HCV vaccine: how do we prove it works?

Transcription

1 HCV vaccine: how do we prove it works? Kimberly Page, Ph.D. MPH Professor, Chief of Epidemiology, Biostatistics & Preventive Medicine University of New Mexico Health Sciences Center

2 No conflicts of interest

3 Outline Reasons to develop an HCV vaccine Possibility of protective immunity to HCV Challenges in HCV vaccine development Overcoming the challenges The first prophylactic HCV vaccine trial in at-risk people is underway

4 HCV- Do we need a vaccine? Therapies dramatically and can cure the majority of HCV infected!! but

5 HCV- Do we need a vaccine? Treatment is expensive, and out of reach for many

6 HCV- Do we need a vaccine? Treatment is expensive & out of reach Treatment does not completely reverse risks of advanced liver disease

7 HCV- Do we need a vaccine? Treatment remains expensive and carries side effects Treatment does not completely reverse risks of advanced liver disease Drugs do not provide protection against reinfection: PWID, HIV+ MSM, HCworkers

8 HCV- Do we need a vaccine? Treatment remains expensive and carries side effects Treatment does not completely reverse risks of advanced liver disease Drugs do not provide protection against reinfection Finding the people who need treatment remains challenging

9 Identification of HCV Infected people is challenging Infection usually silent until ESLD present

10 Identification of HCV Infected people is challenging Infection usually silent until ESLD present Knowledge of infection status limited 5% of those infected world-wide CDC MMWR Recomm. Rec. 47 (RR-19), 1-39 (1998), Nature Outlook Hepatitis C vol 474, 7350, S2, Denniston M, et al. Hepatology. 2012:55:

11 Identification of HCV Infected people is challenging Infection usually silent until ESLD present Knowledge of infection status limited 5% of those infected world-wide 30-50% of infected aware in US (HIV 80%) CDC MMWR Recomm. Rec. 47 (RR-19), 1-39 (1998), Nature Outlook Hepatitis C vol 474, 7350, Denniston M, et al. Hepatology. 2012:55:

12 Identification of HCV Infected people is challenging Infection usually silent until ESLD present Knowledge of infection status limited 30-50% of infected aware in US (HIV 80%) 5% of those infected world-wide Australia, Canada, France, Denmark, and Scotland as models Aggressive screening 60-80% aware CDC MMWR Recomm. Rec. 47 (RR-19), 1-39 (1998), Nature Outlook Hepatitis C vol 474, 7350, S2 Denniston M, et al. Hepatology. 2012:55:

13 Identification of HCV Infected people is challenging Infection usually silent until ESLD present Knowledge of infection status limited Highest risk groups are marginalized PWID CDC MMWR Recomm. Rec. 47 (RR-19), 1-39 (1998), Nature Outlook Hepatitis C vol 474, 7350, S2, Denniston M, et al. Hepatology. 2012:55:

14 Identification of HCV Infected people is challenging Infection usually silent until ESLD present Knowledge of infection status limited Highest risk group is marginalized - PWID Most are unaware they are infected Many are not tested or tested for ant-hcv but not RNA Few are evaluated for treatment Fewer are offered or initiate treatment Less complete treatment

15 Identification of HCV Infected people is challenging Infection usually silent until ESLD present Knowledge of infection status limited Highest risk groups are marginalized PWID Living in endemic regions of the world

16 Identification of HCV Infected people is challenging Infection usually silent until ESLD present Knowledge of infection status limited Highest risk groups are marginalized PWID Living in endemic regions of the world limited access to testing poor needle, injection, and blood product hygiene Limited access to therapies

17 Identification of HCV Infected people is challenging Infection usually silent until ESLD present Knowledge of infection status limited Highest risk groups are marginalized Treatment in the later stages doesn t reverse all disease

18 Evidence for Host Protective Immune Responses Genetic factors: IFNL4, HLA- B*57, HLA-Cw*04 Sex Immune responses Re-infection Re-Clearance studies

19 Factors associated with spontaneous clearance Grebely J, Page K, Sacks-Davis R, et al., The Effects of Female Sex, Viral Genotype, and IL28B Genotype on Spontaneous Clearance of Acute Hepatitis C Virus Infection, Hepatology 2014

20 IFNL4* (rs allele) associated with higher probability of spontaneous HCV clearance * Previously termed IL28B Grebely J, Page K, Sacks-Davis R, et al., The Effects of Female Sex, Viral Genotype, and IL28B Genotype on Spontaneous Clearance of Acute Hepatitis C Virus Infection, Hepatology 2014

21 Viral HCV persistence probability by sex and IFNL4

22 T cell Responses Crucial in Control of HCV HLA association studies Chimpanzee CD8+ and CD4+ T cell depletion Association of breadth and magnitude of T cell response with viral clearance IFN-γ 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, Day et. al. J Virol 2002, Urbani et al Hepatology 2006, Thimme et al, Proc Natl Acad Sci USA 2002

23 The Protective Immune Response Can it be acquired? 1 st reinfection does happen so protective immunity is not apparent But Some evidence that says yes

24 Studies of HCV clearance, reinfection and re-clearance* Study Primary infection Reinfection (n) in clearers (N) N Incidence (/100 pyo) Spont. Clear. (%) n/n Incidence (/100 pyo) Reclearance BBASH % 10/ % ALIVE % 6/ % UFO % 4/ % Networks % 3/ % Amsterdam % 3/ % CHASE % 4/ % InC3 7a,b 5, % 28/ % 1. Osburn et al Gastroenterology 2009; 2. Mehta et al Lancet 2002;3. Page et al CID 2013; 4 Aitkin et al Hepatology 2006; 5. Van der Laar et al J Hepatology; 8. Grebely et al Hepatology 2006; 7a. Sacks-Davis et al JID 2015; 7b. Morris et al, in prep. * Grebely et al, HCV clearance, reinfection, & persistence, with insights from studies of injecting drug users: towards a vaccine, Lancet ID 2012

25 Decreased magnitude of viremia Max Detected HCV RNA (IU/ml) 1e+9 1e+8 1e+7 1e+6 1e+5 1e+4 1e+3 1e+2 1e+1 Primary Infection Osburn et. al. Gastroenterology 2010;138: during reinfection P < 0.05 Subsequent Infections includes persistently reinfected subjects

26 Shorter duration of viremia during reinfection Osburn et. al. Gastroenterology 2010;138:

27 Time to reclearance vs. primary clearance Number of participants (2 clearances/ 14 participant): Median (IQR) time to spontaneous clearance 5.5 (2.6- of primary infection (months) 11.2) Median (IQR) time to spontaneous clearance 3.0 ( ) of reinfection (months) Excluding outlier: HR (95% CI) p-value 3.2 ( ) Including outlier: HR (95% CI) p-value 1.9 ( ) Sacks-Davis et al JID 2015

28 Broadening of T cell responses in HCV Reinfection P < 0.05 Updated from Osburn et. al. Gastroenterology 2010;138:

29 Super HCV Controllers Recurrent detectable viremic events with different virus show broadening of the immune response: Lower peak HCV RNA Shorter duration of viremia Recent data suggest that antibody responses play a more important role than what was previously thought. Resolvers develop long-lived memory T cells and are less likely to become persistently infected upon re-exposure.

30 Challenges in HCV vaccine development HCV vaccines in chimpanzee models have not provided sterilizing immunity Sterilizing immunity is a high bar so is it required? Most disease is from chronic infection There remains much to be learned about what constitutes an effective and protective immune response!

31 HCV- Can we make an effective vaccine? Challenges parallel to HIV Highly diverse virus

32 G E D hominoids C A B F a 1c 1 1b HBV 3181 sites 5 F D B G AE A K J HIV 8316 sites C H HCV 9198 sites Ray SC and Thomas DL. PPID 7 th ed, Chapter

33 HCV- Can we make an effective vaccine? Challenges parallel to HIV Highly diverse virus Unsafe to use live attenuated or killed virus

34 HCV- Can we make an effective vaccine? Challenges parallel to HIV Highly diverse virus Unsafe to use live attenuated or killed virus Increasing interest in vaccines that induce robust T cell responses

35 HCV- Can we make an effective vaccine? Challenges parallel to HIV Highly diverse virus Unsafe to use live attenuated or killed virus Increasing interest in vaccines that induce robust T cell responses Few promising candidates

36 HCV- Can we make an effective vaccine? Challenges parallel to HIV Highly diverse virus Unsafe to use live attenuated or killed virus Increasing interest in vaccines that induce robust T cell responses Few promising candidates Current focus is to use vectors to deliver viral antigens in a system that induces robust innate and adaptive immune responses

37 HCV- Can we make an effective vaccine? Challenges parallel to HIV Highly diverse virus Unsafe to use live attenuated or killed virus Increasing interest in vaccines that induce robust T cell responses Few promising candidates 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

38 Other vaccine strategies Recombinant viral glycoproteins to generate neutralizing antibody responses. These include a gpe1/e2 vaccine (1, 2) Phase 1 clinical trial in humans and demonstrating some cross-neutralization capacity, Measles vector with recombinant envelope boost (3) In pre-clinical development: Virus like-particles pseudotyped for HCV (4) Envelope glycoprotiein complex (5,6) 1. Wong JAJ-X, et al.j Virol. 2014;88: Law J et al, PloS One Reyes-del Valle et alj Virol. 2012;86: Garrone P et al.. Sci Transl Med. 2011;3: Ruuwona TB, et al.,. J Virol. 2014;88: Ruwona TB, et al., J Virol. 2014;88:

39 Preventing pre-existing anti-vector immunity from limiting vaccine efficacy Okairos search for novel adenoviral strains in non human primates worldwide Goals: Discover adenoviral vectors that Are highly immunogenic Are easily manufactured to high titers BUT do not stimulate cross reactive immunity (humans rarely exposed)

40 Preventing pre-existing anti-vector immunity from limiting vaccine efficacy Success: Adenoviruses derived from chimpanzees (ChAd) differ from human adenovirus primarily in hexon (surface) proteins, making Ab cross reactivity low many are highly immunogenic

41 Prophylactic vaccines to generate T cell immunity based on viral vectors Low seroprevalence chimpanzee and a human derived Adenoviruses ChAd3, Ad6 MVA attenuated strain, non-replicating in mammalian cells Vectored HCV antigen: NSmut Met NS3 NS3 NS3 Protease NS3-NS5B (NS = 1985 aa) Several CD4 and CD8 T cell epitopes mapped in humans Most conserved HCV region Genotype I, subtype 1b NS5Bmut AAG A NS4 B A NS5 B Aim: induce antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection broadly targeted, durable, functional CD4+CD8+ T cell response

42 HCV Vaccine Healthy Volunteer Trial Summary AdCh3NSmut prime with MVA-NSmut boost is a highly potent inducer of T cell responses. All individuals responded the vaccination. The majority of subjects developed responses against multiple HCV proteins. Polyfunctional CD4 + and CD8 + T cells are induced. T cells responses across genotypes detected. Vaccines safe and well tolerated. Swadling L et al., Science Translational Medicine; 5 November 2014; 6:(261)

43 Peak magnitude of T cell response to each peptime pool after the two vaccines

44 Cross-reactivity of T cell response: magnitude of T-cell response using peptide pools covering NS region of GT1b compared to GT1a, 3a and 4a

45 VIP: Vaccine is Prevention Design: Double blind, randomized, placebo controlled at JHU, UCSF and UNM HSC

46 VIP: Vaccine is Prevention Design: Double blind, randomized, placebo controlled at JHU, UCSF and UNM HSC Population: yo male and female active injection drug users at high risk for but not infected with HCV RNA at screening

47 VIP: Vaccine is Prevention Design: Double blind, randomized, placebo controlled at JHU, UCSF and UNM HSC Population: yo male and female active injection drug users at high risk for but not infected with HCV RNA at screening Size: Total N=450 (±8)

48 VIP: Vaccine is Prevention Design: Double blind, randomized, placebo controlled at JHU, UCSF and UNM HSC Population: yo male and female active injection drug users at high risk for but not infected with HCV RNA at screening Size: Total N=450 (±8) Goal: assessment of safety, induction of HCV specific immune responses, and efficacy in preventing chronic HCV infection

49 VIP: Vaccine is Prevention Design: Double blind, randomized, placebo controlled at JHU, UCSF and UNM HSC Population: yo male and female active injection drug users at high risk for but not infected with HCV RNA at screening Size: Total N=450 (±8) Goal: assessment of safety, induction of HCV specific immune responses, and efficacy in preventing chronic HCV infection

50 VIP Design Two injections administered at 0 and 8 weeks: AdCh3NS mut1 & MVA-NS mut Immune responses assessed W0 W8 W = week W88 AdCh3 MVA immune response assessed

51 VIP Design Two injections administered at 0 and 8 weeks: AdCh3NS mut1 & MVA-NS mut Immune responses assessed HCV RNA tested monthly W0 W8 W = week W88 AdCh3 MVA immune response assessed

52 VIP VIP Design Design Subject participation: Non-viremic subjects followed 20 months Viremic subjects followed 9 months after virus detected or 20 months (all referred for care & Rx) W0 W8 W = week W88 AdCh3 MVA immune response assessed

53 Challenges in testing a vaccine: Need a population at risk People who inject drugs have highest incidence Others: HIV+ MSM, Health-care workers, incarcerated People living in locales with endemic HCV and elevated risk; usually iatrogenic People treated for HCV and at risk of reinfection Infants born to infected mothers: 4% transmission rate; 25% in HIV/HCV coinfected

54 Challenges in testing a vaccine: Estimated sample sizes needed to test vaccines of different efficacies by population incidence rate of chronic infection # Efficacy (HR) Sample size required by incidence of chronic infection 6/100 pyo 12/100 pyo 60% (0.40) % (0.30) % (0.20) # Assuming 80% power (p<0.05), 90% retention White B et al,, Assessing the feasibility of hepatitis C virus vaccine trials: results from the Hepatitis C Incidence and Transmission Study- community (HITS-c) Vaccine Preparedness Study. Vaccine 2014

55 Challenges in testing a vaccine: Study design: according to protocol analysis plan requires even more people! Retention (loss, incarceration, death, drop-out) People get infected before 2 nd vaccine Ethical design must include best practice prevention referrals to drug treatment, sterile injecting equipment, counseling to reduce and or eliminate risk, referrals to HCV care & Rx, participant safety

56 Model attributes of a HCV vaccine Adequate vaccine efficacy (VE) to reduce susceptibility (VE s ) and/or slow or halt disease progression (VE p ) and/or decrease or eliminate infectiousness (VE i ) Safe for all ages and special populations (e.g. pregnant women) Effective for immunosuppressed persons (e.g., HIV, dialysis) Long term protection Protect against reinfection Acceptable to providers and public (e.g., dosing schedule, cost)

57 Model of potential impact of HCV vaccine in PWID Model of a 3-dose vaccine to prevent chronic HCV (VE i ) Target population: HCV-negative PWID Best case - 80% efficacy, 1% vaccinated per month From 13.5% HCV incidence at baseline 4.3% at 5 years 3.2% at 10 yrs Success dependent on efficacy, vaccine coverage Greater declines with addition of other strategies (safe equipment) Hahn J, Wylie D, Dill J, Sanchez MS, Lloyd-Smith JO, Page-Shafer K, Getz WM. Potential impact of vaccination on the hepatitis C virus epidemic in injection drug users. Epidemics 2009: 1(1);

58 HCV Vaccination Strategies: Risk and Age Based Risk-based: PWID HCV incidence 14.5/100 pyo 50% compliance w/vaccination Prevent 248 HCV infections and 89 deaths per 1000 persons offered vaccine 1.6 QALY/ person vaccinated; cost saving $400 per person Favorable regardless of low efficacy (50%) or high cost ($300) General platform- e.g. school based vaccination (age 12) HCV incidence 7.4/100,000 90% compliance Prevent 720 HCV infections; 300 deaths in birth cohort of 400,000 $18 045/QALY; comparable to other vaccines (e.g.hbv) Krahn DW Jean-Baptiste A, Yi Q, Doria A, Remis RS, Ritvo r, Friedman S, Potential cost-effectiveness of a preventive hepatitis C vaccine in high risk and average risk populations in Canada. Vaccine 2005

59 Relative prevalence reduction of HCV after 15 years when treating 20/1000 PWID annually A. Vaccinate after treatment B. Vaccinate same number of people but randomly C. Vaccinate everyone not infected Scott el al BMC Med (2015) 13:198

60 Conclusions A prophylactic HCV vaccine is needed. Protective immunity likely exists in vivo. As with HIV, it will not be easy to create a successful vaccine. A new prophylactic vaccine is in trials for the first time in at risk subjects- data due out in 2016

61 How do we prove it works

62 Acknowledgements Andrea Cox William Osburn Michael Melia Shaneca Bowden Donald Brown Kimberly Page Paula Lum Alice Asher Ellen Stein Kimberly Page Katherine Wagner Elaine Thomas Truman Health Services UNM CTSC Our Study Participants Richard Antrobus Eleanor Barnes Anthony Brown Paul Klenerman Leo Swadling Stefania Capone Antonella Folgori Alfredo Nicosia Elisa Scarselli Cinzia Traboni