The development of a hepatitis C virus prophylactic vaccine strategy
<p>The success of directly-acting antivirals (DAA) has revolutionised hepatitis C virus (HCV) treatment, yet a prophylactic HCV vaccine remains an important clinical asset to achieve HCV elimination by 2030. To date, the development of a prophylactic HCV vaccine has been hindered by viral geno...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2019
|
| Subjects: |
| _version_ | 1797111187895222272 |
|---|---|
| author | Donnison, T |
| author2 | Barnes, E |
| author_facet | Barnes, E Donnison, T |
| author_sort | Donnison, T |
| collection | OXFORD |
| description | <p>The success of directly-acting antivirals (DAA) has revolutionised hepatitis C virus (HCV) treatment, yet a
prophylactic HCV vaccine remains an important clinical asset to achieve HCV elimination by 2030. To date,
the development of a prophylactic HCV vaccine has been hindered by viral genomic variability. In human
trials, a viral vectored genotype (gt)-1b immunogen induced genotype-1b specific T cell responses targeting
highly variable dominant epitopes that displayed reduced cross-recognition of epitope variants at the
population level. Therefore, a simian adenoviral vectored (ChAd) HCV T cell vaccine encoding conserved
sequences across HCV genotypes was developed, containing known T cell epitopes.</p>
<p>In this thesis, I show that conserved sequence vaccines (ChAd-gt1/3, -gt1-6) induce broad, high magnitude,
and functional T cell responses that target subdominant highly conserved HCV epitopes in mice, that can be
increased by encoding the novel genetic adjuvant—truncated shark invariant chain (sIi<sub>47-72</sub>) at the 5’ end of
the transgene. In addition, I demonstrate that conserved HCV epitopes were not targeted by a ChAd-gt-1b
prime and an MVA-gt-3a boost vaccination, unlike a ChAd-gt1-6 prime-boost vaccination, highlighting the
importance of priming naïve T cells specific for conserved epitopes. Furthermore, I show that a mixed
modality HCV vaccination strategy—combining ChAd-gt1-6 and the recombinant E2Δ123<sub>HMW</sub> protein does
not compromise either the T cell or antibody response compared to either vaccine alone. For the prospects
of a single viral vector vaccine that encodes both the gt1-6 T cell immunogen and the E2D123 protein
sequence (a ‘bivalent’ vaccine), I demonstrate that a monovalent ChAd-E2D123 prime vaccine induces
higher antibody titres targeting E2 and CD81-binding epitopes that neutralise HCVpp/cc, when compared to
recombinant E2Δ123<sub>HMW</sub> protein-induced antibody responses. This body of work represents a significant
step forward in the development of a universal prophylactic HCV vaccine and the next step is the assessment
of HCV bivalent vaccine induced cross-reactive T cells and broadly neutralising antibodies.</p>
<p>A universal HCV vaccine that will contribute to the global elimination strategy will need to target multiple
HCV genotypes that circulate in a population and conserved epitopes that can resist viral escape. The work
described in this thesis is the next step towards the generation of a universal prophylactic HCV vaccine.</p> |
| first_indexed | 2024-03-07T08:06:44Z |
| format | Thesis |
| id | oxford-uuid:83071b21-0735-4fba-851f-ac8e882f260a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:06:44Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | oxford-uuid:83071b21-0735-4fba-851f-ac8e882f260a2023-11-01T15:37:48ZThe development of a hepatitis C virus prophylactic vaccine strategyThesishttp://purl.org/coar/resource_type/c_db06uuid:83071b21-0735-4fba-851f-ac8e882f260aVaccinesHCVImmunologyEnglishORA Deposit2019Donnison, TBarnes, E<p>The success of directly-acting antivirals (DAA) has revolutionised hepatitis C virus (HCV) treatment, yet a prophylactic HCV vaccine remains an important clinical asset to achieve HCV elimination by 2030. To date, the development of a prophylactic HCV vaccine has been hindered by viral genomic variability. In human trials, a viral vectored genotype (gt)-1b immunogen induced genotype-1b specific T cell responses targeting highly variable dominant epitopes that displayed reduced cross-recognition of epitope variants at the population level. Therefore, a simian adenoviral vectored (ChAd) HCV T cell vaccine encoding conserved sequences across HCV genotypes was developed, containing known T cell epitopes.</p> <p>In this thesis, I show that conserved sequence vaccines (ChAd-gt1/3, -gt1-6) induce broad, high magnitude, and functional T cell responses that target subdominant highly conserved HCV epitopes in mice, that can be increased by encoding the novel genetic adjuvant—truncated shark invariant chain (sIi<sub>47-72</sub>) at the 5’ end of the transgene. In addition, I demonstrate that conserved HCV epitopes were not targeted by a ChAd-gt-1b prime and an MVA-gt-3a boost vaccination, unlike a ChAd-gt1-6 prime-boost vaccination, highlighting the importance of priming naïve T cells specific for conserved epitopes. Furthermore, I show that a mixed modality HCV vaccination strategy—combining ChAd-gt1-6 and the recombinant E2Δ123<sub>HMW</sub> protein does not compromise either the T cell or antibody response compared to either vaccine alone. For the prospects of a single viral vector vaccine that encodes both the gt1-6 T cell immunogen and the E2D123 protein sequence (a ‘bivalent’ vaccine), I demonstrate that a monovalent ChAd-E2D123 prime vaccine induces higher antibody titres targeting E2 and CD81-binding epitopes that neutralise HCVpp/cc, when compared to recombinant E2Δ123<sub>HMW</sub> protein-induced antibody responses. This body of work represents a significant step forward in the development of a universal prophylactic HCV vaccine and the next step is the assessment of HCV bivalent vaccine induced cross-reactive T cells and broadly neutralising antibodies.</p> <p>A universal HCV vaccine that will contribute to the global elimination strategy will need to target multiple HCV genotypes that circulate in a population and conserved epitopes that can resist viral escape. The work described in this thesis is the next step towards the generation of a universal prophylactic HCV vaccine.</p> |
| spellingShingle | Vaccines HCV Immunology Donnison, T The development of a hepatitis C virus prophylactic vaccine strategy |
| title | The development of a hepatitis C virus prophylactic vaccine strategy |
| title_full | The development of a hepatitis C virus prophylactic vaccine strategy |
| title_fullStr | The development of a hepatitis C virus prophylactic vaccine strategy |
| title_full_unstemmed | The development of a hepatitis C virus prophylactic vaccine strategy |
| title_short | The development of a hepatitis C virus prophylactic vaccine strategy |
| title_sort | development of a hepatitis c virus prophylactic vaccine strategy |
| topic | Vaccines HCV Immunology |
| work_keys_str_mv | AT donnisont thedevelopmentofahepatitiscvirusprophylacticvaccinestrategy AT donnisont developmentofahepatitiscvirusprophylacticvaccinestrategy |