HCV Vaccine Development Thomas Pietschmann TWINCORE Centre for - PowerPoint PPT Presentation

HCV Vaccine Development Thomas Pietschmann TWINCORE – Centre for Experimental and Clinical Infection Research A joint venture between Medical School Hannover and The Helmholtz Centre for Infection Research

Preview 1.Do we need an HCV vaccine? 2.What are the challenges? 3.What are the opportunities? 4.What are the approaches?

Curing Chronic Hepatitis C – The Arc of a Medical Triumph Chung, R.T. et al. N Engl J Med 370;17 April 24 2014

Efficacious and Well tolerated Therapies are Available Dore and Feld Clinical Infectious Diseases 2015

HCV Diagnosis and Treatment (2013) Wedemeyer et al. J Viral Hep. 2015

Importance of Expanding Testing and Treatment to Impact Prevalence of HCV Infection Thomas, D.L. Nat Med. 2013;19

Key Elements in HCV Control Program Thomas, D.L. Nat Med. 2013;19

Treatment as Prevention o Identify infected o Scale up treatment o Target those at risk of transmission o Prevent reinfection (vaccine) Heterogeneity in transmission risk complicates control „… the same fundamental lessen has been learnt for HIV [..] that you cannont control an epidemic without dealing with the „core“ transmission group M. Hickman et al. J Viral Hep. 2014

Treatment Uptake Needed Among PWID To Reduce HCV Prevalence in 15 Years Halfing prevalence in Melburne or Vancouver requires $50 million annually Martin NK et al. Hepatology. 2013 Nov;58(5):1598-609.

Re-infection of HCV Patients with SVR Meta-analysis of 66 studies in 11,071 patients Five-year rate of re-infection 21.7 5-year recurrence rate post SVR % 13.2 1.1 Low Risk Medium Risk High Risk Hill et al. PWID HIV/HCV co-inf. 22nd CROI, 2015 MSM

Do We Need an Vaccine? Potential Target Populations 1. Risk populations HCV/HIV MSM o Injecting drug users (PWID) o 2. Other groups Dialysis patients o Health care workers o Sexual/household contacts o 3. General Population High prevalence o

Cost Effectiveness of an HCV Vaccine Population at risk Cost-effectiveness PWID High Sex workers + MSM Medium Health-care workers Medium Public servants Low to medium Sexual Partners of HCV+ Low to medium Children born to HCV+ Low to medium HIV infected with above risk High Strickland et al. Lancet Inf. Dis. 2008, Krahn et al. Vaccine 2005

Do we Need an HCV Vaccine? 1.Efficacious well tolerated DAAs 2.Challenge to control HCV solely with drugs (scale up diagnosis, treatment) 3.Re-infection 4.Moderate cost effectiveness of vaccine

What are the Challenges? Estimated required sample size per study group in HCV vaccine efficacy trial Strickland et al. Lancet Inf. Dis. 2008

Robust Immuno-competent Animal Models for HCV are Lacking Human Chimpanzee Mouse

HCV is Highly Variable >30% variability < 20% variability Error-prone RNA replication (~ 1 mutation per genome) High replication rate (10 12 new virions per day) Promotes escape from antibody and cellular immune response

HCV Evades Humoral Immune Response o Lipoprotein coat o Variable (flexible) epitopes are immunodominant

What are the Challenges 1.Clinical Evaluation of Efficacy 2.Lack of Animal Models 3.HCV Variability 4.Evasion Strategies (lipoprotein coat)

What are the Opportunities? Natural HCV clearance occurs in up to 50% of exposed individuals Protective immunity is possible Adapted from NIH Consensus Statement, Hepatology 2002; 36(Suppl 1): S2-S20

HCV E2 Core Crystal Structure Reveals Epitopes Of Cross-Neutralizing Antibodies Kong et al. Science 2013

What are the Opportunities 1.Natural protective immunity 2.Advances in (animal) model systems 3.Crystal Structure of E2

Characteristics of a Protective Immune Response Cellular Humoral „Vigorous, multispecific and „Strong association between sustained CD4 + and CD8 + an early neutralizing antibody T-Cell response associated response and HCV clearance.“ with clearance“ (Thimme, R.;Biol Chem. 2008 Mar 6. [Epub ahead of print]) Pestka, J; Proc Natl Acad Sci U S A. 2007 104(14):6025-30

Neutralizing antibodies in patients with resolved or chronic hepatitis Pestka J M et al. PNAS 2007;104:6025-6030

Which Candidates are Developed? 1. HCV E1-E2 heterodimer (Chiron/Novartis + NIAID)

Summary of Chimpanzee Studies No sterilizing immunity But significantly reduced rate of chronicity M. Houghton Immunol Reviews 2010

Result of Phase I Study Vaccine is safe and well tolerated Neutralizing antibodies are induced SE. Frey et al. Vaccine 2010

Which Candidates are Developed? 2. „Prime-boost“, HCV-NS Proteine, Different vectors (Okairos+ NIAID)

Immunogenicity and Virus Load after before CD8+ IFN- γ + 4/5 3/5 RNA ALT GGT Effective immunity against heterologous challenge (cell mediated) A. Folgori et al. Nat. Med. 2006

First in Human Trial Chimp Adeno 3 MVA Swadling et al. Science Trans Med. 2014

Breadth and Cross-Reactivity of Vaccine- Induced T Cell response in Humans Swadling et al. Science Trans Med. 2014

Summary 1. Do we need an HCV vaccine? 1. Controversial 2. What are the challenges? 2. Virus/Models/Trials 3. What are the opportunities? 3. Natural Immunity 4. What are the approaches? 4. T cells and Antibodies

Acknowledgement Experimental Virology Twincore Rockefeller Ulrich Kalinke Bridget Donovan Marcus Dorner Tamar Friling MHH Alex Ploss Michael Manns Charles Rice Heiner Wedemeyer Florian Kühnel Basel Anggakusuma Christina Grethe Markus Heim HZI Dorothea Bankwitz Sibylle Haid Michael Dill Carlos Guzman Patrick Behrendt Kathrin Hüging Dagmar Wirth Funding Richard Brown Paula Perin Dresden Janina Brüning Stephanie Pfänder Lars Kaderali Chris Lauber Mandy Döpke Nina Riebesehl Juliane Dörrbecker Eike Steinmann Ghent Philip Meuleman Anne Frentzen Gabrielle Vieyres Gisa Gerold Stephanie Walter Corinne Ginkel Kathrin Welsch

Van de Ven et al. Hepatology 2015