Neutralizing Antibodies Induced by Cell Culture–Derived Hepatitis C Virus Protect Against Infection in Mice

Akazawa, Daisuke; Moriyama, Masaki; Yokokawa, Hiroshi; Omi, Noriaki; Watanabe, Noriyuki; Date, Tomoko; Morikawa, Kenichi; Aizaki, Hideki; Ishii, Koji; Kato, Takanobu; Mochizuki, Hidenori; Nakamura, Noriko; Wakita, Takaji

doi:10.1053/j.gastro.2013.05.007

Cited by 71 publications

(91 citation statements)

References 42 publications

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“…Thus far, only a few NAb-based vaccines have been evaluated in vivo due to the scarcity of small-animal models for HCV infection (12,19,20,23). For example, an inactivated HCV vaccine was found to induce NAbs capable of protecting chimeric uPA/SCID mice from lower-dose (10 3 RNA copies of HCVcc) HCV challenge, but not higher doses (10 4 and 10 5 RNA copies of HCVcc) (23).…”

Section: Discussionmentioning

confidence: 99%

“…For example, an inactivated HCV vaccine was found to induce NAbs capable of protecting chimeric uPA/SCID mice from lower-dose (10 3 RNA copies of HCVcc) HCV challenge, but not higher doses (10 4 and 10 5 RNA copies of HCVcc) (23). In this study, we used immunocompetent mice to assess the immunogenicity, as well as the prophylactic efficacy, of the vaccine candidate.…”

Section: Discussionmentioning

confidence: 99%

“…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. To address some of these challenges, we aimed to develop an improved method for inducing broadly neutralizing antibodies (bNAbs).…”

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confidence: 99%

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

Schaewen

Wang

et al. 2016

J Virol

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Hepatitis C virus (HCV) infection is a global health problem for which no vaccine is available. HCV has a highly heterogeneous RNA genome and can be classified into seven genotypes. Due to the high genetic and resultant antigenic variation among the genotypes, inducing antibodies capable of neutralizing most of the HCV genotypes by experimental vaccination has been challenging. Previous efforts focused on priming humoral immune responses with recombinant HCV envelope E2 protein produced in mammalian cells. Here, we report that a soluble form of HCV E2 (sE2) produced in insect cells possesses different glycosylation patterns and is more immunogenic, as evidenced by the induction of higher titers of broadly neutralizing antibodies (bNAbs) against cell culture-derived HCV (HCVcc) harboring structural proteins from a diverse array of HCV genotypes. We affirm that continuous and discontinuous epitopes of well-characterized bNAbs are conserved, suggesting that sE2 produced in insect cells is properly folded. In a genetically humanized mouse model, active immunization with sE2 efficiently protected against challenge with a heterologous HCV genotype. These data not only demonstrate that sE2 is a promising HCV vaccine candidate, but also highlight the importance of glycosylation patterns in developing subunit viral vaccines. IMPORTANCEA prophylactic vaccine with high efficacy and low cost is urgently needed for global control of HCV infection. Induction of broadly neutralizing antibodies against most HCV genotypes has been challenging due to the antigenic diversity of the HCV genome. Here, we refined a high-yield subunit HCV vaccine that elicited broadly neutralizing antibody responses in preclinical trials. We found that soluble HCV E2 protein (sE2) produced in insect cells is distinctly glycosylated and is more immunogenic than sE2 produced in mammalian cells, suggesting that glycosylation patterns should be taken into consideration in efforts to generate antibody-based recombinant vaccines against HCV. We further showed that sE2 vaccination confers protection against HCV infection in a genetically humanized mouse model. Thus, our work identified a promising broadly protective HCV vaccine candidate that should be considered for further preclinical and clinical development. I t is estimated that over 2% of the world's population is chronically infected with hepatitis C virus (HCV) (1). Although recently approved direct-acting antiviral (DAA) drugs (2) have greatly improved upon the curing efficacy of the previous interferon (IFN)-based regimen, these new therapies are very expensive and thus unaffordable for the majority of HCV-infected individuals who live in developing countries, where most new infections occur. Since the approval of these highly effective DAAs, the number of chronic HCV carriers has not significantly declined. Furthermore, there is little evidence that patients cured of their chronic infections with DAAs retain antiviral immunity that is protective against future HCV exposures. Therefore, the...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Schaewen

Wang

et al. 2016

J Virol

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“…Also, purified HCV-like particles synthesized in insect cells (from a recombinant baculovirus expressing Core, E1 and E2 proteins) have been evaluated as a potential immunogen for vaccine development [20,276]. Finally, the success during the last 10 years in generating culture viruses expressing the envelope proteins of the different genotypes provide the opportunity of evaluating whole virus inactivated HCV vaccine candidates [277,278]. The difficulty in defining universally conserved epitopes for HCV neutralization also highlights the difficulties in developing a broadly protective HCV vaccine.…”

Section: Protective Immunity Of Neutralizing Antibodies Against Hcvmentioning

confidence: 99%

The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control

Bukh

2016

Journal of Hepatology

207

173

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The discovery of hepatitis C virus (HCV) in 1989 permitted basic research to unravel critical components of a complex life cycle for this important human pathogen. HCV is a highly divergent group of viruses classified in 7 major genotypes and a great number of subtypes, and circulating in infected individuals as a continuously evolving quasispecies destined to escape host immune responses and applied antivirals. Despite the inability to culture patient viruses directly in the laboratory, efforts to define the infectious genome of HCV resulted in development of experimental recombinant in vivo and in vitro systems, including replicons and infectious cultures in human hepatoma cell lines. And HCV has become a model virus defining new paradigms in virology, immunology and biology. For example, HCV research discovered that a virus could be completely dependent on microRNA for its replication since microRNA-122 is critical for the HCV life cycle. A number of other host molecules critical for HCV entry and replication have been identified. Thus, basic HCV research revealed important molecules for development of host targeting agents (HTA). The identification and characterization of HCV encoded proteins and their functional units contributed to the development of highly effective direct acting antivirals (DAA) against the NS3 protease, NS5A and the NS5B polymerase. In combination, these inhibitors have since 2014 permitted interferon-free therapy with cure rates above 90% among patients with chronic HCV infection; however, viral resistance represents a challenge. Worldwide control of HCV will most likely require the development of a prophylactic vaccine, and numerous candidates have been pursued. Research characterizing features critical for antibody-based virus neutralization and T cell based virus elimination from infected cells is essential for this effort. If the world community promotes an ambitious approach by applying current DAA broadly, continues to develop alternative viral- and host- targeted antivirals to combat resistant variants, and invests in the development of a vaccine, it would be possible to eradicate HCV. This would prevent about 500 thousand deaths annually. However, given the nature of HCV, the millions of new infections annually, a high chronicity rate, and with over 150 million individuals with chronic infection (which are frequently unidentified), this effort remains a major challenge for basic researchers, clinicians and communities.

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“…Later, robust production of HCVcc particles was obtained by introducing a few specific mutations in JFH-1 structural proteins [49]. Also, Akazawa et al [50] showed that a protective vaccine can be developed from inactivated HCV particles derived from cultured cells that protected chimeric liver uPA(+/+)-SCID mice against HCV infection. Also, Gottwein and Bukh [51] cultured virus particles constituting the antigen in most antiviral vaccines.…”

Section: Cell Culture-derived Hcv (Hcvcc)mentioning

confidence: 99%

Progress in Vaccine Development for HCV Infection

Tabll¹,

El‐Shenawy²,

El³

2017

Update on Hepatitis C

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Hepatitis C virus (HCV) is a blood-transmitted disease that spreads among 3% of the world's population causing seriously increasing mortality rates. The HCV prevalence in Egypt in October 2008 was 14.7% and declined to 6.3% in the survey carried out in October 2015. Nowadays, the new direct-acting antivirals (DAAs) show amazing results especially with regard to HCV genotype 1, but there is still a great necessity to produce a vaccine to avoid this viral infection. Additionally, neutralizing anti-HCV antibodies could be utilized in combination with DAAs empowering their effect. A powerful candidate HCV vaccine should create comprehensively cross-receptive T cells CD4 and CD8 and effectively neutralizing antibodies to successfully clear the virus. The current clinical trials for HCV vaccines comprise synthetic peptides, DNA-based vaccines, or recombinant protein vaccines. Several preclinical vaccine studies are under research including cell culture-derived HCV (HCVcc), HCV-like particles, and recombinant adenoviral vaccines. This mini-review will discuss the prevalence of HCV worldwide and in Egypt. We will present the recent progress in basic research and preclinical and clinical studies for HCV vaccine. Finally, it will present the phenomena of spontaneous clearance of HCV without treatment as a model for study of HCV vaccine development.

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Neutralizing Antibodies Induced by Cell Culture–Derived Hepatitis C Virus Protect Against Infection in Mice

Cited by 71 publications

References 42 publications

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

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

The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control

Progress in Vaccine Development for HCV Infection

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