The Immune Response to HCV and HCV Vaccine Development

1. The Immune Response to HCV and HCV Vaccine Development Georg M. Lauer Gastrointestinal Unit Massachusetts General Hospital Harvard Medical School

2. No Conflicts of Interest

3. Dranoff, 2004

4. Dranoff, 2004

5. HCV Control and T Cells • HLA association studies • HLA class I (incl. B27, B57 as in HIV) & class II • GWAS (class II) • Chimpanzee CD8+ and CD4+ T cell depletion associated with viral persistence • IFN- HCV specific CD8+ T cell responses are temporally correlated with reduction in viremia after infection Grakoui et. al, Science 2003, Shoukry et. al. J. Exp Med, 2003, Kim et. al.Gastroenterology 2011, Urbani et al Hepatology 2006, Thimme et al,J Exp Med 2001, David Thomas, in submission (GWAS)

6. HCV-specific T-cell responses • What happens during early HCV Infection? • Correlates of protection • Breadth and vigor of HCV-specific T cell responses • T cell function • The T cell road to HCV prevention?

7. HCV-specific T-cell responses • What happens during early HCV Infection? • Correlates of protection • Breadth and vigor of HCV-specific T cell responses • T cell function • The T cell road to HCV prevention?

8. HCV Infection: Acute Infection to Chronicity HCV Viral Load ALT

9. HCV Infection: Acute Infection to Chronicity HCV Viral Load ALT

10. HCV Infection: Dichotomous outcome AcutevsChronic A 20-30% C HCV Viral Load ALT

11. HCV Infection: Outcome Determined within 24 Weeks A C HCV Viral Load ALT

12. HCV-specific T-cell responses • What happens during early HCV Infection? • Correlates of protection • Breadth and vigor of HCV-specific T cell responses • T cell function • The T cell road to HCV prevention?

13. Acute HCV Infection: Adaptive Immune response • Needle stick infections (known exposure) • No adaptive immune responses before week 7 • ALT increase after immune response Thimmeet al. J Exp Med 2001

14. CD4 Responses in Early HCV Infection • Proliferative responses only in acute infection • Usually targeting multiple HCV proteins • Proliferative defect seen very early in chronic infection • Long established observation (Gerlach 1999) A C Schulze zurWiesch et al., J Exp Med 2012

15. CD4 Responses in Early HCV Infection Patient 05V with acute chronically evolving course: Standard proliferation assay short term culture (+exogenous rIl2) Schulze zurWiesch et al., J Exp Med 2012

16. CD4 Responses in Early HCV Infection Standard proliferative assay T Cell Lines with IL-2 A C A C Schulze zurWiesch et al., J Exp Med 2012

17. CD4 Responses in Early HCV Infection T Cell Lines with IL-2: Number of detected responses depends on time post infection, but only in chronic infection C A A C Schulze zurWiesch et al., J Exp Med 2012

18. CD4 Responses in Early HCV Infection Results from Cell Lines confirmed by HCV HLA Class II Tetramer analysis Acute Chronic Schulze zurWiesch et al., J Exp Med 2012

19. HCV-specific CD4+ T-cell responses • Detectable in all subjects • No correlation between early breadth/vigor and outcome • Rapid contraction with viral persistence (in PBMC) • Early functional defect (proliferation) associated with viral persistence • In persistent infection affected earlier and more profoundly compared to CD8 responses • New technologies allow analysis of early T cell responses in HCV – dichotomous outcome makes HCV unique model to define protective immunity

20. Phases of Early HCV Infection/T Cell Response 1: “NOTHING” No Adaptive Immunity Weeks 0 to 6/8 Is time of essence? Role of innate immunity? A C CD8 T Cell Response CD4 T Cell Response

21. Phases of Early HCV Infection/T Cell Response 2: “Emerging Response” ALT Rise Followed by HCV RNA Inflection CD4/8 responses similar breadth and magnitude CD4 proliferative defect Other functional differences? A C CD8 T Cell Response CD4 T Cell Response

22. Phases of Early HCV Infection/T Cell Response 3: “Battle” HCV RNA Fluctuations Emerging differences in CD4/8 response (magnitude/function) Beginning T cell exhaustion? Early viral escape mutations? A C CD8 T Cell Response CD4 T Cell Response

23. Phases of Early HCV Infection/T Cell Response 4: “Resolved/Chronic” Marked differences in T cell numbers/phenotype/function Differences cause or effect of viral control/persistence? Differences reversible? (Immunotherapy) A C CD8 T Cell Response CD4 T Cell Response

24. Phases of Early HCV Infection/T Cell Response 6 to 24 weeks post infection Most important phase to study HCV T cell responses (but most “acute” studies are later) HCV could/should be a unique model to define protective immunity A C CD8 T Cell Response CD4 T Cell Response

25. HCV-specific T-cell responses • What happens during early HCV Infection? • Correlates of protection • Breadth and vigor of HCV-specific T cell responses • T cell function • The T cell road to chronic HCV prevention?

26. HCV- Can we make an effective vaccine? • Challenges parallel to HIV • Correlates of protection not exactly known • Highly diverse virus • Unsafe to use live attenuated or killed virus • Current focus is to use vectors to deliver viral antigens in a system that induces robust innate and adaptive immune responses • Preexisting vector immunity limits responses

27. Preventing pre-existing anti-vector immunity from limiting vaccine efficacy • Okairos search for novel adenoviral strains in chimpanzees worldwide • Goals: Discover adenoviral vectors that are • Highly immunogenic • Easily manufactured to high titers • Not stimulating cross reactive immunity (humans rarely exposed) • Success: • Adenoviruses derived from chimpanzees (ChAd) differ from human adenovirus primarily in hexon (surface) proteins, making Ab cross reactivity low • many are highly immunogenic Folgori et al. Nature Medicine, 2006

28. High frequencies of HCV Specific CD8 T cells 1.52% 0% 7.18% 0.83% 6.24% HLA class-I pentamer (KLSGLGINAV) CD8+ B 4 weeks post prime (TW4 or 8) 4 weeks post boost (TW 12 or 28) Final time point (TW 36 or 52) Ad1 prime (TW0) Ad2 boost (TW 8 or 24) Barnes et. al. Science Translational Medicine 2012

29. HCV Vaccine HealthyVolunteer Trial Summary • AdCh3NS and Ad6NS are highly potent (> 1400 SFU/million PBMC; IFN- ELISpot) following a single injection. • At the highest dose all individuals responded to vaccination. • The majority of subjects developed responses against multiple HCV proteins. • Polyfunctional CD4 and CD8+ T cells are induced. • AdCh3NS and Ad6NS are safe and well tolerated at all tested doses.

30. HCV Prophylactic Vaccine Based on Sequential Use of AdCh3 and MVA with NS • Cross reactivity of AdCh3 with human anti-adenovirus Abs is 12% • MVA boosts well in Phase I trials • Double-blinded, randomized, placebo-controlled two stage study. • Subjects: HCV Ab and RNA negative, active IDU’s at high risk for HCV, 18 -45 y.o. • Two Sites (A. Cox/JHU & K. Page/UCSF) W0 W8 W50 MVA 1.8x108pfu AdCh3 2.5 x1010vp W = week = test immune response

31. Endpoints Primary • Safety of both vaccines • To determine if AdCh3NSmut1 and MVA-NSmut HCV vaccines will reduce incidence of chronic HCV infection compared to placebo among HCV-uninfected IDUs. Secondary • Immunogenicity compared to placebo when administered to HCV uninfected IDUs

32. Exploratory Endpoints • Does it reduce the incidence of primary infection? • Does it protect better against gt1b than others? • Does it reduce the peak magnitude or duration of viremia in those infected?

33. GI Unit (& ID) Daniela Kroy Donatella Ciuffreda David Wolski Julian Schulze z. W. Garrett Hauck Jennifer Cooperrider Stephanie Kulaga Arthur Kim JasneetAneja Leslie Prince Joe Misdraji Michelle Tomlinson Ray Chung OswaldoCruz Inst., RdJ Lia Lewis Lemuel Shattuck Hosp. Barbara McGovern Oxford University Ellie Barnes JHU Andrea Cox FUNDING NIH U19 AI082630 NIH U19 AI066345 Dana Foundation