prospects for an effective hepatitis c virus vaccine
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Prospects for an effective hepatitis C virus vaccine
Thomas F. Baumert, MDInserm Unit 1110, Institut de Recherche sur les Maladies Virales
and HépatiquesLaboratory of Excellence HEPSYS, Center for Digestive and
Liver Diseases, University of Strasbourg HospitalsStrasbourg, France
EASL ViennaApril 22, 2015
Chronic hepatitis C – Milestones for Cure
Chung RT & Baumert TF, N Engl J Med 2014
Hepatitis C virus vaccine – an unmet medical need
Thomas DL Nat Med 2013
• Limited or absent access to efficient therapy in majority of infected patients
• Treatment of advanced cirrhosis and genotype 3 unsatisfactory
• Long-term adverse effects of DAA unknown
• Late-stage or absent detection of infection
• Re-infection is possible – major challenge in IVDA
• HCC risks appears to persist following viral clearance in patients with cirrhosis
• Need for vaccine to prevent global spread of infection
Chung RT & Baumert TF N Engl J Med 2014 , Baumert et al. J. Hepatol. 2015, Thomas DL Nat. Med. 2013, Liang TJ Nat. Med. 2013
Approximately 53 million people infected with HCV genotype 3
Limited tools (HCVpp gt 3 poorly infectious, HCVcc model emerging)
Number of full length G3 sequences available in public databases: 18
From: Messina/Barnes et al. Hepatology 2014
Example of global challenges: HCV genotype 3
Example of clinical challenge: risk of HCC persists after SVR in HCV patients with advanced hepatic fibrosis
• Meta-analysis (n=1000)– 10 cohorts, individual patient data
– SVR with IFN-based therapy
– Bridging fibrosis or cirrhosis
• 51 HCCs over 5.1 years of follow-up• Patients with HCV-induced cirrhosis
who achieve SVR remain at risk for HCC
• Risk increased with age, severity of liver disease, and presence of diabetes mellitus
• What are determinants of persistent risk?
van der Meer AL et al. JAMA 2012 , van der Meer AJ, et al. Hepatology 2013
Rate
(%)
Cumulative HCC by Age Group
0 1 2 3 4 5 6 7 8Years After SVR
P=0.006
12.2%
2.6%
9.7%
Age Group<45 years45 to 60 years>60 years
HCV genetic variability
Ray S C et al. J Exp Med 2005
HCV shows a remarkable genetic variability
Evolution of viral quasispecies rapidly changes during infection
HCV diversity: - promotes escape from nAbs and cellular immune
responses
- Greatest challenge for vaccine developement
HCV: Multiple strategies for evasion of host immune responses
Spontaneous HCV clearance: Maintenance of T cell responses, Early development of neutralizing
antibodies (nAbs)
Development of chronic infection:Loss of T cell responses,Delayed nAbs responses
Baumert TF / Lauer GM J. Hepatol. 2015
Prophylactic HCV vaccine candidates
Examples for candidates evaluated in preclinical animal models and in clinical trials
B cell vaccine: recombinant HCV glycoprotein E1/E2
• Immunogen: recombinant gpE1/E2 isolated from mammalian cells
• Mechanism of action: induction of cross-neutralizing antibodies associated with protection
• Preclinical efficacy data in chimpanzee showed to reduce chronicity in HCV challenge (Choo et al. PNAS 1991)
• gpE1/gpE2 is immunogenic and safe in humans (Frey et al. Vaccine 2010, Law et al. PLoS ONE 2013; Wong et al. J. Virol. 2014)
• Second generation of recombinant gpE1/gpE2 to be tested in clinic
Catanese et al. PNAS 2013
E1E2
M. Houghton, Edmonton, Canada
T cell vaccine – recombinant live viruses HCV NS proteins
• Immunogen: HCV vaccine based on simian adenoviral vectors-optimally boosted with MVA vector encoding the HCV nonstructural proteins
• Simian viruses without preexisting anti-adenovirus Abs, target multiple HCV antigens
• Successful proof-of-concept in chimpanzees with protection against chronic infection (Folgori et al. Nat. Med. 2006)
• Ad/MVA immunogenic and safe in man: high numbers of polyfunctional CD4 and CD8 T cells in healthy volunteers (Swadling et al. Sci. Transl. Med. 2014)
• The vaccine is now in efficacy testing in IVDUs in Baltimore and San Francisco
Immunogen: NS3-NS51,985 aa, gt 1b strain
E. Barnes, Oxford, UK
Despite arrival of DAAs, development of a safe and effectivevaccine remains a key goal for global control and erradicationof HCV infection
Both neutralizing antibodies and T cell responses areimportant for control and protection
Viral diversity and immune evasion greatest challenges
Several vaccine candidates in preclinical and clinicaldevelopment
rE1/E2 and viral vectors are immunogenic and safe in man
Future clinical trials will inform about protection againstchronic infection in man
State-of-the-art Hepatitis C virus vaccine 2015