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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
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
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-ye
ar re
curr
ence
rate
pos
t 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
o HCV/HIV MSM
o Injecting drug users (PWID)
2. Other groups
o Dialysis patients
o Health care workers
o Sexual/household contacts
3. General Population
o 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
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)
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
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