HCV Vaccine where do we stand? U. Spengler University of Bonn

HCV Vaccine where do we stand? U. Spengler University of Bonn

THE IDEAL GOAL: The vaccine should induce sterilizing immunity A MORE REALISTIC GOAL: Prevention of chronic persistent infection

Feinstone et al. CID 2012 Osburn Gastroenterology 2010

Upon HCV re infection patients have reduced max HCV loads and reduced duration of acute disease Re infection is associated with the appearance of new multispecific T cell responses Re infection is associated with generation of cross reactive neutralizing Abs Osburn Gastroenterology 2010

B Cells Antigen Adjuvant MHCII CD4+ Helfer T Helper Cells Neutralising Abs T Co stimulatory signals IFN CD8+ cytotoxic T Cells T MHCI

Correlates of Protective Immunity Neutralising Antibodies: Neutralising antibodies appear much earlier in resolving than persisten hepatitis C and contemporaneous isolates are efficiently neutralized. Pestka et al. PNAS 2007 Dowd et al. Gastroenterology 2009 Rare spontaneous elimination of chronic hepatitis C may involve late neutralizing Ab responses. Rhaguraman et al. JID 2012 Broad, multispecific T cell responses: T cell responses are temporally associated with control of primary and secondary HCV infection. Rehermann J Clin Invest 2009 Depletion of CD4+ and CD8+ T cells in immune chimpanzees results in prolonged or persistent HCV infection. Shoukry et al. J Exp Med 2003 Grakoui et al. Science 2003

The Problem of Global HCV Diversity 1/2/3 1/2/3 1/2/3 1/3 1 4 1/2 1/2/6 4 3 1/2 1/2/6 5 A preventive vaccine should be broadly reactive to many isolates To prevent shifts in dominant genotype in some regions of the world To also protect migrant populations To prevent emerging of new more violent isolates

C. Walker EASL Monothematic Conference on HCV 2012

Meta Analysis of 13 published Chimpanzee Studies Pooled Results: Recombinant envelope glycoproteins (E1/E2) Virus like particles (C E1 E2) Recombinant DNA vaccines Recombinant MVA and VV vectors Dahari et al. Gastroenterology 2010

Meta Analysis of 13 Chimpanzee Studies Dahari et al. Gastroenterology 2010

E1/E2 antibody vaccine Novartis/Chiron Recombinant genotype 1a (HCV1) E1 and E2 proteins Generated in CHO cells micro fluidised (MF59) oil in water emulsion as adjuvant

Sterilizing Immunity and Resolution in Chimpanzees The vaccine seems to also induce HCV specific CD4+ T cells which may protect from HCV persistence M. Houghton Immunol Rev 2011

S.E. Frey et al.; Vaccine 2010; 28: 6367 Safety and Immunogenicity of HCV E1E2 Vaccine Adjuvanted with MF59 Administered to Healthy Adults R. Ray et al.; J Infect Dis 2010; 202: 862 Characterization of Antibodies Induced by Vaccination with Hepatitis C Virus Envelope Glycoproteins Stamataki J Infect Dis 2011

T cell vaccine Okairos Gene cassette encompassing non structural proteins NS3 NS5B Derived from HCV genotype 1b strain Bk Expressed from recombinant adenovirus vectors, sometimes also plasmids and vaccinia vectors

T cell HCV Vaccine in Chimpanzees Anjmals received Ad6, Ad24 or plasmid DNA vaccines and were challenged with a genotype 1a isolate (H77) Peak viraemia 100 fold reduced in vaccinated versus control animals. Duration of disease shorter in vaccinated (1 7 wks) versus control animals (16 20 wks). Folgori et al. Nat Medicine 2006

The NS3 NS5B gene cassette elicits strong T cell responses in humans when delivered with ChAd3 and Ad6 vectors E. Barnes Science Translational Medicine 2012

Cross recognition of genotypes 1a and 3a E. Barnes Science Translational Medicine 2012

Therapeutic Vaccines Targeted to strengthen and recover exhausted T cell responses rather to induce neutralizing antibodies

TG4040 Phase I Study: Treatment naive Patients Design TG4040 = modified poxvirus (Ankara strain) expressing HCV NS3, NS4 and NS5B Habersetzer et al Gastroenterology 2011

TG4040 Phase I Study: Treatment naive Patients 5/15 patients developed vaccine induced strong HCV specific cellular immune responses 8 patients had transient drops in HCV viraemia (from 0.52 log to 1.24 log) The most pronounced drop in HCV RNA occurred in two patients who also showed the strongest T cell responses All doses were well tolerated without serious adverse events Habersetzer et al Gastroenterology 2011

TG4040 Phase I Study: Treatment naive Patients ELISpot Results Habersetzer et al Gastroenterology 2011

DNA Vakzination mit in vivo Elektroporation 2 electric pulses (60 ms) immediately after DNA injection M. Sällberg EASL 2009

M. Sällberg EASL 2009

167 µg no effects on viral load or ALT 500 µg 1500 µg M. Sällberg EASL 2009

Intercell IC41 Peptid Vakzine Poly Arginin Klade et al. Gastroenterology 2008

Intercell IC41 Peptide Vaccine Phase II Study 50 treatment naive patients HCV genotype I Group A: 8 intradermal bi weekly injections plus Imiquimod (TLR 8 Agonist) Group B : 16 subcutaneous injections every week; no imiquimod 0.2 log (p=0.001) In patients with high viral loads (>2x10 6 IU/ml) 0.61 log, p=0,002 0.46 log (p< 0.001) 8 patients (24%) > 0.8 log drop in HCV loads Klade et al. Vaccine 2012

Therapeutic IC41 Vaccine as late add on to standard p interferon/ribavirin 35 patients ; 6 injections weeks 28 48 Increased HCV specific T cell responses in 73%. However, IC41 did not delay relapse, which occurred in 8 patients (32%) Wedemeyer et al. Vaccine 2009

GlobeImmune Phase IIb Study GI 5005 02 Tarmogen = recombinant HCV Core NS3 fusion protein expressed in Yeast Phase II Study in treatment naive (n= 110) and non responder (n=24) Patients Core NS3 Randomisation 1 : 1 Standard therapy versus standard therapy + Tarmogen 5 GI 5005 weekly run in injections, then boostering every 2 months on Peg/R therapy Triple arm: 68 treatment naive, 18 non responder patients SOC arm: 5o treatment naive, 19 non responder patients I.M. Jacobson et al. EASL 2010

GlobeImmune GI 5005 Phase IIb Study 63% TH Naive Non Responder GI5005 Triple 58% 45% 48% SOC 33% 11% 17% 5% 63% IL28B GT TT *: p=0.037 I.M. Jacobson et al. EASL 2010 27% Shiffman et al. AASLD 2012

Conclusions It is unlikely that a HCV vaccine can obtain sterilizing immunity. However, attenuated primary infection may still afford protection from chronic hepatitis Many promising vaccine candidates have entered clinical trials but show limited efficacy Suitable high risk populations should be defined for broader studies on clinical utility.

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