The Immune Response to HCV and HCV Vaccine Development

Georg M. LauerGastrointestinal Unit

Massachusetts General HospitalHarvard Medical School

No Conflicts of Interest

Dranoff, 2004

Dranoff, 2004

HCV Control and T Cells

• HLA association studies HLA class I (incl. B27, B57 as in HIV) & class II

• GWAS (class II)• Chimpanzee CD8+ and CD4+ T cell depletion

associated with viral persistence • IFN- HCV specific CD8+ T cell responses are

temporally correlated with reduction in viremia after infection

Grakoui et. al, Science 2003, Shoukry et. al. J. Exp Med, 2003, Kim et. al. Gastroenterology 2011, Urbani et al Hepatology 2006, Thimme et al, J Exp Med 2001,David Thomas, in submission (GWAS)

HCV-specific T-cell responses

①What happens during early HCV Infection?

②Correlates of protection

Breadth and vigor of HCV-specific T cell responses

T cell function

③The T cell road to HCV prevention?

HCV-specific T-cell responses

①What happens during early HCV Infection?

②Correlates of protection

Breadth and vigor of HCV-specific T cell responses

T cell function

③The T cell road to HCV prevention?

HCV Infection:Acute Infection to Chronicity

HCV Viral Load

ALT

HCV Infection:Acute Infection to Chronicity

HCV Viral Load

ALT

HCV Infection:Dichotomous outcome

Acute vs Chronic

A

CHCV Viral Load

ALT

20-30%

HCV Infection:Outcome Determined within 24 Weeks

A

CHCV Viral Load

ALT

HCV-specific T-cell responses

①What happens during early HCV Infection?

②Correlates of protection

Breadth and vigor of HCV-specific T cell responses

T cell function

③The T cell road to HCV prevention?

Thimme et al. J Exp Med 2001

Acute HCV Infection:Adaptive Immune response

•Needle stick infections (known exposure)

•No adaptive immune responses before week 7

•ALT increase after immune response

CD4 Responses in Early HCV Infection

Schulze zur Wiesch et al., J Exp Med 2012

A C

•Proliferative responses only in acute infection

•Usually targeting multiple HCV proteins

•Proliferative defect seen very early in chronic infection

•Long established observation (Gerlach 1999)

Standard proliferation assay

Patient 05V with acute chronically evolving course:

short term culture (+exogenous rIl2)

CD4 Responses in Early HCV Infection

Schulze zur Wiesch et al., J Exp Med 2012

CD4 Responses in Early HCV Infection

Schulze zur Wiesch et al., J Exp Med 2012

A C A C

Standard proliferative assay T Cell Lines with IL-2

CD4 Responses in Early HCV Infection

Schulze zur Wiesch et al., J Exp Med 2012

A CAC

T Cell Lines with IL-2:Number of detected responses depends on time post infection, but only in chronic infection

CD4 Responses in Early HCV Infection

Schulze zur Wiesch et al., J Exp Med 2012

Results from Cell Lines confirmed by HCV HLA Class II Tetramer analysis

Acute

Chronic

HCV-specific CD4+ T-cell responses • Detectable in all subjects• No correlation between early breadth/vigor and outcome• Rapid contraction with viral persistence (in PBMC)• Early functional defect (proliferation) associated with viral

persistence• In persistent infection affected earlier and more

profoundly compared to CD8 responses• New technologies allow analysis of early T cell responses

in HCV – dichotomous outcome makes HCV unique model to define protective immunity

Phases of Early HCV Infection/T Cell Response

A

C

1: “NOTHING”

No Adaptive Immunity Weeks 0 to 6/8

Is time of essence?

Role of innate immunity?

CD8 T Cell Response

CD4 T Cell Response

Phases of Early HCV Infection/T Cell Response

A

C

2: “Emerging Response”

ALT RiseFollowed by HCV RNA Inflection

CD4/8 responses similar breadth and magnitude

CD4 proliferative defect

Other functional differences?

CD8 T Cell Response

CD4 T Cell Response

Phases of Early HCV Infection/T Cell Response

A

C

3: “Battle”

HCV RNA Fluctuations

Emerging differences in CD4/8 response (magnitude/function)

Beginning T cell exhaustion?Early viral escape mutations?

CD8 T Cell Response

CD4 T Cell Response

Phases of Early HCV Infection/T Cell Response

A

C

4: “Resolved/Chronic”

Marked differences in T cell numbers/phenotype/function

Differences cause or effect of viral control/persistence?

Differences reversible? (Immunotherapy)

CD8 T Cell Response

CD4 T Cell Response

Phases of Early HCV Infection/T Cell Response

A

C

6 to 24 weeks post infection

Most important phase to study HCV T cell responses (but most “acute” studies are later)

HCV could/should be a unique model to define protective immunity

CD8 T Cell Response

CD4 T Cell Response

HCV-specific T-cell responses

①What happens during early HCV Infection?

②Correlates of protection

Breadth and vigor of HCV-specific T cell responses

T cell function

③The T cell road to chronic HCV prevention?

HCV- Can we make an effective vaccine?

• Challenges parallel to HIV– Correlates of protection not exactly known– Highly diverse virus– Unsafe to use live attenuated or killed virus– Current focus is to use vectors to deliver viral

antigens in a system that induces robust innate and adaptive immune responses

• Preexisting vector immunity limits responses

Preventing pre-existing anti-vector immunity from limiting vaccine efficacy

• Okairos search for novel adenoviral strains in chimpanzees worldwide

• Goals: Discover adenoviral vectors that are• Highly immunogenic• Easily manufactured to high titers• Not stimulating cross reactive immunity

(humans rarely exposed)• Success:

• Adenoviruses derived from chimpanzees (ChAd) differ from human adenovirus primarily in hexon (surface) proteins, making Ab cross reactivity low

• many are highly immunogenic

Folgori et al. Nature Medicine, 2006

0% 7.18% 0.83% 6.24% 1.52%

B

Ad1 prime(TW0)

4 weeks post prime(TW4 or 8)

Ad2 boost(TW 8 or 24)

4 weeks post boost(TW 12 or 28)

Final time point(TW 36 or 52)

CD8+

HLA

clas

s-I p

enta

mer

(KLS

GLGI

NAV

) High frequencies of HCV Specific CD8 T cells

Barnes et. al. Science Translational Medicine 2012

• AdCh3NS and Ad6NS are highly potent (> 1400 SFU/million PBMC; IFN- ELISpot) following a single injection.

• At the highest dose all individuals responded to vaccination.

• The majority of subjects developed responses against multiple HCV proteins.

• Polyfunctional CD4 and CD8+ T cells are induced.• AdCh3NS and Ad6NS are safe and well tolerated at all

tested doses.

HCV Vaccine Healthy Volunteer Trial Summary

= test immune responseW = week

HCV Prophylactic Vaccine Based on Sequential Use of AdCh3 and MVA with NS

AdCh32.5 x1010vp

MVA1.8x108pfu

W50W0 W8

• Cross reactivity of AdCh3 with human anti-adenovirus Abs is 12%

• MVA boosts well in Phase I trials• Double-blinded, randomized, placebo-controlled

two stage study.• Subjects: HCV Ab and RNA negative, active IDU’s

at high risk for HCV, 18 -45 y.o.• Two Sites (A. Cox/JHU & K. Page/UCSF)

Endpoints

Primary• Safety of both vaccines• To determine if AdCh3NSmut1 and MVA-NSmut

HCV vaccines will reduce incidence of chronic HCV infection compared to placebo among HCV-uninfected IDUs.

Secondary• Immunogenicity compared to placebo when

administered to HCV uninfected IDUs

Exploratory Endpoints

• Does it reduce the incidence of primary infection?

• Does it protect better against gt1b than others?

• Does it reduce the peak magnitude or duration of viremia in those infected?

GI Unit (& ID)Daniela KroyDonatella CiuffredaDavid WolskiJulian Schulze z. W.Garrett HauckJennifer CooperriderStephanie KulagaArthur KimJasneet AnejaLeslie Prince

Joe MisdrajiMichelle Tomlinson

Ray Chung

Oswaldo Cruz Inst., RdJLia Lewis

Lemuel Shattuck Hosp.Barbara McGovern

Oxford UniversityEllie Barnes

JHUAndrea Cox

FUNDINGNIH U19 AI082630NIH U19 AI066345Dana Foundation