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

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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

Dore and Feld Clinical Infectious Diseases 2015

Efficacious and Well tolerated Therapies are Available

Wedemeyer et al. J Viral Hep. 2015

HCV Diagnosis and Treatment (2013)

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

• Identify infected
• Scale up treatment
• Target those at risk of transmission
• 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

Martin NK et al. Hepatology. 2013 Nov;58(5):1598-609.

Treatment Uptake Needed Among PWID To Reduce HCV Prevalence in 15 Years

Halfing prevalence in Melburne or Vancouver requires $50 million annually

Re-infection of HCV Patients with SVR

1.1 21.7 13.2 Low Risk Medium Risk PWID High Risk HIV/HCV co-inf. MSM 5-year recurrence rate post SVR % Hill et al. 22nd CROI, 2015

Meta-analysis of 66 studies in 11,071 patients Five-year rate of re-infection

• 1. Risk populations
• HCV/HIV MSM
• Injecting drug users (PWID)
• 2. Other groups
• Dialysis patients
• Health care workers
• Sexual/household contacts
• 3. General Population
• High prevalence

Do We Need an Vaccine? Potential Target Populations

Strickland et al. Lancet Inf. Dis. 2008, Krahn et al. Vaccine 2005

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

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?

Strickland et al. Lancet Inf. Dis. 2008

Estimated required sample size per study group in HCV vaccine efficacy trial

Robust Immuno-competent Animal Models for HCV are Lacking

Chimpanzee Mouse Human

Error-prone RNA replication (~ 1 mutation per genome) High replication rate (1012 new virions per day) Promotes escape from antibody and cellular immune response < 20% variability >30% variability

HCV is Highly Variable

HCV Evades Humoral Immune Response

• Lipoprotein coat
• 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)

Adapted from NIH Consensus Statement, Hepatology 2002; 36(Suppl 1): S2-S20

Natural HCV clearance occurs in up to 50% of exposed individuals

What are the Opportunities?

Protective immunity is possible

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

Cellular

Characteristics of a Protective Immune Response

Humoral

„Vigorous, multispecific and sustained CD4+ and CD8+ T-Cell response associated with clearance“ „Strong association between an early neutralizing antibody response and HCV 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

• 2. „Prime-boost“, HCV-NS Proteine,

Different vectors (Okairos+ NIAID)

Which Candidates are Developed?

CD8+ IFN-γ+

RNA ALT GGT

Immunogenicity and Virus Load

before after Effective immunity against heterologous challenge (cell mediated) 4/5 3/5

• A. Folgori et al. Nat. Med. 2006

First in Human Trial

Chimp Adeno 3 MVA Swadling et al. Science Trans Med. 2014

Swadling et al. Science Trans Med. 2014

Breadth and Cross-Reactivity of Vaccine- Induced T Cell response in Humans

Summary

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

Acknowledgement

MHH Michael Manns Heiner Wedemeyer Florian Kühnel HZI Carlos Guzman Dagmar Wirth Dresden Lars Kaderali Chris Lauber Ghent Philip Meuleman Twincore Ulrich Kalinke

Experimental Virology

Rockefeller Bridget Donovan Marcus Dorner Tamar Friling Alex Ploss Charles Rice Basel Markus Heim Michael Dill Funding Anggakusuma Dorothea Bankwitz Patrick Behrendt Richard Brown Janina Brüning Mandy Döpke Juliane Dörrbecker Anne Frentzen Gisa Gerold Corinne Ginkel Christina Grethe Sibylle Haid Kathrin Hüging Paula Perin Stephanie Pfänder Nina Riebesehl Eike Steinmann Gabrielle Vieyres Stephanie Walter Kathrin Welsch

Van de Ven et al. Hepatology 2015