Combined Adenovirus Vector and Hepatitis C Virus Envelope Protein Prime-Boost Regimen Elicits T Cell and Neutralizing Antibody Immune Responses

Abstract

Despite the recent progress in the development of new antiviral agents, hepatitis C virus (HCV) infection remains a major global health problem, and there is a need for a preventive vaccine. We previously reported that adenoviral vectors expressing HCV nonstructural proteins elicit protective T cell responses in chimpanzees and were immunogenic in healthy volunteers. Furthermore, recombinant HCV E1E2 protein formulated with adjuvant MF59 induced protective antibody responses in chimpanzees and was immunogenic in humans. To develop an HCV vaccine capable of inducing both T cell and antibody responses, we constructed adenoviral vectors expressing full-length and truncated E1E2 envelope glycoproteins from HCV genotype 1b. Heterologous prime-boost immunization regimens with adenovirus and recombinant E1E2 glycoprotein (genotype 1a) plus MF59 were evaluated in mice and guinea pigs. Adenovirus prime and protein boost induced broad HCV-specific CD8 Hepatitis C virus (HCV) infection is a major global health problem affecting an estimated 170 million people worldwide, occurring among persons of all ages, genders, races, and regions of the world. Chronically infected subjects are at risk of developing progressive liver disease, including cirrhosis, and primary hepatocellular carcinoma (1). Although the recent introduction of directly acting antiviral drugs (DAAs) has improved therapy for chronic HCV and interferon (IFN)-free regimens are on the horizon (2), treatment success may be limited by a range of factors, including awareness of infection status, access to and cost of therapy, relative efficacy of different regimens for specific HCV genotypes, adverse effects, comorbidities (e.g., cirrhosis or HIV coinfection), and host factors. For these reasons, the development of a safe, effective, and affordable preventive vaccine against HCV is the optimal long-term goal to control the global epidemic (3).Approximately 20% of infected individuals clear the virus spontaneously, and resolution is associated with HLA type and with potent, multispecific, and long-lasting T cell responses (4). T cell depletion experiments with chimpanzees confirmed the essential role of cellular immunity in controlling HCV infection (5). Moreover, antibodies targeting the HCV envelope glycoproteins have been shown to neutralize infection in vitro (6, 7) and to protect against virus challenge in the human liver-Alb-uPA/SCID murine model (8)(9)(10). A recent report demonstrated that spontaneous clearance of HCV is associated with the early appearance of a broadly neutralizing antibody response (11). Recombinant E1E2 glycoproteins have been shown to induce cross-neutralizing antibody responses against het-

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.…”

Designing an HCV vaccine: a unique convergence of prevention and therapy?

“…Some of these vaccines were comprised of the HCV E1 and E2 envelope glycoproteins that are targeted by neutralizing antibodies[19], while others focused on expression of non-structural proteins like NS3, NS4a, NS4b, NS5a and NS5b that are dominant targets of the T cell response[18]. Structural and non-structural HCV proteins have also been combined to elicit humoral and cellular immunity using prime-boost strategies[18,20]. A very small subset of these experimental vaccines were tested for their capacity to protect chimpanzees from virus challenge[18].…”

Progress in Vaccine Development for HCV Infection

“…Various HCV candidate vaccines were described, comprising synthetic peptides [24], recombinant E1 and E2 proteins [25,26], recombinant adenoviral and prime-boost strategies with modified vaccinia Ankara (MVA) vaccines or recombinant E1 and E2 glycoproteins [27][28][29][30]. However, only few proceeded to phases I and II using recombinant poxvirus [31], DNA vaccines [29,32], synthetic peptide-based vaccines [33], and MVA vaccines and adenoviral [34,35].…”