Transcript HCV Vaccines - Hepatitis Viral

Do we still need an HCV vaccine in the
DAA era?
How far we are from its clinical
application?
Daniel Shouval
Liver Unit
Hadassah-Hebrew University hospital
Jerusalem, Israel
Argentina , Hospital Universitario Austral Oct 27,2014
Overall prospects for eradication of hepatitis
viruses - 2014
Cirrhosis Anti-viral
treatment
/HCC
Eradication Available
vaccine
Mass
vaccination
&UMV
Virus
Persistent
infection
HAV
No
No
NA
achievable
Yes
scarce
HBV
Yes
Yes
available
Not yet
Yes
Yes
HDV
Yes
Yes
IFN?/No
rarely
None
NA
HCV
Yes
Yes
available
???
Not yet
NA
HEV
In immune
suppressed
patients
No
Probably
RIBA in
ISP
achievable
Yes
No
Global control of HCV
• Clearance of HCV infection in the individual
patient will sooner or later become a SOC in
countries which can afford it
• The future of vaccines for prevention or
intervention in persistent HCV infection is still
unclear due to a number of technical barriers
as well as gaps in understanding the
immunologic mechanisms involved in
induction of protective immunity
HCV
• Outcome of acute HCV infection is determined by an interplay
between host genetics, the virus and the host immune
response
• The majority of patients with acute HCV infection (70-80%)
develop persistent infection. However in a minority of
patients, a combined cellular and humoral immune response
is efficient in clearing the virus
• Recent data suggest that in contrast to previous assumptions,
antibody responses may play an essential role in
neutralization and development of an immune memory in
those patients who cleared the virus*
*Abdel-Hakim M et al. Protective immunity against HCV: Many shades of gray. Frontiers in immunology 2014;5, article 274
Some imminent challenges in coping with the
recent developments of potent anti-HCV agents
• Limited access to testing
• Cost
• Whom to treat? Priorities in allocation of
funds
HCV
The goal: all oral, pan-genotypic antiviral agent
• 2011- >50 companies worked on development
of anti-HCV agents
• 2011 – FDA approves 1st generation PIs
• 2013- > 12 phase 2 and phase 3 clinical trials
• 2013- FDA approves first 2nd generation PI
• 2014 –Approval of a combination of 2 or 3
DAAs is pending
The revolution in treatment of chronic HCV infection
Kwong AD. Acs Med Chem letters 2014;5:214
Global control of hepatitis C: where
challenge meets opportunity
Thomas DL. Nature Medicine 2013;19:850
Pros and Cons for development of HCV vaccine(s)
Pros
Cons
Control of global HCV
infection
• Reduction in rates of
cirrhosis and hepatocellular
carcinoma
• Control of HCV infection in
specific risk groups
• Priorities and cost
• Limited knowledge on protective
immune response post acute HCV
• Development of DAAs leading to SVR
• Anticipated duration of clinical trials
• Lack of predictive modeling how
combined vaccination with DAA will
reduce global pool and interrupt
transmission in rural and urban
populations
• Scarcity of candidates for controlled
clinical trials on protective vaccines as
well as ethical considerations
•
Debate
In view of the immense progress in
development of anti-viral agents against HCV:
What is the rational for developing a vaccine
against HCV?
– Preventive vaccine (i.e. for specific risk groups Vs
universal mass vaccination)
– Therapeutic vaccine
• Inability of anti-virals to restore protective immunity may
justify induction of HCV T cell mediated responses to
maintain an SVR
• Combination with anti-viral agents with vaccine to prevent
relapse after cessation of anti-virals (variable timing in
administration of anti-virals)
• Induction of viral suppression and control of HCV infection
without complete viral clearance
Impediments for developing an HCV vaccine
•Complex nature of immune response to HCV
•Existence of multiple HCV genotypes(differences in
~30% in nucleotide position)
• HCV exists as a population of related viral
quasi-species which enables emergence of HCV
variants eluding the immune response
•Risk of HCV re-infection
•Limited availability of animal models
Chimpanzees
Immuno-deficient mice
Cell culture systems
HCV genome
(~9.6 kb pairs, 7 genotypes, 67 subtypes*)
*
Reproduced from Abdel-Hakim M et al. Frontiers in immunology 2014;5, article 274
*
Immunity during and after resolution of primary HCV infection
A.
Persistent HCV infection and uncertain influence of DAA on immunity and second. HCV infection
B.
Honegger JR et al. Semin Liv Dis 2014;34:79
Hypothetical model for protective immunity upon HCV infection
Development of long-lasting CD4/CD8 viral specific immune memory post acute infection
maintained by homeostatic cytokines
Abdel-Hakim M et al. Frontiers in immunology 2014;5, article 274
Hypothetical model for non-protective immunity upon HCV infection
Unprotected individuals: Re-infection associated with a weak late recall response
and incomplete T cell control of viremia
Abdel-Hakim M et al. Frontiers in immunology 2014;5, article 274
Correlates of protective HCV immunity and the mechanisms of
viral evasion of immune responses
Clearance of HCV infection requires early and multi-specific class 1 restricted
CD8+ T cell and class 2 restricted CD4+ cell responses to both structural and
non-structural proteins
Torresi J et al. J Hepatol 2011;54:1273
Targets for an HCV vaccine
Base line concepts:
 Clearance of HCV requires early and multi-specific class
1 restricted CD8+ T cells and class 2 restricted CD4+ T
cells
 Potential targets include HLA class 1 restricted HCV
core, E1, NS3, NS4 and NS5 epitopes
 Importance of induction of cross protective HCV
specific neutralizing antibodies to E1 and E2 epitopes
 Targeting of viral entry into hepatocytes (capture of
several cell surface proteins (including LDL receptor,
tetraspanin CD81,SR-B1,tight junction proteins Claudin
1 and Occlodin)
Barriers to development of HCV vaccine(s)
• Questionable role of sterilizing immunity and role of
neutralizing antibodies in HCV clearance
• HCV is capable of evasion of the host immune
response through:
– Inhibition of intracellular interferon pass ways
– Impairs activation of dendritic cells, CD4 and CD8 Tcell responses
– Induces a state of T-cell exhaustion
– Selects escape variants with mutations of
CD8 T-cell epitopes
– Viral polymerase activity is error prone (NS5b)
– HDL lipoprotein and glycoprotein interference in
binding neutralizing antibodies
– Genetically pre-determined polymorphism (IL28)
Candidate HCV vaccines
• Recombinant E1 and E2 proteins(i.e.E1E2/MF59; yeast
derived core poly protein with ISCOMATRIX)
• Synthetic peptides (IC41)
• Virosomes based vaccines
• Tarmogens (GI-5005-1 yeast derived core-NS3 fusion
protein +/- IFN)
• Modified recombinant DNA vaccines:( i.e. vaccinia Ankara
based vaccine TG4040 encoding NS3,NS4,NS5B proteins;
adeno virus NS3-NS5B proteins, used to deliver HCV
antigens to prime a T cell response)
• HCV virus like particles based vaccine
Torresi J et al. J Hepatol 2011;54;1273
Liang TJ. NatureMedicine 2013;19:869
Swadling L et al. Expert Opin Biol Ther 2013;13:1109
Honeger JR et al.Seminars Liv Dis 2014;34:79
Some reasons for limited success in
developing an HCV vaccine
• Limited number of protective epitopes
• Inclusion of incorrectly folded recombinant
proteins
• Limited humoral and cellular mediated
responses associated with recombinant DNA
vaccines
• Suboptimal potency of adjuvants
Primate and human studies describing candidate
prophylactic HVC vaccines
Swadling L et al. Exp Opinion Biol Ther 2013;13:1109
Prophylactic HCV vaccines studies in chimpanzees and in humans 2013
Liang TJ. Nature Medicine 2013;19:869
Ongoing and completed trials for therapeutic HCV
vaccines - 2014
Xue J et al. Infection,Genetics & Evolution 2014;22:140
Major sites of action of different HCV preventive and
therapeutic vaccines
Torresi J et al. J Hepatology 2011;54:1273
Steps for vaccine trial design and follow-up
Liang TJ. Nature Medicine 2013;19:869
Summary
•
•
•
•
During the past 2 years, there is a a general misconception
that we are facing the control and the end of HCV infection.
Yet, despite the exiting recent development of efficient DAAs,
control of the global burden of HCV infection remains an
elusive goal.
Efforts continue to develop an HCV vaccine generating a broad
and long-lasting cellular and humoral immune responses
which is capable of coping with the viral evading properties
However, the development of DAAs may paradoxically slow
down future efforts for further development of HCV vaccines
and especially of therapeutic vaccines
There still is a justification for further development of a
preventive vaccine suitable for specific risk groups (i.e. HCWs.
IVDA, countries with exceedingly high endemicity) ) while the
future of a therapeutic HCV vaccine is undetermined
Candidates for an HCV vaccine
• Preventive vaccine
– Healthcare workers
– IVDA patients
– General population in highly endemic regions (i.e.
Egypt)
• Therapeutic vaccine
– Direct Anti-viral Agents (DAA) treated HCV
patients in SVR who cleared HCV and potentially
at risk for HCV re-infection
– HCV carries not responding to DAA (incl. relapsers
– HIV/HCV co-infection)
The Hadassah Medical Center in Jerusalem
Thank You
Backup
Targets and mechanisms of vaccine induced immunity in prevention of HCV infection
Liang TJ. Nature Medicine 2013;19:869
Primate and human studies describing candidate prophylactic HCV vaccines
Swadling L et al. Exp Opinion Biol Ther 2013; 13:1109