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Progress towards a hepatitis C virus vaccine.

Man John Law L, Landi A, Magee WC, Lorne Tyrrell D, Houghton M - Emerg Microbes Infect (2013)

Bottom Line: However, due to issues of expected drug resistance, suboptimal activity against diverse hepatitis C virus (HCV) genotypes and especially because of their extremely high cost, it is unlikely that these HCV drugs will substantially reduce the world's HCV carrier population of around 170 million in the near future or the estimated global incidence of millions of new HCV infections.After much early pessimism on the prospects for an effective prophylactic HCV vaccine, our recent knowledge of immune correlates of protection combined with the demonstrated immunogenicity and protective animal efficacies of various HCV vaccine candidates now allows for realistic optimism.This review summarizes the current rationale and status of clinical and experimental HCV vaccine candidates based on the elicitation of cross-neutralizing antibodies and broad cellular immune responses to this highly diverse virus.

View Article: PubMed Central - PubMed

Affiliation: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta , Edmonton T6G 2E1, Canada.

ABSTRACT
New drugs to treat hepatitis C are expected to be approved over the next few years which promise to cure nearly all patients. However, due to issues of expected drug resistance, suboptimal activity against diverse hepatitis C virus (HCV) genotypes and especially because of their extremely high cost, it is unlikely that these HCV drugs will substantially reduce the world's HCV carrier population of around 170 million in the near future or the estimated global incidence of millions of new HCV infections. For these reasons, there is an urgent need to develop a prophylactic HCV vaccine and also to determine if therapeutic vaccines can aid in the treatment of chronically infected patients. After much early pessimism on the prospects for an effective prophylactic HCV vaccine, our recent knowledge of immune correlates of protection combined with the demonstrated immunogenicity and protective animal efficacies of various HCV vaccine candidates now allows for realistic optimism. This review summarizes the current rationale and status of clinical and experimental HCV vaccine candidates based on the elicitation of cross-neutralizing antibodies and broad cellular immune responses to this highly diverse virus.

No MeSH data available.


Related in: MedlinePlus

Proliferative CD4+ T-cell response of the first sample in the acute phase of disease to recombinant HCV proteins (HCV-NS3, -NS4, -NS5 and -core) of PBMCs from 38 patients with acute hepatitis C. Patients are grouped according to the final outcome of disease in self-limited hepatitis C (SL, n=20) and patients with chronic evolution (C, n=18). Results are shown as SI=3H-thymidine incorporation of antigen-stimulated PBMCs (counts per minute)/unstimulated control. All patients with self-limited disease displayed a significant proliferative T-cell response against at least one of the viral proteins, while patients with chronic evolution mounted no or only transient antiviral T-cell responses. NS3 and NS4 revealed the most frequent and most vigorous responses. In four patients, the proliferative response against NS5 was not tested in the first sample. The data are reproduced with permission from Gerlach et al.57 PBMC, peripheral blood mononucleated cell; SI, simulation index.
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fig3: Proliferative CD4+ T-cell response of the first sample in the acute phase of disease to recombinant HCV proteins (HCV-NS3, -NS4, -NS5 and -core) of PBMCs from 38 patients with acute hepatitis C. Patients are grouped according to the final outcome of disease in self-limited hepatitis C (SL, n=20) and patients with chronic evolution (C, n=18). Results are shown as SI=3H-thymidine incorporation of antigen-stimulated PBMCs (counts per minute)/unstimulated control. All patients with self-limited disease displayed a significant proliferative T-cell response against at least one of the viral proteins, while patients with chronic evolution mounted no or only transient antiviral T-cell responses. NS3 and NS4 revealed the most frequent and most vigorous responses. In four patients, the proliferative response against NS5 was not tested in the first sample. The data are reproduced with permission from Gerlach et al.57 PBMC, peripheral blood mononucleated cell; SI, simulation index.

Mentions: Another HCV vaccine approach aims at induction of broad cellular immunity using the delivery of HCV genomic regions encoding the non-structural proteins. Spontaneous resolvers of acute HCV infection have been shown to elicit strong, broad HCV-specific cellular immune responses, whereas individuals progressing to chronic, persistent infection exhibit much weaker and narrowly-targeted cellular immune responses (Figure 3).57 Further, immunodepletion of either CD4+ or CD8+ T cells in the chimpanzee HCV infection model leads to a progression to chronic infection confirming the importance of T cell-mediated immunity in preventing chronicity.14,15 Furthermore, eradication of HCV in chimpanzees can still occur in the absence of antibodies against gpE1/gpE2.58,59,60 Since the region encoding the non-structural proteins is less diverse than the structural protein-encoding region, this approach provides an attractive advantage compared to the glycoprotein approach. Okarios Inc. has tested the delivery of the HCV NS3, NS4a, NS4b, NS5a and NS5b genes of genotype 1b using a combination of replication-defective modified vaccinia Ankara and chimpanzee-derived adenovirus 3 vectors.61 Efficacy has been demonstrated by showing suppression of acute viremia and acute hepatitis after heterologous genotype 1a virus challenge in chimpanzees vaccinated with the prototype vaccine.62 However, no significant reduction in the chronic carrier rates was observed, possibly due to the small numbers of animals tested. Currently, this vaccine is being tested for efficacy in intravenous drug users in the United States and this trial is expected to be completed by 2015/2016.63


Progress towards a hepatitis C virus vaccine.

Man John Law L, Landi A, Magee WC, Lorne Tyrrell D, Houghton M - Emerg Microbes Infect (2013)

Proliferative CD4+ T-cell response of the first sample in the acute phase of disease to recombinant HCV proteins (HCV-NS3, -NS4, -NS5 and -core) of PBMCs from 38 patients with acute hepatitis C. Patients are grouped according to the final outcome of disease in self-limited hepatitis C (SL, n=20) and patients with chronic evolution (C, n=18). Results are shown as SI=3H-thymidine incorporation of antigen-stimulated PBMCs (counts per minute)/unstimulated control. All patients with self-limited disease displayed a significant proliferative T-cell response against at least one of the viral proteins, while patients with chronic evolution mounted no or only transient antiviral T-cell responses. NS3 and NS4 revealed the most frequent and most vigorous responses. In four patients, the proliferative response against NS5 was not tested in the first sample. The data are reproduced with permission from Gerlach et al.57 PBMC, peripheral blood mononucleated cell; SI, simulation index.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3924556&req=5

fig3: Proliferative CD4+ T-cell response of the first sample in the acute phase of disease to recombinant HCV proteins (HCV-NS3, -NS4, -NS5 and -core) of PBMCs from 38 patients with acute hepatitis C. Patients are grouped according to the final outcome of disease in self-limited hepatitis C (SL, n=20) and patients with chronic evolution (C, n=18). Results are shown as SI=3H-thymidine incorporation of antigen-stimulated PBMCs (counts per minute)/unstimulated control. All patients with self-limited disease displayed a significant proliferative T-cell response against at least one of the viral proteins, while patients with chronic evolution mounted no or only transient antiviral T-cell responses. NS3 and NS4 revealed the most frequent and most vigorous responses. In four patients, the proliferative response against NS5 was not tested in the first sample. The data are reproduced with permission from Gerlach et al.57 PBMC, peripheral blood mononucleated cell; SI, simulation index.
Mentions: Another HCV vaccine approach aims at induction of broad cellular immunity using the delivery of HCV genomic regions encoding the non-structural proteins. Spontaneous resolvers of acute HCV infection have been shown to elicit strong, broad HCV-specific cellular immune responses, whereas individuals progressing to chronic, persistent infection exhibit much weaker and narrowly-targeted cellular immune responses (Figure 3).57 Further, immunodepletion of either CD4+ or CD8+ T cells in the chimpanzee HCV infection model leads to a progression to chronic infection confirming the importance of T cell-mediated immunity in preventing chronicity.14,15 Furthermore, eradication of HCV in chimpanzees can still occur in the absence of antibodies against gpE1/gpE2.58,59,60 Since the region encoding the non-structural proteins is less diverse than the structural protein-encoding region, this approach provides an attractive advantage compared to the glycoprotein approach. Okarios Inc. has tested the delivery of the HCV NS3, NS4a, NS4b, NS5a and NS5b genes of genotype 1b using a combination of replication-defective modified vaccinia Ankara and chimpanzee-derived adenovirus 3 vectors.61 Efficacy has been demonstrated by showing suppression of acute viremia and acute hepatitis after heterologous genotype 1a virus challenge in chimpanzees vaccinated with the prototype vaccine.62 However, no significant reduction in the chronic carrier rates was observed, possibly due to the small numbers of animals tested. Currently, this vaccine is being tested for efficacy in intravenous drug users in the United States and this trial is expected to be completed by 2015/2016.63

Bottom Line: However, due to issues of expected drug resistance, suboptimal activity against diverse hepatitis C virus (HCV) genotypes and especially because of their extremely high cost, it is unlikely that these HCV drugs will substantially reduce the world's HCV carrier population of around 170 million in the near future or the estimated global incidence of millions of new HCV infections.After much early pessimism on the prospects for an effective prophylactic HCV vaccine, our recent knowledge of immune correlates of protection combined with the demonstrated immunogenicity and protective animal efficacies of various HCV vaccine candidates now allows for realistic optimism.This review summarizes the current rationale and status of clinical and experimental HCV vaccine candidates based on the elicitation of cross-neutralizing antibodies and broad cellular immune responses to this highly diverse virus.

View Article: PubMed Central - PubMed

Affiliation: Li Ka Shing Institute of Virology, Department of Medical Microbiology and Immunology, University of Alberta , Edmonton T6G 2E1, Canada.

ABSTRACT
New drugs to treat hepatitis C are expected to be approved over the next few years which promise to cure nearly all patients. However, due to issues of expected drug resistance, suboptimal activity against diverse hepatitis C virus (HCV) genotypes and especially because of their extremely high cost, it is unlikely that these HCV drugs will substantially reduce the world's HCV carrier population of around 170 million in the near future or the estimated global incidence of millions of new HCV infections. For these reasons, there is an urgent need to develop a prophylactic HCV vaccine and also to determine if therapeutic vaccines can aid in the treatment of chronically infected patients. After much early pessimism on the prospects for an effective prophylactic HCV vaccine, our recent knowledge of immune correlates of protection combined with the demonstrated immunogenicity and protective animal efficacies of various HCV vaccine candidates now allows for realistic optimism. This review summarizes the current rationale and status of clinical and experimental HCV vaccine candidates based on the elicitation of cross-neutralizing antibodies and broad cellular immune responses to this highly diverse virus.

No MeSH data available.


Related in: MedlinePlus