaction. HAV and HEV RNA were detected in the samples from Nepal (51 % for HAV and 2 % for HEV), Thailand (3 % for both viruses), and Japan (1 % for HAV and 24 % for HEV). Only HAV RNA was found in 11 % of the samples in Indonesia, whereas only HEV RNA was detected in Vietnam and the Philippines, with a positive ratio of 15 % and 12 %, respectively. These results highlighted the geographic variability in HAV and HEV prevalence, underscoring the need for localized public health strategies to address specific viral hepatitis challenges in each country.

Clinical characteristics and risk factors of Hepatitis E virus infection in Zhejiang Province: a multicenter case-control study.

Introduction: Hepatitis E (HE), caused by the Hepatitis E virus (HEV), is a significant cause of acute viral hepatitis globally and a major public health concern, particularly in specific high-prevalence areas in China, which have diverse transmission routes and regional differences. Identifying the primary risk factors for HE transmission is essential to develop targeted interventions for vulnerable populations. Methods: This study employed a 1:1 matched case-control methodology, using a standardized questionnaire complemented by medical records for data validation. Results: Among the 442 HE cases and 428 healthy controls, the case group had a higher prevalence of fatigue (46.21%) and loss of appetite (43.84%) compared to the control group. Furthermore, liver function indicators were significantly higher in the case group, with an average alanine aminotransferase (ALT) level of 621.94 U/L and aspartate aminotransferase (AST) level of 411.53 U/L. Severe HE patients were predominantly male, with significantly increased ALT and AST levels reaching 1443.81 U/L and 862.31 U/L respectively, along with a higher incidence of fatigue (90%) and loss of appetite (75%). Multifactorial analysis indicated that frequent dining out (OR = 2.553, 95%CI:1.686-3.868), poor hygiene conditions (OR = 3.889, 95%CI:1.399-10.807), and comorbid chronic illnesses (OR = 2.275, 95%CI:1.616-3.202) were risk factors for HE infection; conversely, good hygiene practices were protective factors against HE infection (OR = 0.698, 95%CI:0.521-0.934). Conclusion: In conclusion, HE infection in Zhejiang Province is closely associated with dietary habits and environmental hygiene, and individuals with chronic diseases or co-infections are at increased risk. This highlights the need for targeted health education to reduce the incidence of HE among these populations.

Spatial-temporal analysis of hepatitis E in Hainan Province, China (2013-2022): insights from four major hospitals.

Objective: Exploring the Incidence, Epidemic Trends, and Spatial Distribution Characteristics of Sporadic Hepatitis E in Hainan Province from 2013 to 2022 through four major tertiary hospitals in the Province. Methods: We collected data on confirmed cases of hepatitis E in Hainan residents admitted to the four major tertiary hospitals in Haikou City from January 2013 to December 2022. We used SPSS software to analyze the correlation between incidence rate and economy, population density and geographical location, and origin software to draw a scatter chart and SAS 9.4 software to conduct a descriptive analysis of the time trend. The distribution was analyzed using ArcMap 10.8 software (spatial autocorrelation analysis, hotspot identification, concentration, and dispersion trend analysis). SAS software was used to build an autoregressive integrated moving average model (ARIMA) to predict the monthly number of cases in 2023 and 2024. Results: From 2013 to 2022, 1,922 patients with sporadic hepatitis E were treated in the four hospitals of Hainan Province. The highest proportion of patients (n = 555, 28.88%) were aged 50-59 years. The annual incidence of hepatitis E increased from 2013 to 2019, with a slight decrease in 2020 and 2021 and an increase in 2022. The highest number of cases was reported in Haikou, followed by Dongfang and Danzhou. We found that there was a correlation between the economy, population density, latitude, and the number of cases, with the correlation coefficient |r| value fluctuating between 0.403 and 0.421, indicating a linear correlation. At the same time, a scatter plot shows the correlation between population density and incidence from 2013 to 2022, with r2 values fluctuating between 0.5405 and 0.7116, indicating a linear correlation. Global Moran's I, calculated through spatial autocorrelation analysis, showed that each year from 2013 to 2022 all had a Moran's I value >0, indicating positive spatial autocorrelation (p < 0.01). Local Moran's I analysis revealed that from 2013 to 2022, local hotspots were mainly concentrated in the northern part of Hainan Province, with Haikou, Wenchang, Ding'an, and Chengmai being frequent hotspot regions, whereas Baoting, Qiongzhong, and Ledong were frequent cold-spot regions. Concentration and dispersion analysis indicated a clear directional pattern in the average density distribution, moving from northeast to southwest. Time-series forecast modeling showed that the forecast number of newly reported cases per month remained relatively stable in 2023 and 2024, fluctuating between 17 and 19. Conclusion: The overall incidence of hepatitis E in Hainan Province remains relatively stable. The incidence of hepatitis E in Hainan Province increased from 2013 to 2019, with a higher clustering of cases in the northeast region and a gradual spread toward the southwest over time. The ARIMA model predicted a relatively stable number of new cases each month in 2023 and 2024.

Tracking the phylogenetic profile of HEV in swine and wild boar in Europe.

Hepatitis E virus (HEV) infection is prevalent among domestic pigs and wild boar in Europe. This study focused on the genetic diversity of HEV subtypes 3c, 3e and 3f among swine and wild boar in Europe as well as their circulation. Phylogenetic analysis and Bayesian phylogenetic inference were applied on the selected ORF2 capsid HEV sequences to co-estimate the viral circulation, the mean evolutionary rates and the dated trees. The estimated mean values of the HEV ORF2 capsid gene evolutionary rate were 8.29 x 10-3, 5.96 x 10-3, and 1.107 x 10-2 substitutions/site/year, respectively for 3c, 3e and 3f. The majority of the HEV 3c and 3e supported clusters did not show intermixing between swine and wild boar. Thus, although the intermixing observed in a minority of HEV 3c and 3e supported clusters suggests that transmission/circulation of these subtypes between swine and wild boar can potentially occur, 3c and 3e European wild boar HEV populations remained mainly segregated. In contrast, one half of the HEV 3f supported clusters showed intermixing between swine and wild boar, providing evidence for transfer/circulation to swine. The data suggest that continued virologic surveillance in swine and wild boar is necessary, together with targeted measures to reduce the chance of HEV transmission to humans.

Plant-Produced Chimeric Hepatitis E Virus-like Particles as Carriers for Antigen Presentation.

A wide range of virus-like particles (VLPs) is extensively employed as carriers to display various antigens for vaccine development to fight against different infections. The plant-produced truncated variant of the hepatitis E virus (HEV) coat protein is capable of forming VLPs. In this study, we demonstrated that recombinant fusion proteins comprising truncated HEV coat protein with green fluorescent protein (GFP) or four tandem copies of the extracellular domain of matrix protein 2 (M2e) of influenza A virus inserted at the Tyr485 position could be efficiently expressed in Nicotiana benthamiana plants using self-replicating vector based on the potato virus X genome. The plant-produced fusion proteins in vivo formed VLPs displaying GFP and 4M2e. Therefore, HEV coat protein can be used as a VLP carrier platform for the presentation of relatively large antigens comprising dozens to hundreds of amino acids. Furthermore, plant-produced HEV particles could be useful research tools for the development of recombinant vaccines against influenza.

Near full-length genome analysis of HEV 4b subtype in pigs showed a similarity up to 99.944% compared to a patient in Guangdong province, China.

Hepatitis E virus (HEV) is a prevalent pathogen responsible for acute viral hepatitis, HEV genotypes 3 and 4 infections causing zoonotic infections. Currently, the nucleotide similarity analysis between humans and pigs for HEV genotype 4 is limited. In this study, stool samples from an HEV-infected patient who is a pig farmer and from pigs were collected to obtain the near full-length genome of HEV, phylogenetic trees were constructed for genotyping, and similarity of HEV sequences was analyzed. The results showed that HEV-RNA was detected in the stool samples from the patient and six pigs (6/30, 20.0%). Both HEV subtype in the patient and pigs was 4b. Additionally, similarity analysis showed that the range was 99.875%-99.944% between the patient and pigs at the nucleotide level. Four isolates of amino acid sequences (ORFs 1-3) from pigs were 100% identical to the patient. Phylogenetic tree and similarity analysis of an additional nine HEV sequences isolated from other patients in this region showed that the HEV sequence from the pig farmer had the closest relationship with the pigs from his farm rather than other sources of infection in this region. This study provides indirect evidences for HEV subtype 4b can be transmitted from pigs to humans at the nucleotide level. Further research is needed to explore the characteristics of different HEV subtypes.

Safety and effectiveness of a recombinant hepatitis E vaccine in women of childbearing age in rural Bangladesh: a phase 4, double-blind, cluster-randomised, controlled trial.

BACKGROUND: Hepatitis E virus (HEV) leads to high mortality in pregnant women in low-income countries. We aimed to evaluate the safety of a HEV vaccine and its effectiveness in preventing hepatitis E during pregnancy. METHODS: In this phase 4, double-blind, cluster-randomised trial, 67 villages in Matlab, Bangladesh, were randomised 1:1 to receive HEV239 (a recombinant HEV vaccine) or a control vaccine (Hepa-B, a hepatitis B vaccine), using block randomisation with random number tables and blocks of size eight, stratified by cluster population size. Eligible non-pregnant women (aged 16-39 years) were vaccinated intramuscularly on day 0, at 1 month, and at 6 months, and followed up for 2 years after the last immunisation. The primary endpoint was hepatitis E in the pregnant, per-protocol population (those who received all three doses within 2 days of the scheduled dates), while safety was a secondary endpoint, assessed in the intention-to-treat (ITT) population (participants who received at least one dose). Solicited adverse events were recorded for the first 7 days after each dose, and unsolicited events until 2 years after a participant's final dose. Pregnancy-related safety outcomes were assessed in the pregnant ITT population. This study is registered with ClinicalTrials.gov (NCT02759991). FINDINGS: Between Oct 2, 2017, and Feb 28, 2019, 19 460 participants were enrolled and received either HEV239 (9478 [48·7%] participants, 33 clusters) or Hepa-B (9982 [51·3%] participants, 34 clusters), of whom 17 937 (92·2%) participants received three doses and 17 613 (90·5%) were vaccinated according to protocol (8524 [48·4%] in the HEV239 group and 9089 [51·6%] in the control group). No pregnant participants were confirmed to have hepatitis E in either treatment group. HEV239 showed a mild safety profile, similar to Hepa-B, with no difference in the proportion of solicited adverse events between groups and no severe solicited events. Pain was the most common local symptom (1215 [12·8%] HEV239 recipients and 1218 [12·2%] Hepa-B recipients) and fever the most common systemic symptom (141 [1·5%] HEV239 recipients and 145 [1·5%] Hepa-B recipients). None of the serious adverse events or deaths were vaccine related. Among pregnant participants, the HEV239 group had a higher risk of miscarriage (136 [5·7%] of 2407 pregnant participants) compared with the control group (102 [3·9%] of 2604; adjusted odds ratio 1·54 [95% CI 1·15-2·08]). INTERPRETATION: The effectiveness of HEV239 in pregnant women remains uncertain. HEV239 was safe and well tolerated in non-pregnant women, but findings regarding miscarriage warrant further investigation. FUNDING: Research Council of Norway; Innovax.