Do we still need an HCV vaccine in the DAA era? How far we are from its clinical application?

Daniel ShouvalLiver Unit

Hadassah-Hebrew University hospitalJerusalem, Israel

Argentina , Hospital Universitario Austral Oct 27,2014

Overall prospects for eradication of hepatitis viruses - 2014

Mass vaccination

&UMV

Available vaccine

Eradication Anti-viral treatment

Cirrhosis/HCC

Persistent infection

Virus

scarce Yes achievable NA No No HAVYes Yes Not yet available Yes Yes HBVNA None rarely IFN?/No Yes Yes HDVNA Not yet ??? available Yes Yes HCV

No Yes achievable Probably RIBA in

ISP

No In immune suppressed

patients

HEV

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

HCVThe goal: all oral, pan-genotypic anti-viral 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

• Control of global HCV infection

• Reduction in rates of cirrhosis and hepatocellular carcinoma

• Control of HCV infection in specific risk groups

Cons• 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 indevelopment 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 modelsChimpanzeesImmuno-deficient miceCell 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

Persistent HCV infection and uncertain influence of DAA on immunity and second. HCV infection

A .

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 infectionmaintained by homeostatic cytokines

Abdel-Hakim M et al. Frontiers in immunology 2014;5, article 274

Hypothetical model for non-protective immunity upon HCV infection

Abdel-Hakim M et al. Frontiers in immunology 2014;5, article 274

Unprotected individuals: Re-infection associated with a weak late recall response and incomplete T cell control of viremia

Correlates of protective HCV immunity and the mechanisms of viral evasion of immune responses

Torresi J et al. J Hepatol 2011;54:1273

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

Targets for an HCV vaccineBase 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 T-cell

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 vaccineTorresi J et al. J Hepatol 2011;54;1273Liang TJ. NatureMedicine 2013;19:869Swadling L et al. Expert Opin Biol Ther 2013;13:1109Honeger 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

Liang TJ. Nature Medicine 2013;19:869

Prophylactic HCV vaccines studies in chimpanzees and in humans 2013

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

Liang TJ. Nature Medicine 2013;19:869

Steps for vaccine trial design and follow-up

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

Liang TJ. Nature Medicine 2013;19:869

Targets and mechanisms of vaccine induced immunity in prevention of HCV infection

Primate and human studies describing candidate prophylactic HCV vaccines

Swadling L et al. Exp Opinion Biol Ther 2013; 13:1109