The challenge of developing new TB vaccines - …...new TB vaccines Paul-Henri LAMBERT Centre of...

The challenge of developing new TB vaccines

Paul-Henri LAMBERTCentre of VaccinologyUniversity of Geneva

ADVAC 2009

Tuberculosis: the global figure

WHO 2007

about 2 billion individuals infected with M.tb9.273 million new tuberculosis cases/year (20%MDR, 2%XDR)1.772 million deaths / year (2/3 Afr. + S-E Asia)

Tuberculosis: the global MDG goals

1990 2015 1990 2015 1990 2015

WHO 2007

by 2015: reduce death rates by 50% vs 1990

Time

persistence

Bact

erial

load

TB- Infection profile

Naive host

Time

persistence

Bact

erial

load

Naive host

Early protection in children (used in >2 billion infants)

BCG

Time

persistence

Bact

erial

load

Naive host

Early protectionIn children

BCG•Variable efficacy in adolescents and adults; •little impact on TB epidemiol.

-20 0 20 40 60 80 100

UK, BIRMINGHAM

CANADA Indians

NORWAY, gen popn

HAITI

SWEDEN, gen popn

USA, Indians

USA, NEW YORK infants

UK, schoolchildren

UK, gen popn 1983

SOUTH AFRICA, miners

SWEDEN, military

ISRAEL, children

INDONESIA JAKARTA

PUERTO RICO

INDIA MADANAPALLE

MALAWI KARONGA

INDIA CHINGLEPUT

CohortC. Trial

Published estimates of efficacy of BCG against pulmonary tuberculosisP. FineLancet 1995; 346: 1339-45

Time

persistence

Bact

erial

load

Naive host

Early protectionIn children

BCG

•Poor efficacy in adolescents and adults; little impact on TB epid.

•Reduced efficacy if previous exposure to environmental-mycob.

Time

persistence

Bact

erial

load

Naive host

Early protectionIn children

BCG

•Poor efficacy in adolescents and adults; little impact on TB epid.

•Reduced efficacy if previous exposure to environmental-mycob.

•Risk of disseminated BCG disease in HIV infected children

Data for Cape Town children less than 2 years of ageTB incidence: 860/100’000 person-yearsTBM & MTB incidence: 61 / 100’000 person-yearsMahomed et al. Ped Infect Dis J. Dec 2006

417 / 100’000

Risk scenarios of disseminated BCG disease

BCGPros

• most used vaccine at global level

• very low cost

• recognized protective efficacy against infanttuberculosis(e.g. TB-meningitis, MTB)

Cons

•Poor efficacy in adolescents and adults;

•Reduced efficacy if previous exposure to environmental mycob.

•Risk of disseminated BCG disease in HIV inf. children

M tb

Mycobacterium tuberculosis (M tb)

Strategies towards new TB vaccines

Candidate vaccinesLive mycobacteriaLive vectorsProteins + Th1 AdjGlycolipids

From Kaufmann SH & McMichael AJ. (2005) Nature Medicine 11, S33 - S44

New TB vaccines desirable immunological target

persistence

Bact

erial

load

Time

1 2

New TB vaccinesA- Pre-exposure vaccines

(1) more rapidly effective than BCG (2) more efficient bacterial clearance(3) less susceptible to previous mycobacterial exposure

persistence

Bact

erial

load

Time

1 23 4

(3) to reduce the persistent bacterial load (4) To prevent re-activation of latent Mtb

New TB vaccinesB- Post-exposure vaccines

C- Multi-stage vaccines?

1- Genetically engineered live TB vaccines

BCG

Improved rBCG

Increase expression of protective gene(s)

Add genes to improve immunogenicity (CD8) & safety

a- Modified BCG

1- Genetically engineered live TB vaccines

BCG

Improved rBCG

Increase expression of protective gene(s)

Add genes to improve immunogenicity (CD8) & safety

rBCG30 Increased expressionof 30-kDa

Horwitz

BCG::RD1 Expression of Mtb ag Cole

rBCG-ΔUreC:Hly+

Expression of Listeria cytolysin

KaufmannGrode

rBCG-AERAS403

Expression of Perfringolysin + Ag85&TB10.4

AERAS

a- Modified BCG

To be used as BCG-replacement vaccines

Candidate -vaccines Developer

Initial cGMP

Production

Regulatory Assessm.

Phase IClinical Trials

Estimated Phase 3 initiation

rBCG-Hly

VPM2005-06 2007-08 2008-09 2013

rBCG(rBCG-ΔUreC:Hly+)

BCG antigens escape from endosome to cytoplasm: increased immunogenicity & safety

rBCG-ΔUreC:Hly+

Candidate -vaccines Developer

Initial cGMP

Production

Regulatory Assessm.

Phase IClinical Trials

Estimated Phase 3 initiation

rBCG-Hly

VPM2005-06 2007-08 2008-09 2013

rBCG-ΔUreC:Hly+

Protection against M. tb Beijing/W (mice)

ΔureC hly+ rBCG

parental BCG

Challenge 200 CFU “Beijing“ 120 d post vaccination)

Grode L. & al. , J Clin Invest 2005

1- Genetically engineered live TB vaccines

M tb

Attenuated rMtb

Delete virulence genesfrom Mtb

Identify virulence genes

b- Attenuated Mtb

1- Genetically engineered live TB vaccines

M tb

Attenuated rMtb

Delete virulence genesfrom Mtb

Identify virulence genes

M. tb PhoPmutant

Deletion PhoP virulence genes

Martin

M. Tb mc2

6020/30 mutant

Deletion LysA+panCD or panCD+RD1 virulence genes

Jacob

b- Attenuated Mtb

Appears efficient and safe in pre-clinical studies

The live Mycobacterium tuberculosis phoP mutant strain is more attenuated than BCG and confers protective immunity against tuberculosis

in mice and guinea pigs. Martin C, et al. Vaccine 2006 Protective efficacy in guinea pigs

Mtb phoP mutant

phoP mutant

BCG

High safety profile in SCID micephoP mutant

Lung

Spleen

phoP mutant

High dose Mtb H37Rv challenge @ 10wks

POTENTIAL ADVANTAGES MAIN ISSUES

Relatively easy to produce Mutant strain stability, QC?

Will benefit from BCG experience Must be at least as safe as BCG (including HIV infected people)

For initial protection & for priming

Have to appear significantly betterthan BCG

May exert adjuvant effect for concomitant vaccines

Ethical issues re: clinical assessment

Live mycobacterial vaccines

POTENTIAL ADVANTAGES MAIN ISSUES

Relatively easy to produce Mutant strain stability, QC?

Should benefit from BCG experience Must be safer than BCG in HIV infectedand immunocompromised

For initial protection & for priming Should be at least as good as BCG

May exert adjuvant effect for concomitant vaccines

Some ethical issues re: clinical trials

Live mycobacterial vaccines

2- New Sub-unit TB vaccines

Clone relevant genesM tb

Mycobacterium tuberculosis (M tb)

Identify « protective » antigens

To prime or boost BCG-induced

immunity

Sub-unit vaccinesProtein(s) + adjuvant

Live vectors

Candidate -vaccines Vaccine antigens

Ag85B-ESAT6 (H1)+ IC-31

SSI

MVA-Ag85A, live vector

U-Oxford

Mtb72recAg + AS-02

GSKBE

Leading sub-unit TB vaccine candidates

Mtb orBCG

Protein(s) + adjuvant

Live vector + Mb-ag

Clone relevant genes(« protective » antigens)

Ra35TbH9 39 kDaRa12

34 kDa -Serine protease

Mycolyl transferase

MVA expressing Ag85A

ESAT-6Ag85BMycolyl transferase Mtb- spec ag

Candidate -vaccines Vaccine antigens CT

Ag85B-ESAT6 (H1)+ IC-31

SSI - IC 1

Ag85B-TB10.4 (H4)recAg + IC-31

SSI-Sanofi-P 1

MVA-Ag85A, live vector

U-Oxford 2

Adeno35-Ag85A-B-TB10.4

Crucell 1

Mtb72recAg + AS-02/01

GSK1-2

Leading sub-unit TB vaccine candidates

Mtb orBCG

Protein(s) + adjuvant

Live vector + Mb-ag

Clone relevant genes(« protective » antigens)

Ra35TbH9 39 kDaRa12

34 kDa -Serine protease

Mycolyl transferase

MVA expressing Ag85A

ESAT-6Ag85BMycolyl transferase Mtb- spec ag

TB10.4Ag85BBCG- spec ag

Ad 35 vector + Ag85 + TB10.4

Discovery

Pre-clinicalefficacy

GMP-Production

Non-clinicalsafety

INDfile

Effective protection (mice , g-pigs, N-hu Prim)

Lot consistency-- Formulation

Incl. neonatal. TOXstudies

As RQ by RA

Ph1 Trials Safety / immunogenicityadults (in area of production)

PPD neg BCG primed LTBI or treated TB

Discovery

Pre-clinicalefficacy

GMP-Production

Non-clinicalsafety

INDfile

Effective protection (mice , g-pigs, N-hu Prim)

Lot consistency-- Formulation

Incl. neonatal. TOXstudies

As RQ by RA

Ph1 Trials Safety / immunogenicity adults (in area of production)

PPD neg BCG primed LTBI or treated TB

Ph2a- Safety / immunogenicity ados. + infants

Adults/Ados Infants [Formulation. Bridg.]

Interference studies

HIV pos ados/infants

Ph1-Safety / immunogenicity adults (high endemicity area)

PPD neg & BCG primed LTBI

Phase IIb Phase III

Adults/ados infant Adults/ados infants

Discovery

Pre-clinicalefficacy

Effective protection (mice , g-p, N-hu P)

Ag85B-ESAT6 + IC31 (H1)SSI + IntercellDK-AT

ESAT-6Ag85B

Ag85B-ESAT6Non-vaccinated

Lymph node destruction

Lung granuloma

Reduced TB pathology in vaccinated cynomolgus monkeys

Langermans J, Vaccine. 2005 ;23(21):2740-50

Discovery

Pre-clinicalefficacy

GMP-Production

Non-clinicalsafety

INDfile

Effective protection (mice , g-p, N-hu P)

Lot consistency-- Formulation

neonatal & immunocomp.

TOXstudies

As RQ by RA

Safety / immunogenicity(EU- adults)

PPD neg PPD pos LTBI

Ag85B-ESAT6 + IC31 (H1)SSI + IntercellDK-AT

ESAT-6Ag85B

Phase 1 –trial in PPD-neg 2006-07 Leiden- NL

Immunogenicity:excellent primary response

Safety: very low reactogenicity

0

1000

2000

30003000

15000

pg/m

l

-2 0 6 12 32

Ag85B ESAT6 H1

-2 0 6 12 32-2 0 6 12 32weeks

IFNγ ELISA

-2 0 6 12 320

250

500

750

Ag85B ESAT6 H1

IFNγ

SFU

/ 106

PBMC

-2 0 6 12 32-2 0 6 12 32weeks

IFNγ ELISPOT

Resp. to:

Ag85B-ESAT6 + IC31 (H1)SSI + IntercellDK-AT

ESAT-6Ag85B

It is unlikely that H1 vaccination would interfere with ESAT6-based diagnostic (QFT)

Discovery

Pre-clinicalefficacy

GMP-Production

Non-clinicalsafety

INDfile

Effective protection (mice , g-p, N-hu P)

Lot consistency-- Formulation

neonatal & immunocomp.

TOXstudies

As RQ by RA

Safety / immunogenicity(EU- adults)

PPD neg BCG primed

LTBI or treated TB

Ph1-Safety / immunogenicity(AFR- adults)

PPD neg & BCG primed LTBI

Ag85B-ESAT6 + IC31 (H1)SSI + IntercellDK-AT

ESAT-6Ag85B

Discovery

Pre-clinicalefficacy

GMP-Production

Non-clinicalsafety

INDfile

Effective protection (mice , g-p, N-hu P)

Lot consistency-- Formulation

immunocompr. TOXstudies

As RQ by RA

Safety / immunogenicity(EU- adults)

PPD neg BCG primed LTBI

MVA-Ag85A U-OXF + IDTUK + DE

MVA live vectorexpressing Ag85A

from H McShane & al., Nature Medicine 10, 1240 (2004)

0 4 12 24

BCG + MVA85A

MVA85A

0

250

500

750

SFC/

1x10

6PB

MC

Response to: Ag85Aweeks

IFNγ-ELISPOT

Phase 1 trial in PPD negMVA85A alone or BCG + MVA85A

Immunogenicity:excellent primary responseVery good boosting effect (12 yrs!)

Safety: low reactogenicity

Discovery

Pre-clinicalefficacy

GMP-Production

Non-clinicalsafety

INDfile

Effective protection (mice , g-p, N-hu P)

Lot consistency-- Formulation

neonatal & immunocomp.

TOXstudies

As RQ by RA

Safety / immunogenicity (EU- adults)

PPD neg BCG primed

LTBI or treated TB

HIV infected

Ph2a-Safety / immunogenicity ados. + infants (AFR)

Ados/ Infants Age de-escalation

Dose escalation

Interferencestudies

HIV infected ados/infants

Ph1- Safety / immunogenicity(AFR- adults)

PPD neg & BCG primed LTBI HIV infected

MVA-Ag85A U-OXF + IDTUK + DE

MVA live vectorexpressing Ag85A

Discovery

Pre-clinicalefficacy

GMP-Production

Non-clinicalsafety

INDfile

Effective protection (mice , g-p, N-hu P)

Lot consistency-- Formulation

neonatal & immunocomp.

TOXstudies

As RQ by RA

Ph1- Safety / immunogenicity(EU- adults)

PPD neg BCG primed

LTBI or treated TB HIV

Mtb72 + AS-01/2GSKBE

Ra35TbH9 39 kDaRa12

BCG+VAC BCG only

0 60 90 240 0 60 90 240

0

200

400

600

800

1000

1200

1400

1600

1800

Median

Vaccination with Mtb72F in BCG-primed and Mtb-exposed individuals (Lausanne/ TBVAC)

• Highly immunogenic (boosting)

• Safe with acceptable local reactogenicity in BCG-primed individuals

Mtb72F-specific cellular responses (IFN-γ ELISPOT)Mtb72F + AS-02

GSKBE

Ra35TbH9 39 kDaRa12

Discovery

Pre-clinicalefficacy

GMP-Production

Non-clinicalsafety

INDfile

Effective protection (mice , g-p, N-hu P)

Lot consistency-- Formulation

neonatal & immunocomp.

TOXstudies

As RQ by RA

Ph1- Safety / immunogenicity (EU- adults)

PPD neg BCG primed

LTBI or treated TB

HIV infected

Ph1-Safety / immunogenicity(AFR- adults)

PPD neg & BCG primed

LTBI HIV infected

Mtb72 + AS-01GSKBE

Ra35TbH9 39 kDaRa12

POTENTIAL ADVANTAGES MAIN ISSUES

-Good for boosting - would benefit from neonatal exposure to BCG

Subunit mycobacterial vaccines

Prior exposure to environmental mycobacteria interferes with the protective effect of BCG

but not of a subunit vaccine

0

0.2

0.4

0.6

0.8

1

1.2

1.4

NoneBCGAG85-ESAT6

PROT

ECTI

VE E

FFEC

TLo

g 10

resis

tanc

e

no pre-exposure

env-mycpre-exposure

From Peter Andersen, SSI, Copenhagen ADVAC 9

POTENTIAL ADVANTAGES MAIN ISSUES

-Good for boosting - would benefit from neonatal exposure to BCG

- Safe in immunocompromised- May be combined with othervaccines

Subunit mycobacterial vaccines

- Single dose (live vectored vaccines)

POTENTIAL ADVANTAGES MAIN ISSUES

-Good for boosting - would benefitfrom neonatal exposure to BCG

- Cost? Not really …- Need for adjuvant (protein vacc.)

- Safe in immunocompromised- May be combined with othervaccines

- Risk of pathology enhancement? Koch phenomenon in previouslyinfected individuals?

Subunit mycobacterial vaccines

- Single dose (live vectored vaccines)

- Single use of live vectoredvaccines

DISCOVERY

DOWNSTREAMDEVELOPMENT

New Antigens

HBHAHeparin-binding Hemagglutinin ( IP-Lille)

e.g. Diacylated Sulfoglycolipids(CD1-restricted)(G Puzzo)

Latency TB antigens

e.g. Rv2660 -SSI

Combined strategies?

rBCG or att-Mtb priming

Combined strategies?

Ag85A or Ag85B or M72 boosting

(+/- TB10.4 / ESAT6)

rBCG or att-Mtb priming

Combined strategies?

Latency ag

Ag85A or Ag85B or M72 boosting

(+/- TB10.4 / ESAT6)

rBCG or att-Mtb priming

Combined strategies?

Lipid?

Latency Ag

Ag85A or Ag85B or/& M72 boosting

(+/- TB10.4 / ESAT6)

rBCG or att-Mtb priming

New TB vaccination Strategies1- adding on BCG

Pre-exposure vaccines

Leve

l of I

mm

unity

(T-c

ells)

Boostimmunity

(infant or ado)BCG

priming(infant)

New TB vaccination Strategies2- improving priming?

Pre-exposure vaccines

Leve

l of I

mm

unity

(T-c

ells)

rBCGpriming(infant)

Boost with sub-unit latency

vaccine?

Post-exposure vaccines

Boost(infant or ado)

e.g.M72

MVA85AH1/4-IC31