Therapeutic vaccines for HCV Chasing a Moving Target

Transcription

1 Therapeutic vaccines for HCV Chasing a Moving Target Ellie Barnes (Fondation Merieux-Annecy March 213)

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3 Do we need a vaccine for HCV? HCV infects 17 million people worldwide Leading cause of end-stage liver disease and transplantation in UK

4 Do we need a vaccine for HCV? HCV infects 17 million people worldwide Leading cause of end-stage liver disease and transplantation in UK 25% HIV+ people infected with HCV Leading cause of death in HIV+ people on HARRT

5 Tackling diversity

6 Defining protective immune responses Acute disease Persistent infection >8% Host genetics T cell immunity Resolved infection <2%? Mild disease Progressive disease

7 A T cell vaccine for HCV-the rationale HCV specific T cell responses crucial role in HCV viral clearance in acute infection HLA association studies (A3, B57, B27 with clearance) (Neumann C, et al. Hepatology 26) Chimpanzee CD4+ and CD8+ T cell blocking experiments (Shoukry N J Ex Med 23) Association of breadth and magnitude of T cell response with viral clearance (Lauer et al Gastro 24) IFN- HCV specific CD8 + T cell responses are temporally correlated with reduced viremia after infection (Lechner F J Ex Med 2) Prophylactic vaccine data (Adeno/DNA) in a chimp challenge model. (Folgori et al Nat med 28)

8 HCV genomes/ml ALT or GGT Vaccinated animals Control animals Vaccinated HCV Ad-NS animals Control animals HCV challenge Folgori et al. Nature Medicine, 26 HCV challenge

9 Adenoviral vectors-phylogenetic analysis Ad Hex protein Colloca et al Science translational medicine Jan 212

10 The HCV immunogen NS3-NS5B (NS = 1985 aa) Genotype 1, subtype 1b Multiple epitopes Genetically inactivated NS5B (NSmut) NS5Bmut AAG

11 Study aims To develop a prophylactic vaccine for HCV Phase I study healthy volunteers (dose escalation) Safety and immunogenicity First in human study HCV prophylactic T cell vaccine To develop a therapeutic vaccine for HCV Phase I study in HCV infected patients Safety and immunogenicity With interferon/ribavirin therapy

12 HCV polyprotein (1b genotype) The primary assay; IFN-Υ ELISpot NS3p NS3h NS4 NS5a NS5b 15mer peptide pools (1b genotype) Pool F Pool G Pool H Pool I Pool L Pool M Secondary assays; ICCS -functionality Tetramer analysis-phenotype CFSE and thymidine incorporation assays-proliferative responses Viral sequencing-in vivo targets

13 T cell responses increase with dose escalation Barnes et el Science Translation Medicine Jan 212

14 IFN? SFC/1 6 PBMC Broad T cell responses are induced mock pool NS3p pool NS3h pool NS4 pool NS5A pool NS5B-I pool NS5B-II 5 Volunteer n Ad6NS 2,5x1 1 AdCh3NS 2,5x1 1 - Assay: IFN- ELIspot - Results show responses to individual peptide pools spanning the HCV NS region

15 IL-2 TNFα T cells are polyfunctional CD4 CD8 DMSO NS3/4 DMSO NS3/ % % %.11% 1 5.3% % 1 5.4%.21% % 1 2.8%.4% 1.5% %.1% 1 5 %.2% 1 5 % % 1 5 %.2% %.4% %.4% % % 1 5.3%.5% 1 5 % % 1 5.3%.21% % 1 2.5% %.62% IFNγ IFNγ

16 % Pentamer positive CD8 (KLSGLGINAV) HLA class-i pentamer (KLSGLGINAV) A 1 5 % % % % % CD8+ TW Ad1 prime TW 4 (4 wks post prime) TW 8 (Ad2 boost) TW 12 4 wks post boost TW 36 (study end) 1 B TW Ad1 prime TW4 (4 wks post prime) TW 8 (Ad2 boost) TW 12 4 wks post boost TW 36 (study end)

17 phenotypic marker <FITC-A>: PERFORIN <PerCP-Cy5-5-A>: GZA <PE-Cy7-A>: PD-1 <Alexa Fluor 7-A>: GZB <APC-A>: CD161 <FITC-A>: CD45RA <PerCP-Cy5-5-A>: CD38 <PE-Cy7-A>: CCR7 <APC-A>: CD127 <Alexa Fluor 7-A>: HLA-DR Cellular phenotype using HLA class-i tetramers TW4 (4Wks Post Prime) CD45RA CD38 CCR7 CD127 HLA-DR <PE-A>: PENTAMER <PE-A>: PENTAMER <PE-A>: PENTAMER <PE-A>: PENTAMER <PE-A>: PENTAMER Perforin GzA PD-1 GzB CD <PE-A>: PENTAMER <PE-A>: PENTAMER <PE-A>: PENTAMER <PE-A>: PENTAMER <PE-A>: PENTAMER pentamer gated on CD8+ T cells

18 Kinetics of HCV specific T cells over time

19 Why boost? Sustain responses Enhance responses Assess functionality

20 Humans are not monkeys? poorly functional T cells primed? anti vector immunity

21 Plan B-change boosting vector MVA-Long track safety record Cheap and easy to produce Excellent emerging data in malaria field

22 HCV exists as multiple genotypes U.K

23 Therapeutic vaccination-can we induce a functional HCV specific T cell response? Lauer et al gastro 24 p=.29 Why? Viral escape (in part) Liver immunomodulation High viral load HCV specific cells in chronic infection; 1. Weak 2. Narrowly focused 3. Poorly functional Can a therapeutic vaccine strategy overcome this?

24 In conclusion Developed an HCV vaccine based on simian adenoviral vectors-optimally boosted with MVA vector Very high numbers of polyfunctional CD4 and CD8 T cells in healthy volunteers Target multiple HCV antigens Able to induce T cells in patients with chronic HCV infection-need to take autologous virus into account Viral variability remains a problem-but with a solution

25 Future plans Phase II-study in IVDU in Baltimore-3 years interim results Assessment of HCV vaccines in patients with HIV infection Strategies to further enhance T cell immunogenicity in patients with persistent infection Re-design the HCV immunogen to deal with viral variation

26 Acknowledgements Adrian Hill Paul Klenerman John Halliday Richard Antrobus Christabel Kelly Leo Swaddling Jose Lorenco Steven Aston Eleanor Berrie Anthony Brown Abby Harrison Rachel Huddart Rachel Townsend Isla Humphreys Kira Smith Chris Willberg Virginia Ammendola Marta Bartiromo Stefania Capone Stefano Colloca Riccardo Cortese Maria Luisa Esposito Antonella Folgori Mariarosaria Naddeo Alfredo Nicosia Loredana Siani Angela Sparacino Cinzia Traboni Funding David Adams David Mutimer Ye oo Patients and volunteers Oxford Biomedical Research centre BEI Resources