Chimeric hepatitis B virus/hepatitis C virus envelope proteins elicit broadly neutralizing antibodies and constitute a potential bivalent prophylactic vaccine

Abstract

The development of a prophylactic vaccine against hepatitis C virus (HCV) has become an important medical priority, because 3-4 million new HCV infections are thought to occur each year worldwide. Hepatitis B virus (HBV) is another major human pathogen, but infections with this virus can be prevented with a safe, efficient vaccine, based on the remarkable ability of the envelope protein (S) of this virus to self-assemble into highly immunogenic subviral particles. Chimeric HBV-HCV envelope proteins in which the N-terminal transmembrane domain of S was replaced with the transmembrane domain of the HCV envelope proteins (E1 or E2) were efficiently coassembled with the wild-type HBV S protein into subviral particles. These chimeric particles presented the full-length E1 and E2 proteins from a genotype 1a virus in an appropriate conformation for formation of the E1-E2 heterodimer. Produced in stably transduced Chinese hamster ovary cells and used to immunize New Zealand rabbits, these particles induced a strong specific antibody (Ab) response against the HCV and HBV envelope proteins in immunized animals. Sera containing anti-E1 or anti-E2 Abs elicited by these particles neutralized infections with HCV pseudoparticles and cellcultured viruses derived from different heterologous 1a, 1b, 2a, and 3 strains. Moreover, the anti-hepatitis B surface response induced by these chimeric particles was equivalent to the response induced by a commercial HBV vaccine. Conclusions: Our results provide support for approaches based on the development of bivalent HBV-HCV prophylactic vaccine candidates potentially able to prevent initial infection with either of these two hepatotropic viruses. (HEPATOLOGY 2013;57:1303-1313 C hronic hepatitis C virus (HCV) infection is a major public health problem affecting more than 170 million people worldwide. 1 Three to four million new infections are thought to occur each year and a prevalence of 10%-30% has been reported in countries in which this virus is highly endemic, including Egypt, which has the highest HCV prevalence in the world. 2 HCV infection is one of the leading causes of chronic liver disease; it is associated with a high risk of cirrhosis and hepatocellular carcinoma and is the major indication for liver transplantation in industrialized countries. Provided it is detected sufficiently early, progression to severe disease can be prevented by treatment with a combination of pegylated interferon (IFN)-a and ribavirin, in some cases supplemented with recently approved nonstructural protein 3/4A protease inhibitors. 3 This triple therapy yields a sustained virologic response, but is very expensive and may be associated with drug-drug interactions and severe side effects. Therefore, the development of a prophylactic vaccine against HCV is a major medical priority. However, the development of such a vaccine

Altered Glycosylation Patterns Increase Immunogenicity of a Subunit Hepatitis C Virus Vaccine, Inducing Neutralizing Antibodies Which Confer Protection in Mice

“…The HCV envelope proteins E1 and E2 are responsible for mediating HCV entry into target cells by direct or indirect interaction with numerous host molecules (16,17) and are thus the natural targets of NAbs (18). Consequently, all experimental HCV vaccines that aim to generate NAbs contain E2 and/or E1 components in a variety of modalities or prime-boost regimens (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Although significant progress has been made toward the development of an efficacious HCV vaccine mediating protection by inducing humoral immune responses, several important issues remain: (i) the spectrum of NAbs elicited by existing vaccine candidates is still insufficiently broad to cover all seven HCV genotypes; (ii) the complexity of the heterologous prime-boost regimens with different antigen modalities renders vaccine production and vaccination difficult; (iii) the low yield of antigen manufacture hampers the application of some promising vaccine candidates, such as inactivated cell culture-derived HCV (HCVcc) (23); (iv) few of these vaccines have been evaluated in an immunocompetent-animal model by active immunization, as the utilization of chimpanzees is limited for ethical and financial reasons and murine models, such as human liver chimeric mice (29), are immunodeficient.…”

Modification of Asparagine-Linked Glycan Density for the Design of Hepatitis B Virus Virus-Like Particles with Enhanced Immunogenicity

“…The HBsAgS VLPs are processed by DCs and antigens presented via the major histocompatibility complex (MHC) class I and II antigen presentation pathways (10). In addition to HBsAgS VLPs being an immunogen of medical interest to prevent or to overcome HBV infections, the particles have been used as platforms for the delivery of foreign antigenic sequences and facilitated the induction of anti-foreign antigen-specific immune responses (11)(12)(13)(14)(15)(16)(17)(18). The most advanced malaria vaccine RTS,S is based on HBsAgS VLPs with a circumsporozoite epitope fused to the subunits.…”

Prophylactic vaccinations in chronic kidney disease: Current status

“…66 Chimeric HBV-HCV envelope proteins were recently developed and such particles elicited a strong specific neutralizing antibody response against HCV and HBV envelope proteins in rabbits. 67 These data may be a chance for the development of a bivalent vaccine able to prevent infection from both HBV and HCV.…”