Progress in Developing New TB Vaccines Jerald C. Sadoff, MD Reversing the Tide: The End of Tuberculosis Columbia University March 7 th 2006.

Progress in Developing New TB Vaccines

Jerald C. Sadoff, MDReversing the Tide: The End of Tuberculosis

Columbia UniversityMarch 7th 2006

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Potential Impact of 50-90% Effective Vaccines

• Vaccines in combination with antibiotics could control the epidemic

• Pre-exposure or post-exposure vaccines could eliminate about 1/3 of disease and death

• A TB vaccine with pre- and post-exposure efficacy could achieve global control of TB

Ziv et al, Emerging Infectious Diseases, Vol.10, No.9 September 2004

Lietman, T, Blower SM, Clin. Inf Dis.2000:30:S316-22

Lietman, T. Blower SM. Science. 1999:286:1300-01

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Aeras Global TB Vaccine Foundation

Mission:

To develop new TB vaccines and ensure their availability to all who need them

Goals:

- To obtain regulatory approval and ensure supply of a new TB vaccine regimen within 7-10 years

- To introduce 2nd generation vaccines with improved product profiles and efficacy against latent TB in 9-15 years

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Aeras

AcademiaCapetown Univ. S. Africa

St. Johns, BangaloreKarolinska, Stockholm

Max Plank, BerlinLeiden Univ.

UCLAU.C. Davis

Vanderbilt Univ.Colorado St. Univ.

Harvard U.European TBVac

Foundations/GovernmentBill & Melinda Gates Foundation

U.S. CDC, NIH, FDADANIDA, Denmark

EDCP, EuropeSTOP TB, WHO

Industry GSK, Rixenstart Belgium

Crucell, HollandSSI, Denmark

ImmunoBiology, UKSerum Institute, India

Thymed, Germany

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Field Site Developed in the Breede River Valley of the Boland-Overberg Region of Western

Cape Province, South Africa

Boland-Overberg Region

Breede RiverValley

Ceres

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India Site

Palamaner Taluk

St. John’s MedicalCollege, Bangalore

Palamaner Taluk• Population of 350,000• Mostly rural • ~ 3 hours from Bangalore• TB incidence rate in adults of 150-200/100,000• St. Johns has long standing relationship with Emauss Leprosy Hospital in Palamner and has conducted large nutritional cohort studies in this community.

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13

0

10

20

30

40

50

60

0 6 12 18 24 30 36 42 48

Months of Age

Inci

den

ce p

er 1

0,00

0

Incidence observed in BCG Trial w ith active surveillance

Incidence of tuberculosis in 11,667 BCG vaccinated infants with a smear

and/or culture positive for M.tb

Total TB incidence = 3.1%2-year TB incidence = 2.7%

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Preliminary Conclusions and Approach

Conclusion:

• Field trials of new TB vaccines feasible in this population

Approach:

• Large cohort studies in 9000 infants and 12000 adolescents in S. Africa and India to confirm high incidence

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Basis for New TB Vaccine Development• Humans are resistant to infection & disease

– Only ~30% of exposed individuals are infected– Only ~10% of infected individuals get disease

• Human resistance related to the immune system– Humans with INFγ and TNF genetic and

pharmacologic pathway defects highly susceptible to TB

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Potential Uses of Effective TB Vaccine

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Prime Boost Strategies

14 Weeks

24 Weeks

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Protection in Eight BCG Trials

Trial and Subjects Duration(years)

Percentprotection

North American Indians (2792 subjects from 1935-1995

9-11 (60) 80 (52)

Chicago : infants 12-23 75

Georgia : school children 20 None

Puerto Rico : population below 20 years 5 ½ - 7 ½ 31

Georgia and Alabama : general pop. 14 14

Great Britain : school children (54,239 subjects age 14-15 from 1950-72

15 78

Mandanapalle, South India: general pop 9-14 31

Chingleput, South India : general population (265,172 subjects)

7 ½ None

Baily, G. V. J., et al, Indian Journal Medical Research 70, September 1979, pp. 349-363.

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BCG Replacements:Recombinant BCG & TB ready for Phase I

• rBCG30 over-expressing TB antigen 85B: Horwitz at UCLA which is not acceptable to regulatory authorities as a final product

• rBCGs escaping the endosome: Kaufmann at Max Planck Institute

• Aeras 403 rBCG – Aeras recombinant BCG combines Horwitz and Kaufmann discoveries

• Recombinant attenuated TB: Bill Jacobs at Albert Einstein University

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% Ag85B-specific IFN- Producing CD8+ T cells (Hanekom Assay)(Means ± SEs)

Tice rBCG30

Group

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Day 0 Day 56 Day 112 Day 252

p=.05

*

*Wilcoxon matched pairs test (compared w ith Day 0)

Preliminary data from 17/30 subjects in trial

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Intracellular tropism of intracellular bacteria

Courtesy of Dr. Stefan Kaufmann, Max Plank Inst. Infect. Dis., Germany

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pAF112

oriM

PAg85B Ag85A Ag85B Ag 10.4

rBCG Aeras 403 Strain Construction

BCG Danish 1331

Pfo integrationPlasmid for endosome

escape

AFV102

Phsp60sacB

OriE

PkanKanR

ureCL-flank

PAg85B

Ag85Bleader peptide

pfo

ureCR-flank

MCS

ENpAF102

AFV112 Aeras 403

Over-expressionPlasmid

oriE

PRv3130

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rBCG Vaccine - Aeras 403

• New Fermentation and foam drying process developed which produces very high yield of room temperature stable vaccine

• Aeras factory can produce the worlds needs for bulk vaccine- 150-300 million doses/year

• Aeras bulk vaccine will be shipped to developing world manufacturers for foam drying, packaging and distribution

• Phase I clinical trials scheduled for August 06

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Prime Boost Strategies

14 Weeks

24 Weeks

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Candidates for boosting infants and adolescents in or about to start Phase I

• Recombinant fusion proteins in adjuvant– M72 fusion GSK/Aeras

– Ag85B::ESAT6 SSI/TBVAC

– Ag85B::10.4 fusion SSI/Aeras

• Vectored vaccines– rMVA-Ag85A Oxford

– rAd35-Ag85A-Ag85B-TB10.4 fusionAeras/Crucell

– Oral Shigella dsRNA capsids Aeras

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rBCG prime with rAd35 Aeras 403 BoosterFold rise in CD8+T cells

0

1

2

3

4

5

6

85a 85b 10.4

BCGAFRO-1

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Prime Boost Strategies

14 Weeks

24 Weeks

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EM of procapsids in S. flexneri MPC51

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Completion of second strand triggers mRNA synthesis and secretion

Nucleocapsid (NC)

L

M

S

P2 catalyzes synthesis of mRNA, which is passively secreted back through P4 hexamers on capsid surface for translation

mRNA

Shigella-rdsRP vector

• Access cytoplasm• Lysis due to murI• Release of rdsRP

Invasion

Nucleus

Delivery of rdsRP by Shigella vectors

to host antigen presenting cells

Synthesis of recombinant segment-S and segment-M mRNA by RNA-dependent RNA polymerase activity of rdsRP

EF2-independent translation of TB antigens

Presentation of TB antigensin the context of HLA class I&II

Induction of TB-specificCD4+ and CD8+ T cells

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rdsRP encoded antigen mRNA expression by HeLa cells

HeLa cell 14 hr post-invasion by MPC51 carrying rdsRP LSMtb4 (85A-85B-10.4 encoded on rSeg-M) Probed with anti-85A IgY

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Mouse Dose Response/Immunogenicity Study

Cellular immune responses of BALB/c mice vaccinated intranasally with varying doses of the Shigella-vectored nucleocapsid LSMtb4 (expresses Ag85A-85B-10.4 fusion) or Ad35 TBS administered IM

IFN+ CD4 Ag85A

LSMtb

4 (1

0e5

cfu)

LSMtb

4 (5

x10e

4 cf

u)

LSMtb

4 (1

0e4

cfu)

Ad35TBS (1

0e9

pfu)

0.00

0.25

0.50

0.75

1.00

x-fo

ld i

ncr

ease

ab

ove

bac

kgro

un

d TNF+ CD8 Ag85A

LSMtb

4 (1

0e5

cfu)

LSMtb

4 (5

x10e

4 cf

u)

LSMtb

4 (1

0e4

cfu)

Ad35TBS (1

0e9

pfu)

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

x-fo

ld i

ncr

ease

ab

ove

bac

kgro

un

d

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Vaccine Development Timelines

2004

Preclinical AerasAeras 404 (oral)

2005

2006

2007 2008

Phase I and IIAeras 403/402

2009 2010

Field Site Preparation & Epidemiology

Preclin. Aeras 402 & Aeras 403

Phase III Aeras 403 Prime Aeras 402 Boost Infants &

Adolescents

AerasCrucell

Aeras

2013

20122011 2014

Phase I and IIAeras 403/404

Phase III Aeras 403 Prime Aeras 404 Boost Infants &

Adolescents

Aeras 402 = Crucell Ad35 vectored TB vaccineAeras 403 = rBCG with overexpression & endosome escapeAeras 404 = capsids In shigella for oral delivery

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Summary

• A moderately effective vaccine + drug control could virtually eliminate the TB epidemic

• Based on 20 years of research, a prime-boost vaccine strategy has great potential

• This new vaccine regimen could be licensed and available in 7-10 years

• The potential of rBCG prime given at birth followed by viral vector, capsid or protein boost to induce high levels of cellular immunity make this a very attractive vaccine regimen for TB, malaria and HIV

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Contact Information

Jerald C. Sadoff, MD

President & Chief Executive Officer

Aeras Global TB Vaccine Foundation

7500 Old Georgetown Road, Suite 800

Bethesda, MD 20814

+1-301-547-2912

[email protected]

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Jerald Sadoff led or contributed to the development of these vaccines

• Licensed– Hepatitis A –Vaqta– H. Influenza conjugate –Liquid Pedvax– Varicella- 4 degree stable Varivax– Combination Hep B & H. Influenza – Comvax– Combination D, T, aP, Polio, H. Influ, Hep B –Hexavac– Measles, Mumps, Rubella, Varicella – MMRV– Rotavirus – Rotatech– Zoster – Zostovac– HPV – (license 06)– Cholera (Killed Whole cell +B -SBL)

• In phase IIB or III– Malaria (Army-GSK-RTSS)– HIV (Merck)– Cholera –Peru 14– Shigella conjugate (NIH)

• In phase I– TB rBCG & M72