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Contents lists available at ScienceDirect

Infection, Genetics and Evolution journal homepage: www.elsevier.com/locate/meegid

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Review

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Therapeutic vaccines against hepatitis C virus

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Jihua Xue, Haihong Zhu, Zhi Chen ⇑ State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, China

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a r t i c l e

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i n f o

Article history: Received 17 May 2013 Received in revised form 31 December 2013 Accepted 7 January 2014 Available online xxxx

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Keywords: Hepatitis C virus Immunity T cells Therapeutic vaccine Epitope

a b s t r a c t Hepatitis C virus (HCV) is a blood-borne pathogen which has chronically infected about 130–210 million people worldwide. Current standard-of-care (SoC) therapy is an inadequate and expensive treatment with more side effects. Two direct-acting antiviral agents (DAAs) (telaprevir and boceprevir) in combination with SoC therapy have been used in patients infected with HCV genotype 1. Although these drugs result in a shortening of therapy, they also have additional side effects and are expensive. In their stead, several second-generation DAAs are being investigated. What important is that all-oral, interferon (IFN)and ribavirin-free regimens for the treatment of HCV-infected patients are now being investigated, and will be applied in the next year. Preventive measures against HCV, including vaccine development, are also now in progress. However, no therapeutic vaccine against HCV has been produced to date. An effective vaccine should induce robust and broadly cross-reactive CD4+, CD8+T-cell and neutralising antibody (NAb) responses. Current data indicate that vaccines can usually not completely prevent HCV infection but rather prevent the progression of HCV infection to chronic and persistent infection, which may be a realistic goal. This review discusses the important roles of NAbs and CD8+T-cells in the development of therapeutic vaccines, and summarizes some important epitopes of HCV recognized by CD8+T-cells and some prospective therapeutic vaccine approaches. Ó 2014 Elsevier B.V. All rights reserved.

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Contents

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4. 5. 6.

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Q2

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current treatment and future treatment strategies for HCV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Therapeutic HCV vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Challenges to HCV vaccine development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. HCV diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Antiviral host immunity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. HCV animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Important role of humoral immunity towards HCV in vaccine development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Important role of CD8+T-cells in vaccine development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scientific approaches in the development of a therapeutic vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Recombinant protein-based vaccines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Peptide-based vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. DNA-based vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Viral vector-based vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Dendritic cells-based Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Future vaccine approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: HCV, hepatitis C virus; SoC, standard-of-care; DAAs, direct-acting antiviral agents; NAb, neutralising antibody; UTRs, untranslated regions; SR-BI, scavenger receptor class B type I; OCLN, tight-junction proteins occludin; CLDN-1, claudin-1; LDL-R, low density lipoprotein receptor; GAGs, glycosaminoglycans; NPC1L1, Niemann-Pick C1-like 1; SVR, sustained virological response; IFN, interferon; PEG-IFN, pegylated interferon; RdRp, RNA-dependent RNA polymerase; VLDL, very lowdensity lipoprotein; GWAS, genome-wide association studies; SNP, single nucleotide polymorphisms; DCs, Dendritic cells. ⇑ Corresponding author. Address: The First Affiliated Hospital of Zhejiang University, 79 Qingchun Road, Hangzhou, Zhejiang 310003, China. Tel.: +86 0571 87236579; fax: +86 0571 87068731. E-mail address: [email protected] (Z. Chen). 1567-1348/$ - see front matter Ó 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.meegid.2014.01.008

Please cite this article in press as: Xue, J., et al. Therapeutic vaccines against hepatitis C virus. Infect. Genet. Evol. (2014), http://dx.doi.org/10.1016/ j.meegid.2014.01.008

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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1. Introduction

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Hepatitis C virus (HCV) has led to chronic infection in approximately 3% of the world population (Ascione et al., 2007; Lavanchy, 2009; Shepard et al., 2005). Each year, 3–4 million people are newly infected with HCV and 476,000 patients die from HCV-associated end-stage liver disease and its complications (Shepard et al., 2005). Among all HCV infected individuals, 20% of them eradicate the virus over weeks or months and are often asymptomatic. The remaining 80% of them will develop chronic disease, of whom about 20% and 1–5% will eventually develop liver cirrhosis and liver cancer, respectively (Afdhal, 2004; Lauer and Walker, 2001). Currently, it was reported that HCV infection was a leading cause of death in human immunodeficiency virus (HIV)-coinfected patients (Salmon-Ceron et al., 2005). HCV-related end-stage liver disease is the most common reason for liver transplantation today in the US and Western Europe (Tang and Grise, 2009). No vaccine is now available to prevent hepatitis C infection (Houghton and Abrignani, 2005). Therefore, previous incidence as well as new incidence all account for future disease burdens. The 9.6 kb viral RNA genome is composed of an open reading frame flanked by 50 - and 30 -untranslated regions (UTRs). When HCV enters into the cytoplasm, the viral RNA genome is translated to a polyprotein (approximately 3,000 amino acids in length) that is post-translationally cleaved into three major structural viral proteins (core, envelope (E) 1 and 2), a small membrane polypeptide p7 and six non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (Grakoui et al., 1993; Reed and Rice, 2000; Tang and Grise, 2009). HCV enters cells through receptor-mediated endocytosis. Several cellular receptor proteins including the tetraspanin CD81 (Lindenbach et al., 2005; Pileri et al., 1998), scavenger receptor class B type I (SR-BI) (Scarselli et al., 2002), tight-junction proteins occludin (OCLN) (Benedicto et al., 2009; Liu et al., 2009; Ploss et al., 2009) and claudin-1 (CLDN-1) (Evans et al., 2007; Liu et al., 2009), low density lipoprotein receptor (LDL-R) (Agnello et al., 1999; Molina et al., 2007), and glycosaminoglycans (GAGs) (Barth et al., 2003; Germi et al., 2002) have been shown to be the receptors for HCV. Recently, Sainz and coworkers demonstrated that the Niemann-Pick C1-like 1 (NPC1L1) cholesterol adsorption receptor is also involved in HCV entry (Sainz et al., 2012). In this review, the important roles of NAbs and CD8+T-cells in vaccine development are discussed. And then some important epitopes of HCV recognized by CD8+T-cells and several prospective therapeutic vaccine approaches are overviewed. After introduction of the current treatment and future treatment options for HCV patients, the problems and challenges associated with the development of therapeutic HCV vaccines will be described.

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2. Current treatment and future treatment strategies for HCV

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According to the EASL and APASL guidelines (European Association for the Study of the Liver Collaboration., 2011; Omata et al., 2012), the combination of pegylated interferon (PEG-IFN)-a and ribavirin is the approved and well accepted therapy for chronic hepatitis C. However, this therapy is long, expensive, toxic, and only effective in around 50% of patients infected with the most common genotype (Fried et al., 2002; Hadziyannis et al., 2004; Manns et al., 2001, 2006). Moreover, telaprevir and boceprevir were recommended to be used in combination with PEG-IFN-a

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plus ribavirin in HCV 1-infected patients according to the AASLD (Ghany et al., 2011) and APASL guidelines. This new treatment regimen clearly demonstrated a 20–30% increase for the SVR rate of genotype 1-infected patients. And treatment can be significantly shortened in proportion to patients with satisfactory early responses (Bacon et al., 2010; Jacobson et al., 2010; Poordad et al., 2010; Sherman et al., 2010). However, use of triple therapy is limited only to genotype 1-infected patients, the cost of treatment rises further and around 40% of the treated patients have the additional side effects such as cutaneous rash and anemia (Bacon et al., 2011; Jacobson et al., 2011; Poordad et al., 2011). Moreover, the triple therapy is associated with the rapid onset of drug resistance (Kwo et al., 2010; McHutchison et al., 2010). In the future, an IFN-free, ribavirin-free regimen with improved tolerability, less frequent dosing for improved adherence and high SVR rates is desirable. In a phase 2a study, the all-oral, IFN- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS791325 was well tolerated and achieved high SVR rates in patients with HCV genotype 1 infection. Further studies of this regimen are warranted (Everson et al., 2013).

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3. Therapeutic HCV vaccine

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New therapies with higher efficacy, lower adverse effects and improved tolerability are urgently required due to the limitations of the current therapies. The development of safe, effective and affordable vaccines for treatment of HCV remains the best choice for controlling the global epidemic. And a balanced T-cell response and broad spectrum NAb activity is ideal for HCV vaccine development. However, a significant challenge for vaccine development is to identify protective epitopes conserved in the majority of viral genotypes and subtypes. This problem is compounded by the fact that the envelope E1E2 proteins, the targets for NAb response, are two of the most variable proteins of the virus.

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3.1. Challenges to HCV vaccine development

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3.1.1. HCV diversity Due to the high production rate and the short half-life of HCV and the low-fidelity of the NS5B RNA-dependent RNA polymerase (RdRp), HCV mutates at nearly one nucleotide per replication cycle. These frequent mutations result in the presence of many distinct but closely related HCV variants (known as quasispecies) typically in one infected individual, which clearly poses a significant challenge to successful vaccine development. The greatest genetic variability is identified in the E1 and E2 glycoproteins (Simmonds et al., 2005). Thus, the envelope region may causes difficulties in the development of cross-protective vaccines to induce NAbs. However, studies have demonstrated that plasma samples and monoclonal antibodies could cross-neutralize the different genotypes (Kachko et al., 2011; Law et al., 2008; Simmonds et al., 2005; Stamataki et al., 2008; Zhang et al., 2009). Indeed, the phase I trial of the HCV E1E2MF59C.1 vaccine showed that the recombinant E1/E2-puried proteins is safe and induced significant lymphoproliferative and antibody responses in humans (Frey et al., 2010). Therefore, despite the challenges presented by HCV diversity, there are promising indications that cross-protective immune responses exist in natural infection and can be mimicked by vaccination.

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3.1.2. Antiviral host immunity 3.1.2.1. HCV-specific T-cell responses. The HCV-specific T cell responses play a crucial role in determining the outcome of primary HCV infection. Comparative human studies have demonstrated that a broad, multi-specific and sustained CD8+ and CD4+ T-cell response is associated with spontaneous viral clearance. But a weak and narrow CD8+ and CD4+ T-cell response is a hallmark of persistent infection (Grakoui et al., 2003; Schulze zur Wiesch et al., 2005; Thimme et al., 2001; Wertheimer et al., 2003). Which suggest that a HCV therapeutic vaccine will be able to overcome the diverse mechanisms of T-cell response impairment. Findings from several studies demonstrated that both chimpanzees and humans who have previously cleared HCV are at least partially protected against reinfection in the majority of cases (Bassett et al., 2001; Mehta et al., 2002; Nascimbeni et al., 2003; Osburn et al., 2010). This form of protective immunity usually not prevents acute infection with sterilizing immunity but rather prevents the chronicity of HCV infection. Since chronic infection, not acute infection, is associated significantly with morbidity and mortality, the prevention of chronicity is an acceptable end point. 3.1.2.2. Humoral immunity towards HCV. Viral clearance during acute infection is in direct correlation with the rapid induction of circulating cross-NAbs (Pestka et al., 2007), which indicates that the circulating antibodies play important roles in controlling HCV during early infection. However, high titers of NAbs are also observed in the majority of chronically infected patients and clearly are unable to control infection (Bartosch et al., 2003). The failure of NAbs in controlling HCV infection could be caused by several different factors. Firstly, the highest virus level of genetic heterogeneity is observed in the envelope protein, which is the major target for HCV antibodies. Variation between quasispecies in these envelope proteins may allows the virus to evade the host humoral immunity (von Hahn et al., 2007). Secondly, HCV can bind to very low-density lipoprotein (VLDL), which facilitates the uptake of HCV by hepatocytes and therefore helps HCV avoid recognition by NAbs (Maillard et al., 2006). HCV evades the humoral immunity also by other mechanisms, including direct cell-to-cell viral transfer, induction of interfering antibodies (von Hahn et al., 2007; Zhang et al., 2009) and the shielding of neutralizing epitopes by glycosylation (Helle et al., 2007). 3.1.2.3. Innate immunity. The fact that IFN-a forms the mainstay of treatment for HCV clearly demonstrates that innate immune cytokines play crucial roles in eradicating the virus. Recent genomewide association studies (GWAS) and candidate gene studies identified single nucleotide polymorphisms (SNP) in and near IFN-k (also known as IL-28B) that are associated with spontaneous clearance of HCV and sustained responses to standard treatment (Ge et al., 2009; Suppiah et al., 2009; Tanaka et al., 2009; Thomas et al., 2009). Possibly, the impact of IFN-k on the effectiveness of adaptive immune responses induced by therapeutic vaccinees should be investigated. 3.1.3. HCV animal models The lack of immunocompetent small animal models for HCV infection stands in the way of evaluation of the efficacy of vaccine candidates. Firstly, chimpanzee, the only immunocompetent animal model for HCV, are very useful in the preclinical phases of vaccine development. However, there are practical, financial and ethical limitations in using these animals for research (Bettauer, 2010). Secondly, it was difficult to extrapolate the results of HCV non-susceptible animal models to human, the prediction of the most effective approach and/or target antigens for humans can not be made. Therefore, in order to accelerate the preclinical screening for potential therapeutic HCV vaccine candidates, an

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HCV-susceptible immunocompetent small animal model would be very essential. Recently, an immunocompetent transgenic mouse model expressing human CD81 and OCLN that can support HCV cell entry has been generated (Dorner et al., 2011). Further development of this model will accelerate the development of therapeutic vaccines for HCV infection in the future.

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4. Important role of humoral immunity towards HCV in vaccine development

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Various studies have shown that a broad and vigorous cellular immune response is needed to clear the virus in the acute phase (Lechner et al., 2000; Missale et al., 1996) while the role of NAbs is less clear (Meuleman et al., 2011; Pestka et al., 2007; Raghuraman et al., 2012). More recently, studies have demonstrated an association between the presence of NAbs and the clearance of acute infection without the development of chronic, persistent infection (Osburn et al., 2010; Pestka et al., 2007). However, most chronically infected HCV patients develop high-titer of antibodies but they were not able to control HCV infection (Lagging et al., 2002) which may be due to poor immunogenicity of the virus envelope glycoproteins and/or generation of an inappropriate immune response in infected humans. A recent study showed that neutralization resistance of HCV can be overcomed by applying recombinant antibodies (Pedersen et al., 2013). Therefore, eliciting NAbs should be explored as at least an important part of successful vaccine development. Several newly identified highly conserved neutralizing epitopes that could elicit a protective humoral immune have been summarized in a review publised this year (Wahid and Dubuisson, 2013). Previous studies revealed that the NS3 helicase contained immunodominant B-cell epitopes eliciting high levels of antibodies in HCV infected individuals (Jolivet-Reynaud et al., 2004; Zhang et al., 2000). A study pointed out that novel monoclonal antibodies, which recognized highly conserved epitopes at crucial functional sites within NS3 helicase (linear epitope: 1231–1239 or core motif: 1373–1380), may become important antibodies for diagnosis and antiviral therapy in chronic HCV infection (Bian et al., 2013). The results of an open-label study showed that the vaccine Cenv3, which was composed of 3 envelop peptides (p315 from E1, p412 and p517 from E2), were able to induce responses sufficient to reduce significantly viral RNA concentrations in HCV-infected patients shown to be non responders to SoC therapy. The vaccine is safe and tolerable with slight improvement in liver functions and platelet counts (El-Awady et al., 2013). Earlier work showed that a recombinant gpE1/gpE2 HCV vaccine was immunogenic in guinea pigs (Stamataki et al., 2007) and chimpanzees (Meunier et al., 2011) and was shown to induce protective immune responses in the latter model against experimental challenge with either homologous or heterologous genotype 1a HCV strains (Meunier et al., 2011). A phase I dose ranging clinical trial has been conducted at the Saint Louis University Vaccine and Treatment Evaluation Unit to test the safety and immunogenicity of this vaccine in healthy volunteers (Frey et al., 2010). All volunteers elicited antibodies against the glycoproteins gpE1/gpE2 and the vaccine was effective in inducing strong T-helper (Th) responses (Frey et al., 2010; Ray et al., 2010). Further studies have shown that the vaccine induced antibodies targeting well characterized epitopes on E1/E2, and the sera from the phase I clinical trial showed very broad cross neutralization activity against representatives of all seven major genotypes of HCV that occur globally (Law et al., 2013). Which suggested that a vaccine derived from a single strain of HCV can elicit broad cross-NAbs against all known major genotypes of HCV and provide considerable encouragement for the further development of a human vaccine against

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Epitopes (aa sequence, restriction molecules)

Functional properties

NS5B

2841–2849 (ARMILMTHF, HLA-B27)

IFN-c secreting and protective epitope

Cooper et al. (1999)

E1 E2 P7 NS2 NS3 NS5A

306–315 (CSIYPGHITG, Pat r-A⁄ 0402); 366–375 (GNWAKVLVVL, Pat r- C⁄ 0601/C⁄ 0602) 621–629 (T INYTIFKI, Pat r- B⁄ 2001); 651–665 (RCDLEDRDRSELSPL, Pat r- A⁄ 0601) 781–791 (KWVPGAVYTFY, Pat r-A⁄ 0601) 997–1008 (INGLPVSARRGR, Pat r-A⁄ 0402) 1629–1637 (GAVQNEITL, Pat r- B⁄ 1701) 2055–2065 (MWSGTFPINAY, Pat r- A⁄ 0601)

Cytotoxic epitopes identified in recovered champanzees

Wedemeyer et al. (2002)

Core NS3

35–44 (Y LLPRRGPRL, HLA-A2); 132–140 (DLMGYIPLV, H LA-A2) 1073–1081 (CVNGVCWTV, HLA-A2); 1406–1415 (KLVA LGINAV, H LA-A2)

Cytotoxic and IFN-c secreting epitopes identified in chronic and recovered individuals

Lauer et al. (2004)

Core E1 E2 NS2 NS3

41–49 (GPRLGVRAT, H LA-B7); 88–96 (NEGCGWM GW, H LA-B44); 111–119 (DPRRRSRNL, HLA- B7) 207–214 (CPNSSIVY, HLA-B35); 322–330 (MMMNWS PTT) 541–551 (NTRPPLGNWFG, HLA- B57); 610–619 (YRL WHYPCTI, HLA- Cw7) 831–840 (LSPYYKRYIS, HLA-A25); 941–960 (LGALT GTY V YNHLTPLRDWA); 957–964 (RDWAHNGL, HLA- B37) 1070–1089 (ATCINGVCWTVYHGAGTRTI); 1073–1081 (CINGVCWTV, HLA-A2); 1175–1183 (HAVGLFR AA, HLA-A68); 1359–1367 (HPNIEEVAL, HLA- B35); 1395–1403 (HSKKKCDEL, H LA-B8); 1406–1415 (KLV A LGINAV, HLA-A2); 1435–1443 (ATDALMTGY, HLA-A1); 1610–1627 (CLIRLKPTLHGPTPLLYR) 1695–1702 (IPDREVLY, HLA-B35); 1745–1754 (VIAPA VQTNW, HLA-A24); 1751–1770 (VFTGLTHIDAHFLSQ TKQSG); 1758–1766 (ETFWAKHMW, HLA-A25); 1771 –1790 (GIQYLAGLSTLPGNPAIASL); 1801–1809 (LT TSQTLLF; H LA-B57); 1966–1976 (SECCTPCSGS W, HLA-B37); 1987–1995 (VLDSFKTWL, HLA-A2) 2162–2170 (EPEPDVAVL, H LA-B35); 2225–2233 (ELI EANLLW, H LA-A25); 2461–2480 (TSRSACQRQKKVT FDRLQVL); 2594–2602 (ALYDVVTKL, HLA-A2); 2629–2637 (KSKKTPMGF, HLA-B57); 2819–2828 (TAR HTPVNSW, H LA-A25); 2912–2921 (LGVPPLRAWR, H LA-B57)

IFN-c secreting epitopes identified in recovered individuals

NS4 NS5

Duan et al. (2011)

NS4B P7

1793–1801 (SMMAFSAAL, HLA-A2) 774–782 (AAWYIKGRL, HLA-B7)

Cytotoxic and IFN-c secreting epitopes identified in chronic individuals

Guglietta et al. (2009)

Core NS3

IFN-c secreting epitopes identified in chronic and recovered individuals

Doi et al. (2009)

NS3 E2 NS5A NS5B NS4

1367–1386 (LSNTGEIPFYGKAIPIEAIK, HLA-l); 1637–1656 (LTHPITKFVMACMSADLEVV, HLA-l) 604–623 (TPRCLVDYPYRLWHYPCTIN,HLA-l) 2284–2303 (ALPIWARPDYNPPLLESWKS, HLA-l) 2551–2570 (TPIDTTIMAKNEVFCVQPEK, HLA-l); 2801–2820 (YYLTRDPTTPLARAAWETVR, HLA-l) 1758–1777 (EAFWAKHMWNFISGIQYLAG, HLA-l); 1958–1977 (KRLHQWINEDCSTPCSGSWL, HLA-l)

IFN-c secreting epitopes identified in recovered and successfully treated individuals

Vertuani et al. (2002)

NS3

1073–1081 (CINGVCWTV, HLA-A2)

Cytotoxic and protective epitope identified in recovered and successfully treated individuals

Kurokohchi et al. (2001)

NS3

1031–1039 (AYSQQTRGL, HLA-A24)

Cytotoxic epitope identified in chronic individuals

Urbani et al. (2001)

Core E2 NS3 NS4B NS5A

178–187 (LLALLSCLTV, HLA-A2) 402–412 (SLLAPGAKQNV, HLA-A2) 1073–1081 (CINGVCWTTV, HLA-A2) 1406–1415 (KLVALGINAV, HLA-A2) 1671–1680 (VLAALAAYCL, HLA-A2) 1992–2000 (VLSDFKTWL, HLA-A2) 2145–2154 (LLREEVSFRV, HLA-A2)

Immunodominant epitopes recognized by HCVspecific CTL during natural infection

Cucchiarini et al. (2000)

Core

Cytotoxic epitope identified in recovered and successfully treated individuals

NS3 NS4 NS5 NS5B

2–9 (STNPKPQK, HLA-A11); 35–44 (YLLPRRG PRL, HLA-A2); 131–140 (ADLMGYIPLV, HLA-A2); 178–187 (LLALLSCLTV, HLA-A2); 1073–1081 (CINGVCWTV, HLA-A2); 1406–1415 (KLVALGINAV, HLA-A2) 1807–1816 (LLFNILGGWV, HLA-A2) 2252–2260 (ILDSFDPLV, HLA-A2) 2794–2802 (HDGAGKRVY, HLA-A2)

NS2 NS3

831–841 (LSPYYKRYISW, HLA-A25) 1073–1081 (CINGVCWTV, HLA-A2)

IFN-c secreting epitopes identified in recovered individuals

Lechner et al. (2000)

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NS5A

41–49 (GPRLGVRAT, HLA-B7) 1639–1653 (HPITKYIMACMSADL, HLA-B8); 1259–1273 (AATLGFGAYMS KAHG, HLA-A11); 1189–1203 (AVCTRGVAKALQFIP, nd) 1993–2001 (VVSDFK T WL, HLA-A2)

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Reference

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Table 1 Important epitopes of HCV recognized by CD8+T cells.

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Cytotoxic epitopes identified in chronic individuals 35–44 (YLLPRRGPRL, HLA-A2.1); 132–140 (DLMGYIPLV, HLA-A2.1); 178–187 (LLALLS CLTV, HLA-A2.1) 1807–1816 (LLFNILGGWV, HLA-A2.1) 2727–2735 (GLQDCTMLV, HLA-A2.1) Core NS4B NS5B Battegay et al. (1995)

A cytotoxic epitope identified in patients with a low titer of serum HCV RNA 88–96 (NEGL(M)GWAGW, HLA-44) Core Hiroishi et al. (1997)

Epitopes (aa sequence, restriction molecules)

43–51 (RLGVRATRK, HLA-A3); 51–59 (KTSE RSQPR, HLA-A3); 169–177 (LPGCSFSIF, HLA-B7) 290–299 (QLFTFSPRR, HLA-A3) 632–641 (RMYVGGVEHR, HLA-A3) 1267–1275 (LGFGAYMSK, HLA-A3) 1863–1872 (GVAGALVAFK, HLA-A3) Core E1 NS1/E2 NS3 NS4 Chang et al. (1999)

NS5A NS5B

NS4

Antigen Reference

Table 1 (continued)

1744–1754 (EVIAPAVQTNW, HLA-A25); 1758–1766 (ETFWAKHMW, HLA-A25); 1966–1976 (SECTTPCSGSW, HLAB37) 2225–2233 (ELIEANLLW, HLA-A25) 2594–2602 (ALYDVVTKL, HLA-A2); 2819–2828 (TARHTPVNSW, HLA-A25)

Functional properties

Cytotoxic epitopes identified in recovered individuals

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this global pathogen. Antibodies can also have antiviral activity by means of complement-dependent virus inactivation or antibodydependent cell-mediated cytotoxicity (ADCC). Weak NAb response induced by HCV E2 glycoprotein could be augmented by complement, and complement-mediated ADCC was evident with cells expressing chimeric HCV E2G glycoprotein on the cell surface in vitro (Meyer et al., 2002). Recombinant E1/E2 glycoproteins can induce polyclonal antibody responses with cross-reactive neutralizing activity, supporting the future development of prophylactic and therapeutic vaccines. Moreover, cooperation from APCs and T and B lymphocytes, which are critical for effective immune responses, should be considered in vaccine development.

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5. Important role of CD8+T-cells in vaccine development

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The studies on host immunity in patients and vaccinated chimpanzees that have spontaneously recovered from HCV challenge have enabled us to address the important immunological parameters related to HCV clearance. Many studies of this field have proposed that CD8+T-cells are the most important effectors in controlling HCV infection. Earlier vaccine approaches aiming to generate NAbs failed to show efficacy in chronic HCV patients. Therefore, most of HCV vaccine approaches are focused on generating cytotoxic CD8+T-cells in addition to antibody responses. This also implied the importance of cytotoxic T lymphocytes (CTLs) in HCV eradication. The clearance of HCV infection is significantly associated with HCV-specific CD8+T-cells that are restricted by the MHC class I molecule HLA-B27 (Dazert et al., 2009; Neumann-Haefelin et al., 2006) further proved the critical role of CTLs in HCV eradication. Earlier studies analysing acute HCV infection in chimpanzees firstly suggested that spontaneously recovered chimpanzees exhibited a strong CD8+T-cell responses to broad range of epitopes and across multiple MHC class I restrictions (Table 1) (Cooper et al., 1999). While a weak and narrow specificity and cytotoxicity in CD8+T-cells toward HCV epitopes was observed in patients with chronic HCV infection (Table 1) (Wedemeyer et al., 2002). Additionally, cross-genotype CD8+T-cells could limit the escape of HCV and help the clearance of viruses (Dazert et al., 2009). Several other studies further supported the point that a robust multispecific and cross-genotype CD8+T-cell response to different epitopes implies a successful response against HCV infection (Table 1) (Battegay et al., 1995; Chang et al., 1999; Cucchiarini et al., 2000; Doi et al., 2009; Duan et al., 2011; Guglietta et al., 2009; Hiroishi et al., 1997; Kurokohchi et al., 2001; Lauer et al., 2004; Lechner et al., 2000; Urbani et al., 2001; Vertuani et al., 2002). These CTL epitopes may of great importance to the development of therapeutic vaccines. Some of these CD8+CTL epitopes including core (111–119), NS3 (1031–1039, 1367–1386 and1406–1415), NS5A (1991–1999), NS4B (1793–1801), P7 (774–782) and core (35–44 and 132–140) had been utilized in vaccine development. The vaccine candidate mT + mE1 include multiple epitopes, mT contains multiple conserved CD4+ and CD8+T -cell epitopes from HCV NS3 (1235–1321, 1371–1430 and 1031–1039) and core (1–53, 111–119 and 169– 177) proteins, mE1 is based on eight dominant neutralizing epitopes of E1 protein from six HCV genotypes. The authors showed that immunization with mT + mE1 induced high titers of antibodies to mE1, and high levels of NS3- or core-specific CTLs. Prophylactic as well as therapeutic administration of mT + mE1 in BALB/c mice led to protecting mice against SP2/0 tumor cells expressing HCV NS3 protein. These results suggested that mT + mE1 elicited strong humoral immune responses and multiple specific cellular immune responses (Zeng et al., 2009). The vaccine candidate is now being tested in pre-clinical trials. The multi-epitope fusion

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Table 2 Ongoing and completed clinical trials for therapeutic hepatitis C virus (HCV) vaccines. Vaccine Recombinant protein hepatitis C vaccine studies GI-5005 (recombinant yeast transfected with HCV NS3–core fusion protein) + SoC therapy (Globeimmune) HCV core protein/ISCOMATRIXÒ (CSL Ltd)

Peptide hepatitis C vaccine studies IC41: five peptides from core, NS3 and NS4 + poly-Larginine adjuvant (Intercell AG)

Peptide (core, 35–44)/emulsified with ISA51 (Karume University) NS3/Virosome (Pevion Biotech) DNA hepatitis C vaccine studies CIGB-230: plasmid core/E1/E2 + recombinant core protein (University of Montreal + others) ChonVac-C (plasmid NS3/4a) in combination with electroporation + SoC therapy (ChronTech Pharma AB) Viral-vectored hepatitis C vaccine studies TG4040 (MVA vector expressing NS3/4/5B proteins) + SoC therapy (Transgene) Ad6Nsmut, AdCh3Nsmut: adenovirus vector (Ad6 and AdCh3) expressing NS3–5B proteins (Okairos) Dendritic cells-based vaccines Autologous dendritic cell delivered HLA A2 epitopes (core 132–140, 35–44, 177–187; NS3 1406– 1415; NS4B 1807–1816, 1851–1859; universal Th epitopes, Burnet Institute + others)

Subject

Phase

Outcome

ID No.a [Publication]

159 chronic HCV-1-infected patients without or not responding to the SoC therapy 30 healthy volunteers

II

No result released

NCT00606086 [unpublished]

I

Well tolerated, mild local redness; all developed antibody response, 7/8 showed cytokine production and 2/8 showed cytotoxic T cell response in the group with highest antigen dose group

Drane et al. (2009)

60 HLA-A2+ chronic HCV patients not responding to or relapsing from standard therapy 26 chronic HCV patients without or not responding to the SoC therapy 30 healthy volunteers

II

Increase of CD4+T cell proliferation (67%); increase of IFN-c ELIspot (42%);>1 log declines of HCV serum RNA (3 of 60 patients)

NCT00602784 Klade et al. (2008))

I

Well tolerated with no severe toxicity; 15/25 responder; 2/25 with 1 log decline on HCV RNA

Yutani et al. (2009)

I

No result released

NCT00445419 [unpublished]

15 HCV-1-infected patients not responding to the SoC therapy 32 chronic HCV-1-infected, treatment-naïve patients

I

Safe, immunogenic, and improved or stabilized liver histology

II

No result released

AlvarezLajonchere et al. (2009) NCT01335711 [unpublished]

153 treatment-naïve, chronic HCV-1-infected patients 36 HCV-1-infected patients

II

No result released

NCT01055821 [unpublished]

I

No result released

NCT01094873 [unpublished]

6 HLA-A2+ chronic HCV-1infected patients not responding to the SoC therapy

I

Well tolerated. All patients generated de novo specific- IFN-c response

Gowans et al. (2010)

Abbreviations: ID, identification. a Therapeutic trials registered with clinicaltrials.gov. 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394

protein pET-11d that include three conserved broadly neutralizing B-cell epitopes and a series of T-cell epitopes located in the HCV NS3 region (NS3–1287-1296 and 1406–1415), was immunogenic and could elicit both humoral and cellular immune responses (Qiu et al., 2012). VAL-44 peptide consists of two HCV CTL epitopes, NS5A (1991–1999) and NS4B (1793–1801) and a Th epitope. Immunization with the VAL-44 peptide induced strong cellular immune responses. And the VAL-44 peptide stimulated IFN-c production from viral-specific peripheral blood mononuclear cells (PBMCs) of patients infected with HCV (Huang et al., 2013). These results suggested that VAL-44 could be developed as a potential HCV multi-epitope peptide vaccine. Dendritic cells (DCs) were infected with recombinant replication-defective adenoviruses (Ads) expressing two HCV sequences. One sequence contained the HCV CTL epitopes, NS4B (1793–1801) and P7 (774–782), as well as the HCV Th epitope, NS3 1248–1261. A second sequence was the positive epitope control which contained HCV core (35–44 and 132–140) and NS3 (1248–1261). The results showed that Ad infection significantly enhanced DC maturation and interleukin (IL)-12p70 production, resulted in T cell proliferation and increased IFN-c secretion. And the CTLs stimulated by Ad-infected DCs specifically killed Huh7.5 human hepatoma cells (Zhou et al., 2013). The recombinant Ad-expressing multiple CTL HCV epitopes effectively infected the DCs in vitro and promoted T-cell antiviral immune responses, thereby laying the foundation for the development of anti-HCV DC vaccines.

6. Scientific approaches in the development of a therapeutic vaccine

395

6.1. Recombinant protein-based vaccines

397

The principle of recombinant protein vaccine is to isolate the gene(s) encoding the appropriate protein and clone it in bacteria, yeast or mammalian cells. The theory basis for this approach is that inducing an immune response to a limited number of viral epitopes is sufficient to develop protective immunity. GI5005 is a therapeutic protein-based vaccine candidate has been completed a phase II trial aiming to investigate the treatment effect of combining GI5005 and SoC treatment (Table 2) (ClinicalTrials.gov Identifier: NCT00606086). Another vaccine based on conserved HCV core protein with an adjuvant composed of saponin, cholesterol and phospholipid, called ISCOMATRIXÒ, has been evaluated in a phase I trial of 30 healthy volunteers (Table 2) (Drane et al., 2009).

398

6.2. Peptide-based vaccines

410

Peptide-based vaccines induce HCV-specific T-cell immunity through the direct presentation of vaccine peptide to the T-cell receptor via HLA molecules. These vaccines often contain multiple epitopes for the induction of broad CTL and Th responses to avoid the risk of immune escape. However, they in general are not very

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immunogenic and are often combined with adjuvants. IC41 is a peptide vaccine which has been completed a randomized doubleblind phase II study in 60 HLA-A2-positive chronic HCV patients who had either relapsed or failed to respond to previous PEGIFN/ribavirin therapy (Klade et al., 2008). Another peptide vaccine composed of peptides derived from HCV core region (C35–44) with ISA51, an emulsified incomplete Freud adjuvant, were shown to be well tolerated in HCV-infected patients (Table 2) (Yutani et al., 2009). Finally, a phase I single-blinded, randomised, placebo controlled, dose escalating study of a virosome-based vaccine containing NS3 peptides has recently been completed but no data have been released (Table 2) (ClinicalTrials.gov Identifier: NCT00445419).

429

6.3. DNA-based vaccines

430

443

Plasmid DNA encoding antigenic HCV protein(s) or peptide epitope(s) with varying sizes can induce both humoral and cellular immune responses in vivo. DNA vaccine can mimic the process of the generation of the viral proteins within cells, which is the most active field of HCV experimental vaccine (Beckebaum et al., 2002; Forns et al., 2002; Houghton and Abrignani, 2005; Torresi et al., 2004). The main advantage of DNA-based vaccine is the high flexibility of the approach, thereby allowing combinations of the following strategies. The first therapeutic HCV vaccine based on plasmid DNA evaluated in a phase I clinical study was CIGB-230 (Table 2) (Alvarez-Lajonchere et al., 2009), the second HCV DNA-based vaccine now in phase II clinical trials for HCV infection was ChronVac-C (Table 2) (ClinicalTrials.gov Identifier: NCT0133 5711).

444

6.4. Viral vector-based vaccines

416 417 418 419 420 421 422 423 424 425 426 427

431 432 433 434 435 436 437 438 439 440 441 442

457

The use of viral vectors for the delivery of HCV RNA is an appealing vaccine choice. The viral vector vaccines similar to DNA vaccines also encode target proteins or peptides but are more immunogenic than DNA-based vaccines. The mostly tested viral vector vaccines against HCV are based on replication-defective adenovirus (Ads) and the modified non-replicative vaccinia virus Ankara (MVA) (Fournillier et al., 2007). A MVA-based therapeutic vaccine (TG4040) that expresses NS3/4/5B proteins has been entered phase II clinical trials (Table 2) (ClinicalTrials.gov Identifier: NCT01055821). Adenovirus vectors are also being employed in a phase I vaccine trial to deliver NS HCV proteins (NS3–5B) to patients with HCV infection (Table 2) (ClinicalTrials.gov Identifier: NCT01094873).

458

6.5. Dendritic cells-based Vaccines

459

471

Dendritic cells (DCs), which are modified ex vivo to express foreign proteins, have been regarded as safe and promising tools for the development of more effective therapeutic vaccines (Banchereau et al., 2001; Cerundolo et al., 2004). The phenotypes and immunological functions of antigen-loaded DCs can be extensively characterized before administration of the vaccine to the patients. However, it is difficult to obtain the functional DCs from patients owing to some factors (e.g. the disease stage, treatment history of the patients and so on) affecting DC function (Barnes et al., 2008; Echeverria et al., 2008; Gelderblom et al., 2007). A phase I clinical trial was conducted to investigate the safety and efficacy of vaccination with autologous DCs loaded with HCV-specific CTL epitopes in HCV-infected individuals (Table 2) (Gowans et al., 2010).

472

6.6. Future vaccine approaches

473

Novel future vaccine approaches include virus-like particle (VLP)-based vaccines that have now been successfully licensed for

445 446 447 448 449 450 451 452 453 454 455 456

460 461 462 463 464 465 466 467 468 469 470

474

7

persistent viral infections, such as hepatitis B virus (Hilleman, 2001; Kao and Chen, 2002) and human papilloma virus (Giannini et al., 2006). VLPs are usually highly immunogenic due to their relatively large size and repetitive structure. They are also advantageous over whole virus-based vaccines because they cannot replicate and are noninfectious. Moreover, most VLPs can stimulate potent immune responses without adjuvants. VLPs will soon be tested in a clinical setting. As more information is gained about the mechanism of immune dysfunction in persistently infected patients, therapeutic vaccines may be tailored to include specialized immunostimulatory molecules that can restore immune function.

475

7. Conclusion

487

A therapeutic vaccine that increases cure rates for infected patients are of important clinical significance (Strickland et al., 2008). Substantial progress have been made in the development of HCV vaccines by better understanding the correlates of an effective immune response. To date, a few vaccine candidates have been progressed to phase I/II trials, but published data on both the efficacy and safety of these vaccines is limited, and none of them has yet reached a phase III clinical trial. Peptide/protein-based T cell vaccines can only induce the weak T-cell responses – this approach is likely to only progress with the development of novel adjuvants that enhance appropriate responses and do not elicit severe adverse effects. The limited humoral and cell-mediated responses are associated with DNA vaccines – this approach requires additional techniques to enhance the delivery and immunogenicity. The viral-vector based vaccines face the problems associated with the pre-existing immunity. And it is difficult to obtain the functional DCs from patients with regard to the DCs-based vaccines. Virus-like particles (VLPs) – which have many favorable immunological characteristics – are considered as promising future HCV vaccine candidates. Additional strategies include molecules that induce innate immune responses and combination therapy with PEG IFN and ribavirin or possibly with the newly developed DAAs. There is a genuine need for an effective vaccine for this disease owing to its enormous global burden. And it is possible to develop the effective therapeutic vaccine strategies when the association with the effective immune responses is understood well.

488

Acknowledgment

515

This work was supported by National Natural Science Foundation of China (81201291), National Science and Technology Major Project (2012ZX10002003) and Science and Technology Major Projects of Zhejiang Province (2009C03011-2).

516

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Please cite this article in press as: Xue, J., et al. Therapeutic vaccines against hepatitis C virus. Infect. Genet. Evol. (2014), http://dx.doi.org/10.1016/ j.meegid.2014.01.008