scholarly journals Progress in Vaccine Development for HCV Infection

2017 ◽  
Author(s):  
Ashraf Tabll ◽  
Reem El-Shenawy ◽  
Yasmine El Abd
Keyword(s):  
Vaccine Development ◽  
Hcv Infection

Recent Advances in Clinical Trials of HCV Vaccines

2014 ◽  
Vol 3 (1) ◽  
pp. 10 ◽  
Author(s):  
Yongneng Luo ◽  
Limin Jiang ◽  
Zi'an Mao
Keyword(s):  
Clinical Trials ◽  
Viral Vectors ◽  
Vaccine Development ◽  
Viral Vector ◽  
Core Protein ◽  
Therapeutic Vaccine ◽  
Hcv Infection ◽  
Effective Vaccine ◽  
Protein Subunit ◽  
Preclinical Development

<p>  Hepatitis C virus infects nearly 3% of the global population, and spreads to 3-4 million new people annually. HCV infection is a leading cause of liver cirrhosis, hepatocellular carcinoma, and end-stage liver diseases and causes liver-related death in more than 300,000 people each year. Unfortunately, there is currently no vaccine for HCV prevention (prophylactic vaccine) or treatment (therapeutic vaccine). Circulating HCV is genetically diverse, and therefore a broadly effective vaccine must target conserved T- and B-cell epitopes of the virus and induce strong cross-reactive CD4+/CD8+ T-cell and neutralizing antibody responses in preventing or clearing HCV infection. So far, a few of vaccine development approaches are successful and some of the HCV vaccine candidates have reached human clinical trials, including those modalities mainly based on recombinant proteins (envelope proteins and core protein subunit), synthetic peptides, DNA (plasmid) and viral vectors (virosome). Encouraging results were obtained for those HCV vaccine formulations consisting of prime-boost regimen involving a live recombinant viral vector vaccine alone or in combination with DNA or subunit vaccine. Among several other vaccine strategies under preclinical development, the most promising one is virus like particle based vaccine that will be moving into human studies soon.</p>

scholarly journals A Novel Approach To Display Structural Proteins of Hepatitis C Virus Quasispecies in Patients Reveals a Key Role of E2 HVR1 in Viral Evolution

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Yimin Tong ◽  
Qingchao Li ◽  
Rui Li ◽  
Yongfen Xu ◽  
Yu Pan ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Vaccine Development ◽  
Viral Evolution ◽  
Hcv Infection ◽  
Clinical Isolates ◽  
Structural Proteins ◽  
Structural Protein ◽  
Protein Coding ◽  
Viral Structural Proteins

ABSTRACT Hepatitis C virus (HCV) infection remains a major worldwide health problem despite development of highly effective direct-acting antivirals. HCV rapidly evolves upon acute infection and generates multiple viral variants (quasispecies), leading to immune evasion and persistent viral infection. Identification of epitopes of broadly neutralizing anti-HCV antibodies (nAbs) is critical to guide HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on trans-complementation of viral structural proteins. The HCV genome (JFH1 strain) lacking the structural protein-coding sequence can be efficiently rescued by ectopic expression of core-E1-E2-p7-NS2 (core-NS2) or core-E1-E2-p7 (core-p7) in trans, leading to production of single-round infectious virions designated HCVΔS. JFH1-based HCVΔS can be also rescued by expressing core-NS2 of other HCV genotypes, rendering it an efficient tool to display the structural proteins of HCV strains of interests. Furthermore, we successfully rescued HCVΔS with structural proteins from clinical isolates. Multiple viral structural proteins with different sensitivities to nAbs were identified from a same patient serum, demonstrating the genetic diversity of HCV quasispecies in vivo. Interestingly, the structural protein-coding sequences of highly divergent viral quasispecies from the same patient can be clustered based on their hypervariable region 1 (HVR1) in viral envelope protein E2, which critically dictates the sensitivity to neutralizing antibodies. In summary, we developed a novel reverse genetics system that efficiently displays viral structural proteins from HCV clinical isolates, and analysis of quasispecies from the same patient using this system demonstrated that E2 HVR1 is the major determinant of viral evolution in vivo. IMPORTANCE A cell culture model that can recapitulate the diversity of HCV quasispecies in patients is important for analysis of neutralizing epitopes and HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on trans-complementation of viral structural proteins (HCVΔS). This system can be used to display structural proteins of HCV strains of multiple genotypes as well as clinical isolates. By using this system, we showed that multiple different HCV structural proteins from a same patient were displayed on HCVΔS. Interestingly, these variant structural proteins within the same patient can be classified according to the sequence of HVR1in E2, which dictates viral sensitivity to nAbs and viral evolution in vivo. Our work provided a new tool to study highly divergent HCV quasispecies and shed light on underlying mechanisms driving HCV evolution.

scholarly journals Cross-Genotype Immunity to Hepatitis C Virus

2004 ◽  
Vol 78 (3) ◽  
pp. 1575-1581 ◽  
Author(s):  
Robert E. Lanford ◽  
Bernadette Guerra ◽  
Deborah Chavez ◽  
Catherine Bigger ◽  
Kathleen M. Brasky ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Primary Infection ◽  
Vaccine Development ◽  
Amino Acid Level ◽  
Gamma Interferon ◽  
Hcv Infection ◽  
Interferon Response ◽  
Genotype 4 ◽  
Interferon Stimulated Genes

ABSTRACT Recent studies in humans and chimpanzees suggest that immunity can be induced to diminish the incidence of chronic hepatitis C virus (HCV) infection. However, the immunity that promotes viral recovery is poorly understood, and whether the breadth of this adaptive immunity is sufficient to overcome the substantial intergenotype antigenic diversity represents a final obstacle to demonstrating the feasibility of vaccine development. Here we demonstrate that recovery from a genotype 1 HCV infection protects chimpanzees against infection with representatives of other genotypes that exhibit up to 30% divergence at the amino acid level, including challenges with genotype 4, a mixture of genotypes 2 and 3, and a complex inoculum containing genotypes 1, 2, 3, and 4. In each instance, the level and duration of viremia were markedly reduced in comparison to the primary infection in the same animal. The data indicate that epitopes conserved between genotypes must play an essential role in immunity. The inocula used in the rechallenge studies induced typical primary infection profiles in naïve chimpanzees. Rechallenge infections were associated with rapid increases in the intrahepatic transcripts of interferon-stimulated genes, even in animals exhibiting apparent sterilizing immunity. Protective immunity was often associated with an early increase in gamma interferon transcripts in the liver and increases in intrahepatic transcripts of Mig, a T-cell chemokine that is a gamma interferon response gene. These studies are the first to show that cross-genotype immunity can be induced to HCV, demonstrating the feasibility of developing a vaccine protective against all HCV strains.

scholarly journals A Multiancestry Sex-Stratified Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus

2020 ◽  
Author(s):  
Candelaria Vergara ◽  
Ana Valencia ◽  
Chloe L Thio ◽  
James J Goedert ◽  
Alessandra Mangia ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Ribosomal Protein ◽  
X Chromosome ◽  
Genome Wide Association Study ◽  
Vaccine Development ◽  
Hcv Infection ◽  
Spontaneous Clearance ◽  
Acute Hepatitis C ◽  
Septin 6

Abstract Background Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. Methods To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. Results A male-specific region near the adenosine diphosphate–ribosylation factor–like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10−07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10−06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. Conclusions These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

scholarly journals Broadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2

2019 ◽  
Vol 93 (14) ◽  
Author(s):  
Michelle D. Colbert ◽  
Andrew I. Flyak ◽  
Clinton O. Ogega ◽  
Valerie J. Kinchen ◽  
Guido Massaccesi ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Infected Individual ◽  
Hcv Infection ◽  
Broadly Neutralizing Antibodies ◽  
Genotype 1A ◽  
Antigenic Sites

ABSTRACTIncreasing evidence indicates that broadly neutralizing antibodies (bNAbs) play an important role in immune-mediated control of hepatitis C virus (HCV) infection, but the relative contribution of neutralizing antibodies targeting antigenic sites across the HCV envelope (E1 and E2) proteins is unclear. Here, we isolated thirteen E1E2-specific monoclonal antibodies (MAbs) from B cells of a single HCV-infected individual who cleared one genotype 1a infection and then became persistently infected with a second genotype 1a strain. These MAbs bound six distinct discontinuous antigenic sites on the E1 protein, the E2 protein, or the E1E2 heterodimer. Three antigenic sites, designated AS108, AS112 (an N-terminal E1 site), and AS146, were distinct from previously described antigenic regions (ARs) 1 to 5 and E1 sites. Antibodies targeting four sites (AR3, AR4-5, AS108, and AS146) were broadly neutralizing. These MAbs also displayed distinct patterns of relative neutralizing potency (i.e., neutralization profiles) across a panel of diverse HCV strains, which led to complementary neutralizing breadth when they were tested in combination. Overall, this study demonstrates that HCV bNAb epitopes are not restricted to previously described antigenic sites, expanding the number of sites that could be targeted for vaccine development.IMPORTANCEWorldwide, more than 70 million people are infected with hepatitis C virus (HCV), which is a leading cause of hepatocellular carcinoma and liver transplantation. Despite the development of potent direct acting antivirals (DAAs) for HCV treatment, a vaccine is urgently needed due to the high cost of treatment and the possibility of reinfection after cure. Induction of multiple broadly neutralizing antibodies (bNAbs) that target distinct epitopes on the HCV envelope proteins is one approach to vaccine development. However, antigenic sites targeted by bNAbs in individuals with spontaneous control of HCV have not been fully defined. In this study, we characterize 13 monoclonal antibodies (MAbs) from a single person who cleared an HCV infection without treatment, and we identify 3 new sites targeted by neutralizing antibodies. The sites targeted by these MAbs could inform HCV vaccine development.

scholarly journals Extracellular Interactions between Hepatitis C Virus and Secreted Apolipoprotein E

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Zhihua Li ◽  
Yadong Li ◽  
Yanwei Bi ◽  
Hui Zhang ◽  
Yufeng Yao ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Apolipoprotein E ◽  
Vaccine Development ◽  
Envelope Proteins ◽  
Host Immunity ◽  
Hcv Infection ◽  
Host Cells ◽  
Dependent Manner ◽  
Dose Dependent

ABSTRACT Interactions between hepatitis C virus (HCV) and lipoproteins in humans play an important role in the efficient establishment of chronic infection. Apolipoprotein E (ApoE) on the HCV envelope mediates virus attachment to host cells as well as immune evasion. This interaction is thought to occur in hepatocytes, as ApoE plays dual functions in HCV assembly and maturation as well as cell attachment. In the present study, we found that secreted ApoE (sApoE) can also bind to viral particles via its C-terminal domain after HCV is released from the cell. Furthermore, the binding affinity of interactions between the sApoE N terminus and cell surface receptors affected HCV infectivity in a dose-dependent manner. The extracellular binding of sApoE to HCV is dependent on HCV envelope proteins, and recombinant HCV envelope proteins are also able to bind to sApoE. These results suggest that extracellular interactions between HCV and sApoE may potentially complicate vaccine development and studies of viral pathogenesis. IMPORTANCE End-stage liver disease caused by chronic HCV infection remains a clinical challenge, and there is an urgent need for a prophylactic method of controlling HCV infection. Because host immunity against HCV is poorly understood, additional investigations of host-virus interactions in the context of HCV are important. HCV is primarily transmitted through blood, which is rich in lipoproteins. Therefore, it is of interest to further determine how HCV interacts with lipoproteins in human blood. In this study, we found that secreted ApoE (sApoE), an exchangeable component found in lipoproteins, participates in extracellular interactions with HCV virions. More significantly, different variants of sApoE differentially affect HCV infection efficiency in a dose-dependent manner. These findings provide greater insight into HCV infection and host immunity and could help propel the development of new strategies for preventing HCV infection.

A trivalent HCV vaccine elicits broad and synergistic polyclonal antibody response in mice and rhesus monkey

Gut ◽  
2017 ◽  
Vol 68 (1) ◽  
pp. 140-149 ◽  
Author(s):  
Xuesong Wang ◽  
Yu Yan ◽  
Tianyu Gan ◽  
Xi Yang ◽  
Dapeng Li ◽  
...  
Keyword(s):  
Cell Culture ◽  
Antibody Response ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
T Cell Response ◽  
Hcv Infection ◽  
Neutralising Antibodies ◽  
Monovalent Vaccine ◽  
Direct Acting ◽  
Trivalent Vaccine

ObjectiveDespite the development of highly effective direct-acting antivirals, a prophylactic vaccine is needed for eradicating HCV. A major hurdle of HCV vaccine development is to induce immunity against HCV with high genome diversity. We previously demonstrated that a soluble E2 (sE2) expressed from insect cells induces broadly neutralising antibodies (NAbs) and prevents HCV infection. The objective of this study is to develop a multivalent HCV vaccine to increase the antigenic coverage.DesignWe designed a trivalent vaccine containing sE2 from genotype 1a, 1b and 3a. Mice and rhesus macaques were immunised with monovalent or trivalent sE2 vaccine, and sera or purified immunoglobulin were assessed for neutralisation against a panel of cell culture-derived virion (HCVcc) of genotype 1–7 in cell culture. Splenocytes from the vaccinated macaques were assessed for HCV-specific T cell response.ResultsWe showed that the trivalent vaccine elicited pangenotypic NAbs in mice, which neutralised HCVcc of all the seven genotypes more potently than the monovalent vaccine. Further analyses demonstrated that each sE2 component of this trivalent vaccine elicited unique spectrum of NAbs which acted synergistically to inhibit HCV infection. Finally, the trivalent vaccine triggered stronger and more uniform multigenotypic neutralising antibody response than the monovalent vaccine in rhesus macaques.ConclusionsIn summary, we developed a trivalent HCV vaccine that induces broad and synergistic-acting neutralising antibodies in mice and non-human primates.

scholarly journals Immune Response of Cytotoxic T Lymphocytes and Possibility of Vaccine Development for Hepatitis C Virus Infection

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Kazumasa Hiroishi ◽  
Junichi Eguchi ◽  
Shigeaki Ishii ◽  
Ayako Hiraide ◽  
Masashi Sakaki ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Cytotoxic T Lymphocytes ◽  
Vaccine Development ◽  
Hcv Infection ◽  
Ctl Response ◽  
Host Immune Responses ◽  
Ctl Responses

Immune responses of cytotoxic T lymphocytes (CTLs) are implicated in viral eradication and the pathogenesis of hepatitis C. Weak CTL response against hepatitis C virus (HCV) may lead to a persistent infection. HCV infection impairs the function of HCV-specific CTLs; HCV proteins are thought to actively suppress host immune responses, including CTLs. Induction of a strong HCV-specific CTL response in HCV-infected patients can facilitate complete HCV clearance. Thus, the development of a vaccine that can induce potent CTL response against HCV is strongly expected. We investigated HCV-specific CTL responses by enzyme-linked immuno-spot assay and/or synthetic peptides and identified over 40 novel CTL epitopes in the HCV protein. Our findings may contribute to the development of the HCV vaccine. In this paper, we describe the CTL responses in HCV infection and the attempts at vaccine development based on recent scientific articles.

scholarly journals A New Insight into Hepatitis C Vaccine Development

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Chun I. Yu ◽  
Bor-Luen Chiang
Keyword(s):  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Hcv Infection ◽  
Viral Immune Evasion ◽  
Cell Responses ◽  
Potential Success ◽  
Chronic Hcv Infection ◽  
Hcv Genotype 1 ◽  
Chronic Hcv

Chronic hepatitis C virus (HCV) infection remains a serious burden to public health worldwide. Currently, HCV-infected patients could undergo antiviral therapy by giving pegylated IFN- with ribavirin. However, this therapy is only effective in around 50% of patients with HCV genotype 1, which accounts for more than 70% of all HCV infection, and it is not well tolerated for most patients. Moreover, there is no vaccine available. The efforts on identifying protective immunity against HCV have progressed recently. Neutralizing antibodies and robust T cell responses including both and have been shown to be related to the clearance of HCV, which have shed lights on the potential success of HCV vaccines. There are many vaccines developed and tested before entering clinical trials. Here, we would first discuss strategies of viral immune evasion and correlates of protective host immunity and finally review some prospective vaccine approaches against chronic HCV infection.

scholarly journals Identification and expression analysis of antigenic sites of hepatitis C virus genotype 3a NS3 and NS5A genes of local isolate

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sabeen Sabri ◽  
Muhammad Idrees Khan ◽  
Shazia Rafique ◽  
Amjad Ali ◽  
Muhammad Saleem Khan
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Recombinant Proteins ◽  
Expression Analysis ◽  
Vaccine Development ◽  
Hcv Infection ◽  
Virus Genotype ◽  
Local Isolate ◽  
Antigenic Sites ◽  
Antigenic Regions

Abstract Background Hepatitis C virus, a silent killer, has infected 71 million people globally. The recombinant viral antigenic proteins might be used in the early diagnosis of HCV infection. The NS3 and NS5A genes of HCV function in HCV replication and influence host cellular factors that are involved in HCV pathogenesis. The current study was designed to select NS3 and NS5A antigenic sites, amplified, cloned, and expressed in order to find out better assays for diagnosis or drug and vaccine development. The antigenic sites within NS3 and NS5A genes were selected and confirmed through sequencing and were cloned. The antigenic recombinant proteins were expressed in bacterial strain E. coli BL21ply*, and the expression was confirmed by western blotting by using gene-specific and vector-specific antibodies. Results Specific antigenic regions within the NS3 and NS5A genes of the HCV 3A genotype were amplified. PCR results showed 328 bp and 747 bp antigenic regions, respectively. The regions were confirmed by DNA sequencing and cloned into a bacterial expression vector. Expression analysis showed 12 kDa and 28 kDa of NS3 and NS5A antigenic recombinant proteins, respectively. Taken together, these studies will help to analyze the genetic variability within the local HCV isolates as these antigenic recombinant proteins were quite important in the screening of HCV-infected patients. Conclusions This study might help to enhance the progress in the treatment of HCV infection through the modeling of HCV non-structural genes (NS3 and NS5A) from local isolate, and it might also present the viral genes as potential therapeutic targets.

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