Present and future DNA vaccines for chronic hepatitis B treatment

ABSTRACT

Introduction: With at least 240 million hepatitis B virus (HBV) carriers worldwide, being at a high risk of cirrhosis and hepatocellular carcinoma (HCC), chronic hepatitis B remains a major public health issue. Because current antiviral treatments are only virostatic, there is an urgent need for the development of innovative anti-HBV strategies leading to the functional cure. In this context, DNA-based vaccines appear as a promising approach.

Area covered: In this review, the authors summarize the pertinent features of DNA vaccines for chronic hepatitis B therapy. They review several technologies that improve DNA vaccines efficacy evaluated in animal models of hepadnaviral infection. They also discuss the clinical trials of therapeutic DNA vaccination initiated in HBV-carrier patients.

Expert opinion: Preclinical studies in HBV transgenic mice, DHBV-carrier ducks and WHV-infected woodchucks, have clearly demonstrated a benefit of DNA vaccine-based combination therapies for chronic hepatitis B treatment. However, the results of clinical trials conducted in HBV patients were rather disappointing and frustrating, as DNA-vaccines have not shown the same efficacy in patients as in animal models. We are convinced that the design of innovative clinical trials based on strategies able to increase DNA vaccine immunogenicity will allow to advance in this challenging field.

KEYWORDS:

• DNA vaccine
• hepatitis B virus (HBV)
• chronic infection
• woodchuck HBV (WHV)
• duck HBV (DHBV)
• electroporation
• immune therapy
• viral suppression

Article highlights

• DNA-based vaccines offer advantage for immune therapy of HBV-carriers by activation, in addition of humoral responses, also cellular and innate host immunity.

• DNA vaccines have additional attractive attributes such as simplicity and rapidity of design, high flexibility, easy production, capacity to encode different HBV antigens and absence of elicited anti-vector immunity.

• Preclinical studies in chronic hepadnaviral infection models (WHV-infected woodchuck, DHBV-carrier duck) demonstrated the ability of DNA vaccines to break immune tolerance and to enhance infection clearance, including the recurrent, intranuclear viral cccDNA form.

• DNA vaccines administration with antiviral drugs, molecular adjuvants, prime-boost regimens, anti-PDL-1 antibody and importantly, in vivo elctroporation-mediated plasmid delivery, have considerably enhanced their immunological performance and therapeutic potency, as highlighted by preclinical studies.

• Clinical trials conducted in HBV patients showed safety and good tolerance of DNA vaccines. Although a poor therapeutic efficacy was observed in most of these trials based on ‘first generation’ DNA vaccines that solely targeted viral envelope and were delivered by conventional injection.

• The improved DNA vaccine candidate will encode multiple HBV proteins, include immune molecular adjuvants and should be delivered by electroporation to NUCs-treated chronic hepatitis B patients. The combination of such vaccine with innovative molecules targeting viral capsid and envelope will hopefully contribute to functional cure of chronic hepatitis B.

Declaration of interest

L Cova has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

L Cova is funded by INSERM.