THE H1/H56 TB SUBUNIT - AN UPDATE

Peter Andersen Statens Serum Institut H1/H56 FUSION PROTEINS AND ADJUVANTS

Cationic particles (IC31)  Vehicle: Cationic peptide (KLK)  PAMP: ODN1a (TLR 9)  Profile: Th1 - Memory

Ag85B ESAT-6 Rv2660c Cationic liposomes (CAF01)  Vehicle – Cationic Surfactant (DDA)  PAMP: TDB (Mincle)  Profile: Th1/Th17 - Memory H56 VACCINATION PROMOTES LESS DIFFERENTIATED TCM LIKE T CELLS

CXCR3 (IP10 receptor)

H56

TB

KLRG1+ (exhaustion marker)

Woodworth et al., Mucosal Imm. 2016 H56 SPECIFIC T CELLS FROM THE LUNG VASCULATURE EFFICIENTLY TRAFFIC INTO THE LUNG

Control IV label or Harvest H56-vacc. 6 wk 7 wk lungs Transfer Airway Lung IV+CD4+ cells (BAL) Parenchyma C57BL/6 Infect (CD45.2) Mtb 7 wk

BL/6.SJL (CD45.1) Ctrl H56

Input (IV+ESAT6+)

KLRG1 Blood vessel

IV stain In vivo staining

iv- iv+

Recipient

(ESAT6+) CD45-FITC KLRG1

IV stain

Woodworth et al., Mucosal Imm. 2016 TCM LIKE T CELLS GET ACCESS TO LUNG PARENCHYMA

H56/CAF01 promotes a population of less differentiated/Tcm like KLRG1- CXCR3+ recirculating IL2

CXCR3 +T cells that efficiently home into

TCM the lung parenchyma

CXCR3

TCM

KLRG1 IL-2 IL-17 TEFF INF-g

KLRG1

TEFF

Woodworth et al., Mucosal Imm. 2016 H56/IC31 BOOST BCG IN NHP’S

ExperimentSurviva l1 100 None

) 80 BCG

g

%

(

n

BCG+H56/IC31

i

s 60

v

l

i

a

v

r

m

i u 40

n

S

a 20

0 0 20 40 60 80

ExperimentSurviva l2 100 None

) 80 BCG

g

%

( BCG+H56/IC31

n

i

s 60

v

l

N=10 i

a

v

Unvaccinated group r

m

i u 40

n

S

a Mtb (10 CFU) necropsy 20 0 N=10 0 20 40 60 80

BCG H56/ H56/ Mtb (10 CFU) ExperimentSurvival 3 CAF01 CAF01 100 None weeks 0 10 14 22 ) 80 BCG

18 g

%

F-FDG PET/CT ( BCG+H56/IC31

n

i

s 60

v

l

i

a

v

r

m

i u 40

n

S

a 20

0 0 20 40 60 80

Lin et al. JCI 2012 Ag85B ESAT-6 H1:IC CLINICAL TRIALS

Phase I – Safety (low endemic, NL) Adjuvant dose escalation study Healthy adults, N=36

THYB-01

THYB-02 Phase I - Safety (high endemic, ET) M.tb. naive / BCG vacc / LTBI Adults, N=48

THYB-03 Phase IIa - Target population Antigen dose / schedule study Phase IIa - HIV infected In depth immunogenicity Adults, N=48 240 adolescents, SATVI, ZA THYB-05 Aurum inst, ZA, Bagamoyo TZ

THYB-04 Ag85B ESAT-6 RV2660 H56:IC CLINICAL TRIALS

Phase IIa – Dose / Schedule study Phase I - ”First In Man” Relevant target pop. (Adults +/- LTBI) Safety / Antigen dose-escalation study N=98, SATVI, ZA, dose recently unblinded Relevant target pop. (Healthy / LTBI) N=25, SATVI, ZA Phase IIa - Safety in TB patients C-035-456 C-037-456 Safety and dose finding C-032-456 H1/H56 OVERALL PICTURE FROM CLINICAL TRIALS

• Safe – well-tolerated with minimal reactogenecity at site of injection

• Longlived CD4 response

• A T cell response dominated by IFNg+/IL2+/TNF+ and IL2+/TNF+ with a TCM/TEM phenotype PREVENTION OF INFECTION TRIAL

Vaccine IGRA conversion

ESAT6 CFP10 TB7.7 H56:IC31 PREVENTION OF INFECTION TRIAL

EPI pilot 4% conversion confirmed at Mwanza

Vaccine ESAT-6 free IGRA conversion

Q3 2017

Mwanza, Tanzania Sites Aurum, South Africa Sponsor AERAS Trial duration 24 months Vaccine efficacy 50% Incidence 4% IGRA conversion / yr Loss to follow up 15% Power 80% Significance level 0.05 Sample size/arm 700 Expected prim. endpoints 44 ACKNOWLEDGEMENTS

TB Vaccine Adjuvant Research Collaborators/partners Rasmus S. Mortensen Dennis Christensen Flynn, Lin and DiFazio; Pittsburg Claus Aagaard Jes Dietrich Uhrdahl; Seattle BioMed Rolf Billeskov Gabriel K. Petersen Scriba, Hateril and Nemes; SATVI Niels Peter Knudsen Signe T. Schmidt Churchyard; Aurum Institute Joshua Woodworth Gabriel Thomas Lindenstrøm Human Immunol. Grevall; Bergen Universiy Ginsberg, Tait, Lempicki; AERAS Helena Clemmesen Morten Ruhwald Thomas Blauenfeldt Kidola, Changalucha, Mwanza,Tanzania TB Vaccine Developm. Line L. Holm SATVI; Tom Scriba Ingrid Kromann Dyrhol-Riise; Oslo University Friis,Faurholt-Jepsen,Bengaard; Copenh. Ottenhoff; LUMC