Nucleic acid vaccines: A taboo broken and prospect for a hepatitis B virus cure

Abstract

Although a prophylactic vaccine is available, hepatitis B virus (HBV) remains a major cause of liver-related morbidity and mortality. Current treatment options are improving clinical outcomes in chronic hepatitis B; however, true functional cure is currently the exception rather than the rule. Nucleic acid vaccines are among the emerging immunotherapies that aim to restore weakened immune function in chronically infected hosts. DNA vaccines in particular have shown promising results in vivo by reducing viral replication, breaking immune tolerance in a sustained manner, or even decimating the intranuclear covalently closed circular DNA reservoir, the hallmark of HBV treatment. Although DNA vaccines encoding surface antigens administered by conventional injection elicit HBV-specific T cell responses in humans, initial clinical trials failed to demonstrate additional therapeutic benefit when administered with nucleos(t)ide analogs. In an attempt to improve vaccine immunogenicity, several techniques have been used, including codon/promoter optimization, coadministration of cytokine adjuvants, plasmids engineered to express multiple HBV epitopes, or combinations with other immunomodulators. DNA vaccine delivery by electroporation is among the most efficient strategies to enhance the production of plasmid-derived antigens to stimulate a potent cellular and humoral anti-HBV response. Preliminary results suggest that DNA vaccination via electroporation efficiently invigorates both arms of adaptive immunity and suppresses serum HBV DNA. In contrast, the study of mRNA-based vaccines is limited to a few in vitro experiments in this area. Further studies are needed to clarify the prospects of nucleic acid vaccines for HBV cure.

Keywords: Chronic hepatitis B; Therapeutic vaccination; Nucleic acid vaccines; DNA vaccines; Electroporation; Immunotherapy

Core Tip: A nucleic acid vaccine could be of particular value in the field of hepatitis B virus therapies. DNA vaccines have been studied more extensively over the past two decades and have been shown to overcome immune exhaustion in preclinical models of chronic infection. Although vaccination elicited robust humoral and cellular immune responses, it had negligible effects on clinical endpoints. Therefore, the scientific community has focused on optimizing vaccine design and delivery to improve immunogenicity. Electroporation-mediated delivery of multivalent plasmids in combination with molecular adjuvants could efficiently restore adaptive immunity in virally suppressed patients and be part of future combination therapy.