Highly immunogenic virally vectored T-cell vaccines cannot overcome subversion of the T-cell response by HCV during chronic infection
An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection would significantly reduce the global burden of disease associated with chronic HCV infection. <...
| Κύριοι συγγραφείς: | , , , , , , , , , , , , , , , , , , , , |
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| Μορφή: | Journal article |
| Έκδοση: |
MDPI
2016
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| _version_ | 1826272477504864256 |
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| author | Swadling, L Halliday, J Kelly, C Brown, A Capone, S Ansari, M Bonsall, D Richardson, R Hartnell, F Collier, J Ammendola, V Del Sorbo, M Von Delft, A Traboni, C Hill, A Colloca, S Nicosia, A Cortese, R Klenerman, P Folgori, A Barnes, E |
| author_facet | Swadling, L Halliday, J Kelly, C Brown, A Capone, S Ansari, M Bonsall, D Richardson, R Hartnell, F Collier, J Ammendola, V Del Sorbo, M Von Delft, A Traboni, C Hill, A Colloca, S Nicosia, A Cortese, R Klenerman, P Folgori, A Barnes, E |
| author_sort | Swadling, L |
| collection | OXFORD |
| description | An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection would significantly reduce the global burden of disease associated with chronic HCV infection. <br/><br/> A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with Interferon/ribavirin therapy), determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated the heterologous Ad regimen. <br/><br/> Vaccination of HCV infected patients with ChAd3-NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T- cell responses were rarely detected, and overall the magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFa production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression) compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T- cell response. Full-length, next generation sequencing of circulating virus demonstrated that T-cells were only induced by vaccination when there was sequence mismatch between autologous virus and the vaccine immunogen. However, these T cells were not cross -reactive with endogenous viral variant epitopes. Conversely when there was complete homology between immunogen and circulating virus at a given epitope T-cells were not induced. T-cell induction following vaccination had no significant impact on HCV viral load. In vitro T-cell culture experiments identified the presence of T-cells at baseline that could be expanded by vaccination; thus HCV-specific T-cells may have been expanded from pre-existing low-level memory T-cell populations that had been exposed to HCV antigen during natural infection, explaining the partial T-cell dysfunction. <br/><br/> In conclusion, vaccination with ChAd3-NSmut and MVA-NSmut prime/boost, a potent vaccine regimen previously optimised in healthy volunteers, was unable to reconstitute HCV-specific T-cell immunity in HCV infected patients. This highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure. |
| first_indexed | 2024-03-06T22:13:10Z |
| format | Journal article |
| id | oxford-uuid:5281d872-bdf3-44e4-baf0-c5f54c9e842c |
| institution | University of Oxford |
| last_indexed | 2024-03-06T22:13:10Z |
| publishDate | 2016 |
| publisher | MDPI |
| record_format | dspace |
| spelling | oxford-uuid:5281d872-bdf3-44e4-baf0-c5f54c9e842c2022-03-26T16:26:05ZHighly immunogenic virally vectored T-cell vaccines cannot overcome subversion of the T-cell response by HCV during chronic infectionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5281d872-bdf3-44e4-baf0-c5f54c9e842cSymplectic Elements at OxfordMDPI2016Swadling, LHalliday, JKelly, CBrown, ACapone, SAnsari, MBonsall, DRichardson, RHartnell, FCollier, JAmmendola, VDel Sorbo, MVon Delft, ATraboni, CHill, AColloca, SNicosia, ACortese, RKlenerman, PFolgori, ABarnes, EAn effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection would significantly reduce the global burden of disease associated with chronic HCV infection. <br/><br/> A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with Interferon/ribavirin therapy), determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated the heterologous Ad regimen. <br/><br/> Vaccination of HCV infected patients with ChAd3-NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T- cell responses were rarely detected, and overall the magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFa production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression) compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T- cell response. Full-length, next generation sequencing of circulating virus demonstrated that T-cells were only induced by vaccination when there was sequence mismatch between autologous virus and the vaccine immunogen. However, these T cells were not cross -reactive with endogenous viral variant epitopes. Conversely when there was complete homology between immunogen and circulating virus at a given epitope T-cells were not induced. T-cell induction following vaccination had no significant impact on HCV viral load. In vitro T-cell culture experiments identified the presence of T-cells at baseline that could be expanded by vaccination; thus HCV-specific T-cells may have been expanded from pre-existing low-level memory T-cell populations that had been exposed to HCV antigen during natural infection, explaining the partial T-cell dysfunction. <br/><br/> In conclusion, vaccination with ChAd3-NSmut and MVA-NSmut prime/boost, a potent vaccine regimen previously optimised in healthy volunteers, was unable to reconstitute HCV-specific T-cell immunity in HCV infected patients. This highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure. |
| spellingShingle | Swadling, L Halliday, J Kelly, C Brown, A Capone, S Ansari, M Bonsall, D Richardson, R Hartnell, F Collier, J Ammendola, V Del Sorbo, M Von Delft, A Traboni, C Hill, A Colloca, S Nicosia, A Cortese, R Klenerman, P Folgori, A Barnes, E Highly immunogenic virally vectored T-cell vaccines cannot overcome subversion of the T-cell response by HCV during chronic infection |
| title | Highly immunogenic virally vectored T-cell vaccines cannot overcome subversion of the T-cell response by HCV during chronic infection |
| title_full | Highly immunogenic virally vectored T-cell vaccines cannot overcome subversion of the T-cell response by HCV during chronic infection |
| title_fullStr | Highly immunogenic virally vectored T-cell vaccines cannot overcome subversion of the T-cell response by HCV during chronic infection |
| title_full_unstemmed | Highly immunogenic virally vectored T-cell vaccines cannot overcome subversion of the T-cell response by HCV during chronic infection |
| title_short | Highly immunogenic virally vectored T-cell vaccines cannot overcome subversion of the T-cell response by HCV during chronic infection |
| title_sort | highly immunogenic virally vectored t cell vaccines cannot overcome subversion of the t cell response by hcv during chronic infection |
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