Chronic hepatitis C viral infection subverts vaccine‐induced T‐cell immunity in humans

Kelly, Christabel; Swadling, Leo; Capone, Stefania; Brown, Anthony; Richardson, Rachel; Halliday, John; Delft, Annette von; Oo, Ye Htun; Mutimer, David; Kurioka, Ayako; Hartnell, Felicity; Collier, J. R.; Ammendola, Virginia; Sorbo, Mariarosaria Del; Grazioli, Fabiana; Esposito, Maria Teresa; Marco, Stefania Di; Siani, Loredana; Traboni, Cinzia; Hill, Adrian V. S.; Colloca, Stefano; Nicosia, Alfredo; Cortese, Riccardo; Folgori, Antonella; Klenerman, Paul; Barnes, Eleanor

doi:10.1002/hep.28294

Cited by 47 publications

(53 citation statements)

References 43 publications

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“…Similar vaccination trials in chronically infected patients, however, did not show substantial benefits. This failure of the vaccine-induced CD8+ T-cell response was due to the mechanisms of CD8+ T-cell failure discussed above, underlining that the findings obtained previously and discussed in this review need to be taken into account in vaccine development [84] .…”

Section: Discussionmentioning

confidence: 89%

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

Nitschke

Luxenburger

Kiraithe

et al. 2016

Dig Dis

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Approximately 500 million people are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV) worldwide and are thus at high risk of progressive liver disease, leading to liver fibrosis, cirrhosis and ultimately hepatocellular cancer. Virus-specific CD8+ T-cells play a major role in viral clearance in >90% of adult patients who clear HBV and in approximately 30% of patients who clear HCV in acute infection. However, several mechanisms contribute to the failure of the adaptive CD8+ T-cell response in those patients who progress to chronic infection. These include viral mutations leading to escape from the CD8+ T-cell response as well as exhaustion and dysfunction of virus-specific CD8+ T-cells. Antiviral efficacy of the virus-specific CD8+ T-cell response also strongly depends on its restriction by specific human leukocyte antigens (HLA) class I alleles. Our review will summarize the role of HLA-A, B and C-restricted CD8+ T-cells in HBV and HCV infection. Due to the current lack of a comprehensive database of HBV- and HCV-specific CD8+ T-cell epitopes, we also provide a summary of the repertoire of currently well-described HBV- and HCV-specific CD8+ T-cell epitopes. A better understanding of the factors that contribute to the success or failure of virus-specific CD8+ T-cells may help to develop new therapeutic options for HBV eradication in patients with chronic HBV infection (therapeutic vaccination and/or immunomodulation) as well as a prophylactic vaccine against HCV infection.

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Section: Discussionmentioning

confidence: 89%

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

Nitschke

Luxenburger

Kiraithe

et al. 2016

Dig Dis

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“…The primary T cell-based vaccine candidate for HCV, developed by Okairos and currently in phase I/II studies, contains its nonstructural proteins (NS3–NS5b) in recombinant viral vectors [79]. A version of this vaccine failed to induce a sufficient response in chronically infected patients in the context of therapeutic vaccination trial [80], with T cell exhaustion noted as a likely cause. Though it is still unclear whether antibody, CD4+ or CD8+ T cell response, or a combination thereof, is necessary for an effective vaccine in humans [4], E1E2 and virus-like particle (core-E1–E2) protein vaccines were found to produce strong B and T cell responses [77,81].…”

Section: Previous B Cell and T Cell Vaccine Studiesmentioning

confidence: 99%

Viral evasion and challenges of hepatitis C virus vaccine development

Pierce

Keck

Foung

2016

Current Opinion in Virology

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Hepatitis C virus (HCV) is a major global disease burden, often leading to chronic liver diseases, cirrhosis, cancer, and death in those infected. Despite the recent approval of antiviral therapeutics, a preventative vaccine is recognized as the most effective means to control HCV globally, particularly in at-risk and developing country populations. Here we describe the efforts and challenges related to the development of an HCV vaccine, which after decades of research have not been successful. Viral sequence variability poses a major challenge, yet recent research has provided unprecedented views of the atomic structure of HCV epitopes and immune recognition by antibodies and T cell receptors. This, coupled with insights from deep sequencing, robust neutralization assays, and other technological advances, is spurring research toward rationally HCV designed vaccines that preferentially elicit responses toward conserved epitopes of interest that are associated with viral neutralization and clearance.

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“…Likewise, AdCh3NSmut and Ad6NSmut, which were found to induce broad and multifunctional responses in healthy individuals, failed to enhance or broaden the exhausted and narrower T cell responses when employed in a therapeutic setting, indicating the benefit of inducing de novo T cell responses against epitopes that are not under high antigenic pressure and therefore not driven to a dysfunctional state during natural infection (70). Thus, the concept of inducing new T cell immunity by targeting subdominant epitopes could be a promising approach, not limited to a therapeutic context but also to prevent (re)infection or development of chronicity in patients, e.g., intravenous drug users, who have cleared the virus after successful treatment but nevertheless display dysfunctional HCV-specific T cells.…”

Section: Discussionmentioning

confidence: 99%

Broadening CD4⁺and CD8⁺T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

Filskov

Mikkelsen

Hansen

et al. 2017

J Virol

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Despite the introduction of effective drugs to treat patients with chronic hepatitis C virus (HCV) infection, a vaccine would be the only means to substantially reduce the worldwide disease burden. An incomplete understanding of how HCV interacts with its human host and evades immune surveillance has hampered vaccine development. It is generally accepted that in infected individuals, a narrow repertoire of exhausted T cells is a hallmark of persistent infection, whereas broad, vigorous CD4 ϩ and CD8 ϩ T cell responses are associated with control of acute hepatitis C. We employed a vaccine approach based on a mixture of peptides (pepmix) spanning the entire sequence of HCV nonstructural protein 3 (NS3) in cross-priming cationic liposomes (CAF09) to facilitate a versatile presentation of all possible T cell epitopes, regardless of the HLA background of the vaccine recipient. Here, we demonstrate that vaccination of mice with NS3 pepmix broadens the repertoire of epitopespecific T cells compared to the corresponding recombinant protein (rNS3). Moreover, vaccination with rNS3 induced only CD4 ϩ T cells, whereas the NS3 pepmix induced a far more vigorous CD4 ϩ T cell response and was as potent a CD8 ϩ T cell inducer as an adenovirus-vectored vaccine expressing NS3. Importantly, the cellular responses are dominated by multifunctional T cells, such as gamma interferonpositive (IFN-␥ ϩ ) tumor necrosis factor alpha-positive (TNF-␣ ϩ ) coproducers, and displayed cytotoxic capacity in mice. In conclusion, we present a novel vaccine approach against HCV, inducing a broadened T cell response targeting both immunodominant and potential subdominant epitopes, which may be key elements to counter T cell exhaustion and prevent chronicity.IMPORTANCE With at least 700,000 annual deaths, development of a vaccine against hepatitis C virus (HCV) has high priority, but the tremendous ability of the virus to dodge the human immune system poses great challenges. Furthermore, many chronic infections, including HCV infection, have a remarkable ability to drive initially strong CD4 ϩ and CD8 ϩ T cell responses against dominant epitopes toward an exhausted, dysfunctional state. Thus, new and innovative vaccine approaches to control HCV should be evaluated. Here, we report on a novel peptide-based nanoparticle vaccine strategy (NS3 pepmix) aimed at generating T cell immunity against potential subdominant T cell epitopes that are not efficiently targeted by vaccination with full-length recombinant protein (rNS3) or infection with HCV. As proof of concept, we found that NS3 pepmix excels in broadening the repertoire of epitope-

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Chronic hepatitis C viral infection subverts vaccine‐induced T‐cell immunity in humans

Cited by 47 publications

References 43 publications

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

Viral evasion and challenges of hepatitis C virus vaccine development

Broadening CD4⁺and CD8⁺T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

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Chronic hepatitis C viral infection subverts vaccine‐induced T‐cell immunity in humans

Cited by 47 publications

References 43 publications

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

CD8+ T-Cell Responses in Hepatitis B and C: The (HLA-) A, B, and C of Hepatitis B and C

Viral evasion and challenges of hepatitis C virus vaccine development

Broadening CD4+and CD8+T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

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Resources

About

Broadening CD4⁺and CD8⁺T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes