Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrioR) of Chronically HBV Infected Patients.

Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 µg PreHevbrioR. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent.

Hepatitis A virus infection.

Hepatitis A is a vaccine-preventable infection caused by the hepatitis A virus (HAV). Over 150 million new infections of hepatitis A occur annually. HAV causes an acute inflammatory reaction in the liver that usually resolves spontaneously without chronic sequelae. However, up to 20% of patients experience a prolonged or relapsed course and <1% experience acute liver failure. Host factors, such as immunological status, age, pregnancy and underlying hepatic diseases, can affect the severity of disease. Anti-HAV IgG antibodies produced in response to HAV infection persist for life and protect against re-infection; vaccine-induced antibodies against hepatitis A confer long-term protection. The WHO recommends vaccination for individuals at higher risk of infection and/or severe disease in countries with very low and low hepatitis A virus endemicity, and universal childhood vaccination in intermediate endemicity countries. To date, >25 countries worldwide have implemented such programmes, resulting in a reduction in the incidence of HAV infection. Improving hygiene and sanitation, rapid identification of outbreaks and fast and accurate intervention in outbreak control are essential to reducing HAV transmission.

Impact of COVID-19 on the liver and on the care of patients with chronic liver disease, hepatobiliary cancer, and liver transplantation: An updated EASL position paper.

The COVID-19 pandemic has presented a serious challenge to the hepatology community, particularly healthcare professionals and patients. While the rapid development of safe and effective vaccines and treatments has improved the clinical landscape, the emergence of the omicron variant has presented new challenges. Thus, it is timely that the European Association for the Study of the Liver provides a summary of the latest data on the impact of COVID-19 on the liver and issues guidance on the care of patients with chronic liver disease, hepatobiliary cancer, and previous liver transplantation, as the world continues to deal with the consequences of the COVID-19 pandemic.

EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients.

According to a recent World Health Organization estimate, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which originated in China in 2019, has spread globally, infecting nearly 100 million people worldwide by January 2021. Patients with chronic liver diseases (CLD), particularly cirrhosis, hepatobiliary malignancies, candidates for liver transplantation, and immunosuppressed individuals after liver transplantation appear to be at increased risk of infections in general, which in turn translates into increased mortality. This is also the case for SARS-CoV-2 infection, where patients with cirrhosis, in particular, are at high risk of a severe COVID-19 course. Therefore, vaccination against various pathogens including SARS-CoV-2, administered as early as possible in patients with CLD, is an important protective measure. However, due to impaired immune responses in these patients, the immediate and long-term protective response through immunisation may be incomplete. The current SARS-CoV-2 pandemic has led to the exceptionally fast development of several vaccine candidates. A small number of these SARS-CoV-2 vaccine candidates have already undergone phase III, placebo-controlled, clinical trials in healthy individuals with proof of short-term safety, immunogenicity and efficacy. However, although regulatory agencies in the US and Europe have already approved some of these vaccines for clinical use, information on immunogenicity, duration of protection and long-term safety in patients with CLD, cirrhosis, hepatobiliary cancer and liver transplant recipients has yet to be generated. This review summarises the data on vaccine safety, immunogenicity, and efficacy in this patient population in general and discusses the implications of this knowledge on the introduction of the new SARS-CoV-2 vaccines.

The History of Hepatitis A.

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Immunization against Hepatitis A.

Worldwide, there are multiple formaldehyde-inactivated and at least two live attenuated hepatitis A vaccines now in clinical use. The impressive immunogenicity of inactivated vaccines is reflected in rapid seroconversion rates, enabling both preexposure and postexposure prophylaxis. Universal childhood vaccination programs targeting young children have led to significant drops in the incidence of hepatitis A both in toddlers and in susceptible nonimmune adults in regions with intermediate endemicity for hepatitis A. Although the safety of inactivated vaccines is well established, further studies are needed concerning the implications of fecal virus shedding by recipients of attenuated vaccines, as well as the long-term persistence of immune memory in children receiving novel immunization schedules consisting of single doses of inactivated vaccines.

Viral envelope-specific antibodies in chronic hepatitis B virus infection.

While the cellular immune response associated with acute and chronic HBV infection has been thoroughly studied, the B cell response in chronic hepatitis B and the role of antibodies raised against the HBV envelope antigens in controlling and prevention of infection requires further investigation. The detection of anti-HBs antibodies is considered as one of the biomarkers for functional cure of chronic hepatitis B virus infection, as well as for protective immunity. Indeed, vaccine-induced neutralizing anti-HBs antibodies have been shown to protect against HBV challenge. Yet, the therapeutic potential of viral envelope-specific antibodies and the mechanism involved in protection and prevention of cell-to-cell transmission warrants additional investigative efforts. In this review, we will provide a critical overview of the available preclinical and clinical literature supporting the putative role of active and passive vaccination and neutralizing envelope-specific antibodies for therapeutic intervention in combination regimens intended to cure persistent HBV infection.

Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention.

Although epidemic jaundice was well known to physicians of antiquity, it is only in recent years that medical science has begun to unravel the origins of hepatitis A virus (HAV) and the unique pathobiology underlying acute hepatitis A in humans. Improvements in sanitation and the successful development of highly efficacious vaccines have markedly reduced the worldwide prevalence and incidence of this enterically-transmitted infection over the past quarter century, yet the virus persists in vulnerable populations and remains a common cause of food-borne disease outbreaks in economically-advantaged societies. Reductions in the prevalence of HAV have led to increases in the median age at which infection occurs, often resulting in more severe disease in affected persons and paradoxical increases in disease burden in some developing nations. Here, we summarize recent advances in the molecular virology of HAV, an atypical member of the Picornaviridae family, survey what is known of the pathogenesis of hepatitis A in humans and the host-pathogen interactions that typify the infection, and review medical and public health aspects of immunisation and disease prevention.

Impact of universal mass vaccination with monovalent inactivated hepatitis A vaccines - A systematic review.

The WHO recommends integration of universal mass vaccination (UMV) against hepatitis A virus (HAV) in national immunization schedules for children aged ≥1 year, if justified on the basis of acute HAV incidence, declining endemicity from high to intermediate and cost-effectiveness. This recommendation has been implemented in several countries. Our aim was to assess the impact of UMV using monovalent inactivated hepatitis A vaccines on incidence and persistence of anti-HAV (IgG) antibodies in pediatric populations. We conducted a systematic review of literature published between 2000 and 2015 in PubMed, Cochrane Library, LILACS, IBECS identifying a total of 27 studies (Argentina, Belgium, China, Greece, Israel, Panama, the United States and Uruguay). All except one study showed a marked decline in the incidence of hepatitis A post introduction of UMV. The incidence in non-vaccinated age groups decreased as well, suggesting herd immunity but also rising susceptibility. Long-term anti-HAV antibody persistence was documented up to 17 y after a 2-dose primary vaccination. In conclusion, introduction of UMV in countries with intermediate endemicity for HAV infection led to a considerable decrease in the incidence of hepatitis A in vaccinated and in non-vaccinated age groups alike.

Evidence for Hepatitis A virus endemic circulation in Israel despite universal toddlers' vaccination since 1999 and low clinical incidence in all age groups.

Background: Universal toddlers vaccination (UTV) introduced in 1999, reduced hepatitis A incidence in Israel from 50.4 to <1.0/100,000. The current Hepatitis A virus (HAV) molecular epidemiology in Israel was studied 13-14y post UTV introduction.. Methods: An outbreak in Tel-Aviv with 75 cases in 2012-2013 was investigated. Real-time RT-PCR and sequencing of the VP1-2A region (1100bp) was done on: a. serum samples from patients with acute Hepatitis A (12/ 75 in Tel-Aviv and 31 patients hospitalized in 3 other major cities in 2011-2013); b. in sewage samples (27 from metropolitan Tel-Aviv, 14 from the other 3 cities and 6 from Gaza). Results: The outbreak began among intravenous drug users then spread to the general population. Patients' mean age was 33.2y, 4/75(5.3%) had been vaccinated and 58/75(77.3%) were hospitalized. No common environmental source was found. HAV was detected in sewage samples: 16/27(59.2%) from Tel-Aviv; 4/14(28.6%) collected throughout Israel and 6/6 (100%) from Gaza. Genotype IB predominated (52/53 sequenced samples) and identical strains were demonstrated in the Israeli and Palestinian populations by phylogenetic analysis. Conclusions: Despite the UTV success, HAV circulation in the Israeli population continues, apparently due to its close contacts with the endemic Palestinian population. Reassessment of vaccination policy is recommended.

Hepatitis E in Israel: A nation-wide retrospective study.

AIM: To investigate the epidemiology, risk factors and clinical course of acute hepatitis E virus (HEV) infection in Israel, an industrialized country. METHODS: A retrospective analysis of acute HEV cases diagnosed in Israel from 1993 to 2013. Acute HEV was defined by ALT/AST elevation and a positive HEV PCR test or positive anti-HEV-IgM serology. HEV RNA was tested by quantitative reverse transcription PCR. Antibodies to HEV were tested retrospectively using an ELISA assay. HEV-RNA was sequenced using RT-PCR of ORF1 and ORF2 regions to diagnose genotype of the virus. Epidemiologic and clinical data were collected by reviewing the clinical files and through a telephone interview according to a structured questionnaire. RESULTS: Acute HEV was diagnosed in 68 patients. Among the 59 patients who gave an informed consent and were interviewed, 41% of infections were autochthonous (acquired in Israel), 44% travel-related and 15% imported by foreign workers. Autochthonous patients were mainly females (62.5%), more than half of them pregnant, 26% recalled consuming food or water in areas with poor sanitation, 44% ate non-kosher meat. Fulminant hepatitis developed in 3 patients (5%), all of them were females, two of them with post-partum infection, all acquired the disease in Israel (autochthonous). Israeli travelers with imported infection were predominantly males (73%), acquired the disease in the Indian subcontinent (81%), with 100% reporting having consumed fresh vegetables and drinks with ice cubes abroad. Six patients' sera were tested for genotype and revealed HEV genotype 1 (all cases acquired in the Indian subcontinent). CONCLUSION: This is the first report which highlights the existence of hepatitis E as an autochthonous infection in Israel. Imported HEV originates mostly from the Indian subcontinent.

Innovative sources for funding of viral hepatitis prevention and treatment in low- and middle-income countries: a roundtable meeting report.

Hepatitis B is preventable and hepatitis C is treatable even if still at a high cost; most people who are infected with hepatitis B or C virus have not been screened yet and are unaware of their infections; and most countries, especially developing countries, do not have a national plan to prevent and control viral hepatitis. The advent of effective new treatments for hepatitis C has been an agent of change, allowing consideration of the feasibility of eliminating that disease and accelerating the control of viral hepatitis generally. These facts inspired the Viral Hepatitis Prevention Board (VHPB) to organize a meeting in London (8-9 June 2015) on innovative sources for funding of viral hepatitis prevention and treatment in low- and middle-income countries. The main focus of the meeting was to provide an overview of current health systems controlling viral hepatitis in low- and middle-income countries (LMICs); to identify ways to increase political commitment and financial sustainability of viral hepatitis prevention and control programmes in such countries; to identify potential funders and explore new funding mechanisms; to discuss lessons learnt about funding other disease programmes; to investigate how to convince and motivate decision-makers to fund viral hepatitis programmes in LMICs; to provide options for improving access to affordable screening and treatment of viral hepatitis in LMICs; and to list the commitments required for funding by donors, including governments, bilateral and multilateral organizations, non-traditional donors, development banks, foundations, and commercial financial institutions. To improve viral hepatitis prevention and treatment in LMICs participating hepatitis and financing experts identified the most urgent needs. Data on burden of disease must be improved. Comprehensive hepatitis policies and strategies should be drafted and implemented, and existing strategies and policies improved to increase access to treatment and prevention. Strong political will and leadership should be generated, potential partners identified and partnerships created. Potential funders and funding mechanisms have to be researched. The outcome of this meeting was integrated in a VHPB project to investigate creative financing solutions to expand access to and provision of screening and other preventive services, treatment and care of hepatitis B and C in LMICs. The report is available on www.vhpb.org.

Acute hepatitis E virus in pregnant women in Israel and in other industrialized countries.

BACKGROUND AND OBJECTIVES: Acute hepatitis E virus (HEV) is the most common etiology of viral hepatitis in adults in developing countries. HEV is rare in industrialized countries but its incidence is rising both in returning travelers and through autochthonous infection. In developing countries HEV is associated with a high rate of fulminant hepatitis and mortality during pregnancy and contributes to poor obstetric and fetal outcomes. There are no reliable data on the outcome of HEV during pregnancy in industrialized countries. STUDY DESIGN: A retrospective analysis of acute HEV cases diagnosed in Israel were examined. The clinical course of the disease among pregnant women was retrieved. A systematic review of the literature was performed for cases of HEV and pregnancy, originating or treated in industrialized countries RESULTS: Between the years 1993-2013, 68 cases of acute HEV were diagnosed in Israel, including 9 pregnant women (13%). An additional 6 reported cases were found from a literature search. From the 15 women (10 autochthonous cases and 5 imported cases), the outcome was favorable in 10 cases, however, 5 cases (33%) resulted in fulminant hepatitis and two women underwent an urgent liver transplantation. No fatality occurred in the mothers and all babies were born alive and healthy. DISCUSSION: This is the first case series of acute HEV infection in pregnant women in industrialized countries. Acute HEV infection poses a significant risk in pregnancy, irrespective of patients' country of origin. In contrast to reports from developing countries, all babies and mothers survived.

Hepatotoxicity of herbal and dietary supplements: an update.

Herbal and dietary supplements (HDS) have been used for health-related purposes since more than 5000 years, and their application is firmly anchored in all societies worldwide. Over last decades, a remarkable renaissance in the use of HDS can be noticed in affluent societies for manifold reasons. HDS are forms of complementary and alternative medicines commonly used to prevent or treat diseases, or simply as a health tonic. Another growing indication for HDS is their alleged benefit for weight loss or to increase physical fitness. Access is easy via internet and mail-order pharmacies, and their turnover reaches billions of dollars in the USA and Europe alone. However, HDS are generally not categorized as drugs and thus less strictly regulated in most countries. As a result, scientific evidence proving their beneficial effects is mostly lacking, although some HDS may have purported benefits. However, the majority lacks such proof of value, and their use is predominantly based on belief and hope. In addition to missing scientific evidence supporting their use, HDS are typically prone to batch-to-batch variability in composition and concentration, contamination, and purposeful adulteration. Moreover, numerous examples of preparations emerged which have been linked to significant liver injury. These include single ingredients, such as kava, germander, and several Chinese herbals. Other HDS products associated with liver toxicity consist of multiple, often ill-defined ingredients, such as Hydroxycut and Herbalife. Affirmative diagnostic tests are not available, and the assessment of liver injury ascribed to HDS depends on a thorough and proactive medical history, careful exclusion of other causes, and a search for available reports on similar events linked to the intake of the suspected preparation or ingredients contained therein.

Enhanced immune response to hepatitis B vaccination through immunization with a Pre-S1/Pre-S2/S vaccine.

Efficacy and safety of recombinant yeast-derived hepatitis B vaccines for prevention of hepatitis B have been demonstrated unequivocally worldwide as reflected in reduction in HBsAg carrier rates and hepatocellular carcinoma. A new generation of recombinant HBV vaccines expressed in mammalian cells containing Pre-S/S epitopes has been developed in several countries. Such vaccines are useful in special risk groups, i.e., in non-responders to conventional HBV vaccines including older adults, obese people, health care workers, patients with renal failure and on dialysis, transplant patients, patients with HIV as well as travelers on short notice to HBV endemic regions. The future of such vaccines depends on their enhanced immunogenicity and cost profile. Sci-B-Vac™ is a mammalian cell-derived recombinant Pre-S1/Pre-S2/S hepatitis B vaccine which has been shown to be highly immunogenic, inducing faster and higher seroprotection rates against HBV with higher anti-HBs levels at lower HBsAg doses as compared to conventional yeast-derived vaccines. Recently, it has been suggested that such Pre-S/S vaccines against HBV might be efficacious not only for prevention but also for intervention in persistent HBV infection. Data obtained in a recent clinical trial conducted in Vietnam in patients with chronic hepatitis B suggest that repeated monthly i.m. injections of the Sci-B-Vac™ co-administered with daily oral lamivudine treatment can suppress HBV replication and lead to anti-HBs seroconversion in ~50 % of treated patients. Optimization of protocols and efficacy of such an intervention, intended to bypass T cell exhaustion and immune tolerance to HBV remains to be explored.

Induction of a robust T- and B-cell immune response in non- and low-responders to conventional vaccination against hepatitis B by using a third generation PreS/S vaccine.

Non-responsiveness to conventional hepatitis B vaccines in individuals at high risk of exposure to hepatitis B virus (HBV) is an important public health problem and of particular relevance in health care providers. Yeast-derived conventional HBsAg vaccines fail to induce protective antibody titers in up to 10% of immune competent vaccinees. Therefore, a third generation HBV vaccine, Sci-B-Vac™, was developed which contains in addition to the small S antigen the PreS1 and PreS2 antigens. This vaccine proved to induce a highly potent cellular and humoral immune response in healthy individuals as well as protective antibody levels in non- and low-responders to conventional HBV vaccines. The aim of the study was to examine whether Sci-B-Vac™ triggers cellular and humoral immunity in individuals who failed immunization with conventional vaccines. We immunized 21 volunteers (15 non- and 6 low-responders) according to the standard vaccination schedule (0, 4 and 24 weeks), determined the cellular immunity by proliferation assay and interferon (IFN)-γ ELISpot and measured the anti-HBs antibody titers prior to each vaccination and four weeks after the third vaccine dose. Following three vaccinations, PreS/S-specific T-cell proliferation was detected in 8 out of 15 non-responders and 5 out of 6 low-responders. Specific IFN-γ responses were measured in 2 out of 15 non-responders and 4 out of 6 low-responders. All but one (20/21) study participants developed anti-HBs titers ≥10IU/l after three vaccinations. Anti-HBs ≥100IU/L were detected in 12 out of 15 non-responders and in 6 out of 6 low-responders. Anti-HBs ≥10IU/l and <100IU/l were found in 2 non-responders. These results indicate that Sci-B-Vac™ induces cellular immunity as well as protective anti-HBs antibody titers in non- and low-responders. In conclusion, these results confirm that Sci-B-Vac™ should be administered to non-responders to conventional HBV vaccines and patients with impaired immune function.