Collateral effects of COVID-19 countermeasures on hepatitis E incidence pattern: a case study of china based on time series models.

BACKGROUND: There are abundant studies on COVID-19 but few on its impact on hepatitis E. We aimed to assess the effect of the COVID-19 countermeasures on the pattern of hepatitis E incidence and explore the application of time series models in analyzing this pattern. METHODS: Our pivotal idea was to fit a pre-COVID-19 model with data from before the COVID-19 outbreak and use the deviation between forecast values and actual values to reflect the effect of COVID-19 countermeasures. We analyzed the pattern of hepatitis E incidence in China from 2013 to 2018. We evaluated the fitting and forecasting capability of 3 methods before the COVID-19 outbreak. Furthermore, we employed these methods to construct pre-COVID-19 incidence models and compare post-COVID-19 forecasts with reality. RESULTS: Before the COVID-19 outbreak, the Chinese hepatitis E incidence pattern was overall stationary and seasonal, with a peak in March, a trough in October, and higher levels in winter and spring than in summer and autumn, annually. Nevertheless, post-COVID-19 forecasts from pre-COVID-19 models were extremely different from reality in sectional periods but congruous in others. CONCLUSIONS: Since the COVID-19 pandemic, the Chinese hepatitis E incidence pattern has altered substantially, and the incidence has greatly decreased. The effect of the COVID-19 countermeasures on the pattern of hepatitis E incidence was temporary. The incidence of hepatitis E was anticipated to gradually revert to its pre-COVID-19 pattern.

Long-term efficacy of a recombinant hepatitis E vaccine in adults: 10-year results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Hepatitis E virus (HEV) is a frequently overlooked causative agent of acute hepatitis. Evaluating the long-term durability of hepatitis E vaccine efficacy holds crucial importance. METHODS: This study was an extension to a randomised, double-blind, placebo-controlled, phase-3 clinical trial of the hepatitis E vaccine conducted in Dontai County, Jiangsu, China. Participants were recruited from 11 townships in Dongtai County. In the initial trial, a total of 112 604 healthy adults aged 16-65 years were enrolled, stratified according to age and sex, and randomly assigned in a 1:1 ratio to receive three doses of hepatitis E vaccine or placebo intramuscularly at month 0, month 1, and month 6. A sensitive hepatitis E surveillance system including 205 clinical sentinels, covering the entire study region, was established and maintained for 10 years after vaccination. The primary outcome was the per-protocol efficacy of hepatitis E virus vaccine to prevent confirmed hepatitis E occurring at least 30 days after administration of the third dose. Throughout the study, the participants, site investigators, and laboratory staff remained blinded to the treatment assignments. This study is registered with ClinicalTrials.gov (NCT01014845). FINDINGS: During the 10-year study period from Aug 22, 2007, to Oct 31, 2017, 90 people with hepatitis E were identified; 13 in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% (95% CI 69·4-91·4) in the modified intention-to-treat analysis and 86·6% (73·0 to 94·1) in the per-protocol analysis. In the subsets of participants assessed for immunogenicity persistence, of those who were seronegative at baseline and received three doses of hepatitis E vaccine, 254 (87·3%) of 291 vaccinees in Qindong at the 8·5-year mark and 1270 (73·0%) of 1740 vaccinees in Anfeng at the 7·5-year mark maintained detectable concentrations of antibodies. INTERPRETATION: Immunisation with this hepatitis E vaccine offers durable protection against hepatitis E for up to 10 years, with vaccine-induced antibodies against HEV persisting for at least 8·5 years. FUNDING: National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Fundamental Research Funds for the Central Universities.

Vaccination coverage and adverse events following a reactive vaccination campaign against hepatitis E in Bentiu displaced persons camp, South Sudan.

INTRODUCTION: Hepatitis E (HEV) genotypes 1 and 2 are the common cause of jaundice and acute viral hepatitis that can cause large-scale outbreaks. HEV infection is associated with adverse fetal outcomes and case fatality risks up to 31% among pregnant women. An efficacious three-dose recombinant vaccine (Hecolin) has been licensed in China since 2011 but until 2022, had not been used for outbreak response despite a 2015 WHO recommendation. The first ever mass vaccination campaign against hepatitis E in response to an outbreak was implemented in 2022 in Bentiu internally displaced persons camp in South Sudan targeting 27,000 residents 16-40 years old, including pregnant women. METHODS: We conducted a vaccination coverage survey using simple random sampling from a sampling frame of all camp shelters following the third round of vaccination. For survey participants vaccinated in the third round in October, we asked about the onset of symptoms experienced within 72 hours of vaccination. During each of the three vaccination rounds, passive surveillance of adverse events following immunisation (AEFI) was put in place at vaccination sites and health facilities in Bentiu IDP camp. RESULTS: We surveyed 1,599 individuals and found that self-reported coverage with one or more dose was 86% (95% CI 84-88%), 73% (95% CI 70-75%) with two or more doses and 58% (95% CI 55-61%) with three doses. Vaccination coverage did not differ significantly by sex or age group. We found no significant difference in coverage of at least one dose between pregnant and non-pregnant women, although coverage of at least two and three doses was 8 and 14 percentage points lower in pregnant women. The most common reasons for non-vaccination were temporary absence or unavailability, reported by 60% of unvaccinated people. Passive AEFI surveillance captured few mild AEFI, and through the survey we found that 91 (7.6%) of the 1,195 individuals reporting to have been vaccinated in October 2022 reported new symptoms starting within 72 hours after vaccination, most commonly fever, headache or fatigue. CONCLUSIONS: We found a high coverage of at least one dose of the Hecolin vaccine following three rounds of vaccination, and no severe AEFI. The vaccine was well accepted and well tolerated in the Bentiu IDP camp community and should be considered for use in future outbreak response.

Universal nucleic acid donor screening revealed epidemiological features of hepatitis E and prevented transfusion-transmitted infection in Japan.

BACKGROUND: More than 45 cases of transfusion-transmitted hepatitis E virus infection (TT-HEV) have been reported in Japan. Therefore, in 2020, universal individual donation nucleic acid amplification testing (ID-NAT) was implemented for HEV. STUDY DESIGN AND METHODS: We characterized HEV NAT-positive blood donors. The number of new HEV infections and the asymptomatic infection rate were estimated using the HEV NAT-positive rate. HEV RNA quantitation, phylogenetic analysis, and antibody tests were performed, and the residual risk of TT-HEV was assessed based on the lookback study results. RESULTS: A total of 5,075,100 blood donations were screened with ID-NAT during the first year of implementation, among which 2804 (0.055%; males: 0.060%, females: 0.043%) were NAT-positive with regional differences. Approximately 270,000 new HEV infection cases were estimated to occur annually in Japan, with an asymptomatic infection rate of 99.9%. The median HEV RNA concentration, excluding cases below the limit of quantification, was 205 IU/mL. Among the 1113 cases where the genotype could be determined, HEV-3 and HEV-4 accounted for 98.8% (1100) and 1.2% (13), respectively. The maximum duration of HEV viremia, including the pre- and post-ID-NAT window periods, was estimated to be 88.2 days. Within the 3 years since ID-NAT implementation, no confirmed cases of breakthrough TT-HEV were observed. DISCUSSION: Multiple indigenous HEV strains are prevalent in Japan, infecting a significant number of individuals. However, since the implementation of ID-NAT, TT-HEV has been prevented due to the test's high sensitivity.

Knowledge about Hepatitis E and Influencing Factors among Residents in Qingdao: a Cross-Sectional Study.

Hepatitis E infection poses a serious health problem in developing countries. Hepatitis E vaccination is important for prevention, but it is influenced by residents' knowledge. Qingdao residents' knowledge of hepatitis E remains unknown. This study used an online survey on the WeChat platform. The chi-square test was used to compare the hepatitis E influencing factors between the subgroups. Binary logistic regression was used for multiple factor analysis to explore the hepatitis E influencing factors. The total awareness rate of hepatitis E was 60.51%. Females aged between 51 and 60, aged 61 and above, and working in government-affiliated departments were found to have higher awareness rates than other subgroups. Participants with family members infected with hepatitis E had a lower awareness rate. The government and relevant departments should focus on education regarding the hepatitis E vaccination and disease process.

The Re-Emergence of Hepatitis E Virus in Europe and Vaccine Development.

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.

[Strengthening the study of chronic hepatitis E].

This paper summarizes the incidence, modes of transmission, diagnosis, treatment and prevention of chronic hepatitis E.

Epidemiology of Hepatitis E.

Hepatitis E virus (HEV) is globally prevalent with relatively high percentages of anti-HEV immunoglobulin G-positive individuals in the populations of developing and developed countries. There are two distinct epidemiological patterns of hepatitis E. In areas with high disease endemicity, primarily developing countries in Asia and Africa, this disease is caused mainly by genotypes HEV-1 or HEV-2; both genotypes transmit predominantly through contaminated water and occur as either outbreaks or sporadic cases of acute hepatitis. The acute hepatitis has the highest attack rate in young adults and is particularly severe among pregnant women. In developed countries, sporadic cases of locally acquired HEV-3 or HEV-4 infection are observed. The reservoir of HEV-3 and HEV-4 is believed to be animals, such as pigs, with zoonotic transmission to humans. The affected persons are often elderly, and persistent infection has been well documented among immunosuppressed persons. A subunit vaccine has been shown to be effective in preventing clinical disease and has been licensed in China.

Prophylactic Hepatitis E Vaccine.

The hepatitis E has been increasingly recognized as an underestimated global disease burden in recent years. Subpopulations with more serious infection associated damage or death include pregnant women, patients with basic liver diseases, and elderly persons. Vaccine would be the most effective means for prevention of HEV infection. The lack of an efficient cell culture system for HEV makes the development of classic inactive or attenuated vaccine infeasible. Hence, the recombinant vaccine approaches are explored deeply. The neutralizing sites are located almost exclusively in the capsid protein, pORF2, of the virion. Based on pORF2, many vaccine candidates showed potential of protecting primate animals, two of them were tested in human and evidenced to be well-tolerated in adults and highly efficacious in preventing hepatitis E. The world's first hepatitis E vaccine, Hecolin® (HEV 239 vaccine), was licensed in China and launched in 2012.

The pressing need for a global HEV vaccine.

Based on the worldwide distribution of hepatitis E virus (HEV) and its ability to cause major epidemics in low-income countries, the global availability of a HEV vaccine is a pressing clinical need. Populations at risk of severe forms of the infection are well characterised: patients with chronic liver disease - at risk of liver failure; pregnant women - at risk of fulminant hepatitis or obstetrical complications; and immunosuppressed patients, particularly those with solid organ transplants - at risk of chronic hepatitis and rapid progression to cirrhosis. Only one hepatitis E vaccine is presently being manufactured. It has been proven to be effective and safe. However, its accessibility, as well as data on its long-term efficacy and the duration of protection it confers, are limited. While individuals considered to be at risk of severe infection appear to be ideal targets for the vaccine, its effectiveness and tolerability have not yet been studied in populations with chronic liver disease and immunosuppressed patients. Hepatitis E vaccination could also play an important role in controlling outbreaks in large waterborne epidemics. Clinical trials on these populations are needed.

Safety of hepatitis E vaccination for pregnancy: a post-hoc analysis of a randomized, double-blind, controlled phase 3 clinical trial.

Special attention has been paid to Hepatitis E (HE) prophylaxis for pregnant women due to poor prognosis of HE in this population. We conducted a post-hoc analysis based on the randomized, double-blind, HE vaccine (Hecolin)-controlled phase 3 clinical trial of human papillomavirus (HPV) vaccine (Cecolin) conducted in China. Eligible healthy women aged 18-45 years were randomly assigned to receive three doses of Cecolin or Hecolin and were followed up for 66 months. All the pregnancy-related events throughout the study period were closely followed up. The incidences of adverse events, pregnancy complications, and adverse pregnancy outcomes were analysed based on the vaccine group, maternal age, and interval between vaccination and pregnancy onset. During the study period, 1263 Hecolin receivers and 1260 Cecolin receivers reported 1684 and 1660 pregnancies, respectively. The participants in the two vaccine groups showed similar maternal and neonatal safety profiles, regardless of maternal age. Among the 140 women who were inadvertently vaccinated during pregnancy, the incidences of adverse reactions had no statistical difference between the two groups (31.8% vs 35.1%, p = 0.6782). The proximal exposure to HE vaccination was not associated with a significantly higher risk of abnormal foetal loss (OR 0.80, 95% CI 0.38-1.70) or neonatal abnormality (OR 2.46, 95% CI 0.74-8.18) than that to HPV vaccination, as did distal exposure. Significant difference was not noted between pregnancies with proximal and distal exposure to HE vaccination. Conclusively, HE vaccination during or shortly before pregnancy is not associated with increased risks for both the pregnant women and pregnancy outcomes.

Hepatitis E virus: has anything changed?

PURPOSE OF REVIEW: Infection with hepatitis E virus (HEV) is a global health concern, yet a clinically underdiagnosed cause of acute and chronic hepatitis. The WHO estimates that 20 million people are infected with HEV annually, yet the epidemiology, diagnosis and prevention remain elusive in many clinical settings. RECENT FINDINGS: Orthohepevirus A (HEV-A) genotypes 1 and 2 cause acute, self-limited hepatitis through faecal-oral transmission. In 2022, the first-ever vaccine campaign was implemented as a response to an HEV outbreak in an endemic region. HEV-A genotypes 3 and 4 are zoonotic infections that primarily cause chronic HEV infection in immunosuppressed populations. Pregnant women and immunocompromised persons are at high risk for severe illness in some settings. Another recent advance in our knowledge of HEV is the zoonotic transmission of Orthohepevirus C (HEV-C) to humans, presumably from contact with rodents and/or their excrement. Previously, HEV infection in humans was presumed to be limited to HEV-A only. SUMMARY: Clinical recognition and accurate diagnosis are essential to the management of HEV infection and understanding the global burden of the disease. Epidemiology affects clinical presentations. Targeted response strategies in HEV outbreaks are needed for the prevention of disease, and vaccine campaigns may prove to be an effective part of these strategies.

Diagnostic and management strategies for chronic hepatitis E infection.

INTRODUCTION: Hepatitis E Virus (HEV) was initially thought to cause only acute infections, but the discovery of chronic hepatitis E in immunocompromised patients has profoundly changed our understanding of the virus. AREAS COVERED: We describe the physiopathology, diagnosis, and clinical management of chronic HEV infection. The virus can persist in nearly two-thirds of immunosuppressed patients. Reducing immunosuppression is the first immunomodulatory strategy to cure chronic hepatitis E. But this may not always be feasible or effective. Ribavirin monotherapy for 3 months has been recommended as first-line treatment for chronically infected patients. Ribavirin is around 80% effective at eradicating HEV in retrospective studies. Apart from ribavirin, interferon has been successfully used in liver transplants recipients, but if the patient does not respond, no other alternative drug is available. The vaccine available to prevent HEV infection is one available only in China. EXPERT OPINION: HEV infection is a major concern in immunocompromised patients. But the therapeutic arsenal is limited to ribavirin and interferon. Both produce several side effects and new drugs are urgently needed. Moreover, preventive strategies to limit HEV transmission and/or evolution to a chronic infection are also required.

Expression and immunogenicity of hepatitis E virus-like particles based on recombinant truncated ORF2 capsid protein.

Hepatitis E is an emerging zoonotic disease, posing a severe threat to public health in the world. Since there are no specific treatments available for HEV infection, it is crucial to develop vaccine to prevent this infection. In this study, the truncated ORF2 encoded protein of 439aa∼617aa (HEV3-179) from HEV CCJD-517 isolates was expressed as VLPs in E. coli with diameters of approximate 20 nm. HEV3-179 protein was immunized with mice, and the results showed that a higher titre of antibody was induced in NIH mice in comparison with that of KM mice (P < 0.01) and BALB/c mice (P < 0.01). The induced antibody titer is much higher in subcutaneous immunization mice than that in the mice inoculated via abdominal immunization (P < 0.05) and muscles immunization (P < 0.01). Mice immunized with 12 µg and 6 µg candidate vaccine induced higher level of antibody titer than that of 3 µg dosage group (P < 0.01, P < 0.05). Antibody change curve showed that HEV IgG antibody titer increased from 14 days post immunization (dpi) to 1:262144 and reached the peak level on 42 dpi before gradually retreated with the same level antibody titer with 1:131072 until 84 dpi. Mice inoculated with HEV3-179 produced higher titer of cytokines than the mock group, and the concentration of IL-1ß (P < 0.01) and IFN-γ (P < 0.01) further increased after stimulated by candidate vaccine. The result indicated that HEV3-179 possesses good immunogenicity, which could be used as a potential candidate for future HEV vaccine development.

[Consensus on prevention and treatment of hepatitis E].

This consensus was developed by Chinese Society of Hepatology, Chinese Medical Association. It includes introduction, etiology, epidemiology and prevention, pathology, laboratory examination, clinical manifestation, treatment, issues to be studied and solved.

Chronic hepatitis E: Advancing research and patient care.

The hepatitis E virus (HEV) was initially thought to exclusively cause acute hepatitis. However, the first diagnosis of chronic hepatitis E in transplant recipients in 2008 profoundly changed our understanding of this pathogen. We have now begun to understand that specific HEV genotypes can cause chronic infection in certain immunocompromised populations. Over the past decade, dedicated clinical and experimental research has substantiated knowledge on the epidemiology, transmission routes, pathophysiological mechanisms, diagnosis, clinical features and treatment of chronic HEV infection. Nevertheless, many gaps and major challenges remain, particularly regarding the translation of knowledge into disease prevention and improvement of clinical outcomes. This article aims to highlight the latest developments in the understanding and management of chronic hepatitis E. More importantly, we attempt to identify major knowledge gaps and discuss strategies for further advancing both research and patient care.

Efficient production and characterization of immunogenic HEV-PCV2 chimeric virus-like particles.

Zoonotic hepatitis E virus (HEV) infection is an emerging global public health concern. It is usually transmitted to humans from domestic pigs (main host). Since virus-like particles (VLPs) exhibit unique structural and immunological characteristics that make them of momentous applications in vaccine development, the purpose of the present study was the production of immunogenic chimeric VLPs as vaccine candidates for the control of zoonotic HEV in its main host and the prevention of porcine circovirus associated disease, a multi-factorial disease with major economic repercussions on global pig industry. An immuno-informatics approach was applied for the design and screening of new chimeric antigens presenting the dominant immunogenic domains of both HEV and porcine circovirus 2 (PCV2). Then, using molecular cloning techniques, the chimeric proteins were expressed in Escherichia coli. After purification, full characterization of the physicochemical, morphological, and immunological properties of the target proteins has been conducted. The chimeric immunogens were successfully overexpressed and after the optimization of the expression conditions, 5 chimeric proteins were efficiently purified under native conditions. The purified HEV-PCV2 chimeric proteins were found thermo-stable and able to self-assemble into spherical virus-like particles. Four HEV-PCV2 chimeric proteins have displayed optimal antigenicity and immunogenicity properties, with the nPCV2cp-p166 chimeric immunogen slightly outranking the other designed proteins. In conclusion, this study reports the production of stable HEV-PCV2 chimeric VLPs that exhibited optimal antigenicity and immunogenicity and thus with potential applications in diagnostics and vaccine development. Besides, this study provides a reproducible approach for the design, assessment, and production of chimeric antigens.