The generation of a simian adenoviral vectored HCV vaccine encoding genetically conserved gene segments to target multiple HCV genotypes

Delft, Annette von; Donnison, Timothy; Lourenço, José; Hutchings, Claire; Mullarkey, Caitlin E.; Brown, Anthony; Pybus, Oliver G.; Klenerman, Paul; Chinnakannan, Senthil; Barnes, Eleanor

doi:10.1016/j.vaccine.2017.10.079

Cited by 35 publications

(30 citation statements)

References 53 publications

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“…(23,24) All strategies face difficulties dealing with the enormous genetic diversity of HCV, (3,25) leading to a recent focus targeting conserved HCV genomic regions. (26) Further questions on vaccine efficacy cannot be answered in chimpanzees because of a recent moratorium on using chimpanzees in biomedical research. (27) For these reasons, development of a small animal model is critically important for HCV vaccine development.…”

Section: And Peter Simmondsmentioning

confidence: 99%

Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus

Atcheson

Bliss

et al. 2019

Hepatology

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Background and Aims The lack of immunocompetent small animal models for hepatitis C virus (HCV) has greatly hindered the development of effective vaccines. Using rodent hepacivirus (RHV), a homolog of HCV that shares many characteristics of HCV infection, we report the development and application of an RHV outbred rat model for HCV vaccine development. Approach and Results Simian adenovirus (ChAdOx1) encoding a genetic immune enhancer (truncated shark class II invariant chain) fused to the nonstructural (NS) proteins NS3‐NS5B from RHV (ChAd‐NS) was used to vaccinate Sprague‐Dawley rats, resulting in high levels of cluster of differentiation 8–positive (CD8+) T‐cell responses. Following RHV challenge (using 10 or 100 times the minimum infectious dose), 42% of vaccinated rats cleared infection within 6‐8 weeks, while all mock vaccinated controls became infected with high‐level viremia postchallenge. A single, 7‐fold higher dose of ChAd‐NS increased efficacy to 67%. Boosting with ChAd‐NS or with a plasmid encoding the same NS3‐NS5B antigens increased efficacy to 100% and 83%, respectively. A ChAdOx1 vector encoding structural antigens (ChAd‐S) was also constructed. ChAd‐S alone showed no efficacy. Strikingly, when combined with ChAd‐NS, ChAD‐S produced 83% efficacy. Protection was associated with a strong CD8+ interferon gamma–positive recall response against NS4. Next‐generation sequencing of a putative RHV escape mutant in a vaccinated rat identified mutations in both identified immunodominant CD8+ T‐cell epitopes. Conclusions A simian adenovirus vector vaccine strategy is effective at inducing complete protective immunity in the rat RHV model. The RHV Sprague‐Dawley rat challenge model enables comparative testing of vaccine platforms and antigens and identification of correlates of protection and thereby provides a small animal experimental framework to guide the development of an effective vaccine for HCV in humans.

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Section: And Peter Simmondsmentioning

confidence: 99%

Use of an Outbred Rat Hepacivirus Challenge Model for Design and Evaluation of Efficacy of Different Immunization Strategies for Hepatitis C Virus

Atcheson

Bliss

et al. 2019

Hepatology

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“…Recent work has shown that vaccines can induce T cell immunity to conserved regions of the virus. 67 Both mechanisms of CD8+ T cell failure, T cell exhaustion and viral escape, are directly linked to the CD4+ T cell response. Indeed, during chronic infection, CD4+ T cells are only present at a very low frequency, display impaired proliferative and cytokine production, and are characterised by high expression of inhibitory receptors such as PD-1 and cytotoxic T-lymphocyte associated protein 4.…”

Section: Failure Of T Cell Immunitymentioning

confidence: 99%

T cell immunity to hepatitis C virus: Lessons for a prophylactic vaccine

Thimme

2021

Journal of Hepatology

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There is consensus that HCV-specific T cells play a central role in the outcome (clearance vs. persistence) of acute infection and that they contribute to protection against the establishment of persistence after reinfection. However, these T cells often fail and the virus can persist, largely as a result of T cell exhaustion and the emergence of viral escape mutations. Importantly, HCV cure by direct-acting antivirals does not lead to a complete reversion of T cell exhaustion and thus HCV reinfections can occur. The current lack of detailed knowledge about the immunological determinants of viral clearance, persistence and protective immunity is a major roadblock to the development of a prophylactic T cell vaccine. This minireview highlights the basic concepts of successful T cell immunity, major mechanisms of T cell failure and how our understanding of these concepts can be translated into a prophylactic vaccine.

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“…The majority of currently registered clinical trials with a known status are of vaccines using T cell–mediated immunity (Table ) with some encouraging results from phase 2 studies . In addition, a recent preclinical study has characterized an adenoviral vaccine using conserved, immunogenic HCV epitopes to generate HCV‐specific T cell responses in mice across a range of HCV genotypes . Further progress in this field is eagerly awaited.…”

Section: Current Progress In Vaccine Developmentmentioning

confidence: 99%