Current progress in the development of therapeutic vaccines for chronic hepatitis B virus infection (original) (raw)
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Peptide vaccines against hepatitis B virus: from animal model to human studies
2001
An estimated 400 million people are chronically infected with the hepatitis B virus (HBV). Chronic viral hepatitis infection incurs serious sequelae such as liver cirrhosis and hepatocellular carcinoma. Prevention and treatment, thus, represent an important target for public health. Preventive vaccines using HBsAg alone or combined with other antigens allow for the generation of neutralizing antibodies which effectively prevent infection in immunocompetent individuals. Cell-mediated immunological mechanisms are thought to be crucial in determining viral persistence or viral elimination. Therapeutic approaches aiming to shift cellular immunity towards viral elimination have been on the research agenda for many years. This paper summarizes pre-clinical and clinical results obtained with the use of immunogenic peptides formulated as vaccines to selectively boost cellular immune responses. Such vaccines are capable of generating cellular immune responses in animal models as well as in humans and represent an important step towards the development of a therapeutic vaccine against chronic hepatitis.
Journal of Hepatology, 2011
The treatment of chronic hepatitis B virus (HBV) infection has greatly improved over the last 10 years, but alternative treatments are still needed. Therapeutic vaccination is a promising new strategy for controlling chronic infection. However, this approach has not been as successful as initially anticipated for chronic hepatitis B. General impairment of the immune responses generated during persistent HBV infection, with exhausted T cells not responding correctly to therapeutic vaccination, is probably responsible for the poor clinical responses observed to date. Intensive research efforts are now focusing on increasing the efficacy of therapeutic vaccination without causing liver disease. Here we describe new approaches to use with therapeutic vaccination, in order to overcome the inhibitory mechanisms impairing immune responses. We also describe innovative strategies for generating functional immune responses and inducing sustained control of this persistent infection. Ó (M.-L. Michel).
Towards immunotherapy for chronic hepatitis B virus infections
Vaccine, 2002
Chronic liver disease and hepatocellular carcinoma associated with chronic hepatitis B virus (HBV) infection are among the most serious human health problems in highly endemic regions. Although, effective vaccines against HBV have been available for many years, over 350 million people still remain persistently infected with HBV. Current therapies fail to provide long-term control of viral replication in most patients. Viral persistence has been associated with a defect in the development of HBV-specific cell-mediated immunity. Vaccine-based strategies to boost or to broaden the weak virus-specific T cell response of patients with chronic hepatitis B are proposed as a means of terminating this persistent infection.
Immunotherapy of chronic hepatitis B by anti HBV vaccine
Biomedicine & Pharmacotherapy, 1995
Chronic liver disease and hepatocellular carcinoma associated with chronic hepatitis B virus (HBV)-infection are among the most serious human health problems in highly endemic regions. Current therapeutic approaches to control chronic hepatitis such as interferon-alpha and lamivudine are unsatisfactory. Vaccination would be the therapeutic procedure with the lowest cost and the potentially greatest benefit. The immunogenicity of selected HBV envelope-or capsid-based vaccine formulations for the induction or the broadening of T and B cell responses, deficient in HBV chronic carriers, are currently under study in animal models and in clinical trials.
New Approaches to the Treatment of Chronic Hepatitis B
The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.
Immunomodulatory drugs and therapeutic vaccine in chronic hepatitis B infection
Journal of Hepatology, 2003
The main risk of patients with chronic HBV infection is the occurrence of cirrhosis resulting in overmortality related to the development of hepatocellular carcinoma or non carcinomatous complications of cirrhosis (portal hypertension and liver failure). Control of viral replication significantly reduces these risks since pathology of HBV infection is mainly immunemediated.
Therapeutic vaccination in chronic hepatitis B
Journal of Gastroenterology and Hepatology, 2002
Interferon-a and nucleoside analogues are available for the treatment of chronic hepatitis B virus (HBV) infection but do not lead to a satisfactory result. New findings about the immunological control of HBV during acute infection suggest the pivotal role of T-cell mediated immune responses. Several preclinical and clinical trials were undertaken to explore the possibility of stimulating specific immune responses in chronically infected animals and patients by vaccination. However, vaccination with commercially available HBV vaccines in patients and immunization in woodchucks with core or surface proteins of woodchuck hepatitis virus (WHV) did not result in effective control of HBV and WHV infection, suggesting that new formulations of therapeutic vaccines are needed. Some new approaches combining antiviral treatments with nucleoside analogues, DNA vaccines and protein vaccines were tested in the woodchuck model. It could be shown that therapeutic vaccinations are able to stimulate specific B-and T-cell responses and to achieve transient suppression of viral replication. These results suggest the great potential of therapeutic vaccination in combination with antivirals to reach an effective and sustained control of HBV infection.
Advances in hepatitis B therapeutics
Therapeutic Advances in Infectious Disease, 2020
Despite the availability of both effective preventive vaccines and oral antivirals, over 250 million people are chronically infected with the hepatitis B virus (HBV). Globally, chronic hepatitis B is the leading cause of hepatocellular carcinoma, which represents the third cause of cancer mortality, accounting for nearly 1 million annual deaths. Current oral nucleos(t)ide therapy with tenofovir or entecavir suppresses serum HBV-DNA in most treated patients, but rarely is accompanied by HBsAg loss. Thus, treatment has to be given lifelong to prevent viral rebound. A broad spectrum of antivirals that block the HBV life cycle at different steps are in clinical development, including entry inhibitors, cccDNA disrupters/silencers, translation inhibitors, capsid assembly modulators, polymerase inhibitors and secretion inhibitors. Some of them exhibit higher potency than current oral nucleos(t)ides. Drugs in more advanced stages of clinical development are bulevirtide, JNJ-6379, ABI-H0731,...
Future Therapy for Hepatitis B Virus: Role of Immunomodulators
Current Hepatology Reports, 2016
Although currently available therapies for chronic hepatitis B virus infection can suppress viremia and provide long-term benefits for patients, they do not lead to a functional cure for most patients. Advances in our understanding of the virus-host interaction and the recent remarkable success of immunotherapy in cancer offer new and promising strategies for developing immune modulators that may become important components of a total therapeutic approach to hepatitis B, some of which are now in clinical development. Among the immunomodulatory agents currently being investigated to combat chronic HBV are toll-like receptor agonists, immune checkpoint inhibitors, therapeutic vaccines, and engineered T cells. The efficacy of some immune modulatory therapies is compromised by high viral antigen levels. Cutting edge strategies, including RNA interference and CRISPR/Cas9, are now being studied that may ultimately be shown to have the capacity to lower viral antigen levels sufficiently to substantially increase the efficacy of these agents. The current advances in therapies for chronic hepatitis B are leading us toward the possibility of a functional cure.