Global TB Vaccine Foundation. Progress in Developing TB Vaccines Second Stop TB Partners’ Forum New Delhi, India March 25, 2004 Jerald C. Sadoff MD.

Global TB Vaccine Foundation

Progress in Developing TB Vaccines

Second Stop TB Partners’ ForumNew Delhi, IndiaMarch 25, 2004

Jerald C. Sadoff MD

Aeras Mission

To develop and insure availability of new effective TB vaccines for all people who need them

Aeras Goals

• To obtain regulatory approval and insure supply of a new TB vaccine regimen to prevent TB in the next 7-10 years

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

Infants

LatentInfection

AcuteInfection

Reactivation inAdolescentsand Adults

Highly infectious

vaccinate

vaccinateAdolescents

Infants

LatentInfection

AcuteInfection

Reactivation inAdolescents

& Adults

Highly infectious

vaccinate

vaccinateAdolescents

Aeras Strategy

• To bring the best current vaccine candidates forward as fast as possible

• To insure manufacturing and supply at an affordable price

• To eliminate delay between licensure and availability through early factory construction

• Every year lost costs 2 million lives

Rationale for TB vaccine potential• Human immunology – Humans with IL-12

and INF γ pathway defects highly susceptible to TB

• Animal models that mimic human TB can be protected with vaccines

• 20 yrs of iterative testing of antigens that healthy infected humans respond to have narrowed the choices

Prime Boost Strategy

For Protection against Acute Infection and Disease in Infants

Candidates for the Priming of Newborns:

• BCG

• Recombinant BCG

• Live attenuated recombinant TB variant

Candidates for Boosting Infants and adolescents

• Recombinant fusion protein in adjuvant

• Vectored vaccines– MVA recombinant– Adenovirus recombinant – oral shigella auxotroph dsRNA expression

system

• Heat shock associated proteins

Recombinant Live Prime

• rBCG30 recombinant BCG over -expressing Ag85b (Marcus Horowitz) in phase I clinical trials

• rBCG Lysteriolysin O (Steffan Kaufman)

• Auxotrophic live TB– TB Vac candidate– Bill Jacobs, Barry Bloom– Aeras/Kaufmann

Booster Vaccines for infants and Adolescents – Recombinant Fusion

Proteins

• GSK/IDRI Mtb72f fusion protein in AS01/AS02 (Steve Reed) – in Phase I clinical trials

• SSI ESAT-6/Ag85b fusion protein in SSI adjuvant (Peter Anderson)

• SSI Ag X/Ag85a fusion protein in SSI adjuvant (Peter Anderson)

Booster Vaccines for infants and Adolescents – Vectored Vaccines

• Oxford MVA – Expressing Ag85a (Adrian Hill) in Phase I clinical trials

• Aeras/Crucell Adenovirus vector expressing TB antigens

• Aeras Shigella dsRNA vector expressing TB antigens

Vaccines to prevent the latent state or reactivation from the latent state

• DosR regulon controls expression of many proteins expressed during the latent state

• BCG can be locked in latent state and present DosR regulated proteins

• Latent state proteins vaccines as:– Recombinant proteins– Vectors – Adeno, MVA and Shigella– Heat shock associated proteins

rBCG30

• Recombinant Tice BCG which over-expresses Ag85b

• Protects Guinea pigs better than BCG

• Has been produced to cGMP standard at the Korean Institute of Tuberculosis

• A modern bio-fermentation process for its final manufacture being developed at Aeras facility at Biovac in S. Africa

rBCG30

• Thirty subjects enrolled at two sites in phase I trial– Dr. Dan Hoff - St. Louis University– Dr. Thomas Littlejohn – Winston Salem N.C.

• Vaccine shown safe and well tolerated to date in these volunteers

Intracellular tropism of intracellular bacteria

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

rBCG::ureC-llo+

• Max Planck Inst. – Stefan Kaufmann

• Escapes endosome through expression of Lysteriolysin O and Urease C which punch holes

Protective capacity of rBCG::ureC-llo+ in the murine aerosol model of tuberculosis

BALB/c mice were immunized with 106 CFU BCG or rBCG::ureC-llo+ and challenged 120 days after vaccination. Bacterial load in lungs was determined post aerosol-challenge with M. tuberculosis H37Rv.

0 10 20 30 40 50 60 70 80 90 100

2.5

3.5

4.5

5.5

NaiveBCGp

BCGp ureCBCGp ureC-llo+

Days post-challenge

------ 2.12-fold (log10)------ 1.13-fold (log10)

Lo

g10

cfu

in

lu

ng

s

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

0 25 50 75 100 125 1500

10

20

30

40

50

60

70

80

90

100

110

BCG Pasteur rBCGp::llo+rBCGp::ureC-llo+

Intravenous dose/mouse:BCGp -- 8x107

rBCGp::llo+ -- 1x107

rBCGp::ureC-llo+ -- 3x107

Virulence of BCGp::ureC-llo+ in SCID mice

Day post infection

Per

cen

t su

rviv

al

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

Mtb72f is the lead booster candidate

• Produced in partnership with GSK-BIO and IDRI (Steve Reed)

• Given with adjuvant AS01

• Phase I in 30 adult volunteers nearing completion

• Acceptable safety and tolerability

Mtb32 C-term Mtb39 Mtb32 N-term

192

1 391

1951323

~14KD ~39KD ~20KD

Construction of Mtb72fConstruction of Mtb72f

Mtb32 C-term = Ra12

Mtb32 N-term = Ra35

Mtb39 = tbH9

Corim VI Study (monkeys): Corim VI Study (monkeys): 20 weeks post-challenge20 weeks post-challenge

Corim VI Study (monkeys): Corim VI Study (monkeys): 48 weeks post-challenge48 weeks post-challenge

CORIM VI study (monkeys): CORIM VI study (monkeys): 99 weeks Post-Challenge99 weeks Post-Challenge

BCG/Mtb72f

BCG/AS02

AS02

PR 4558A, Group II, 10/30/2001PR 4558A, Group II, 10/30/2001

PR 2799F, Group III, 10/30/2001PR 2799F, Group III, 10/30/2001

PR 2799F, Group III, 12/30/2001PR 2799F, Group III, 12/30/2001

Shigella-rdsRP vector

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

Invasion

Nucleus

A live oral vaccine against TB is possible: Delivery of rdsRP by Shigella vectors

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

Amplification of mRNA encodingTB antigens by alphavirus amplicon

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

Epidemic Dynamics

R = R0 (1-EC) Where:

R0 = the number of infectious TB cases caused by 1 TB case

C = % of population covered by the vaccineE= vaccine efficacy = 1- Incidence vacinees

Incidence controlsIf R< 1 Epidemic is eliminated

Slide courtesy of Chris Dye, WHO, Geneva

Fig 2 rBCG30 Live TB VaccineFig 2 rBCG30 Live TB Vaccine

Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr 7 Yr 8

Process Devel Phase III

Manufacture Release Phase III Material

Release Assay Validation

Operaqtional Chaqracterization Immune Response, Disease, Infection Assays

Clinical Operational Characterization Infection Detection & Disease

Stdy rBCG30-4 Phase I S. Africa PPD- , 11-12 yr

Stdy rBCG30-5 Phase I S. Africa + 2 Other Sites PPD- , 5 yr

Stdy rBCG30-6 Phase I S. Africa + 2 Other Sites

Infants 3 Months

Stdy rBCG30-1 Phase I US PPD- Adults 30 Subjects

110 GP

30 Subjects

30 Subjects

90 Subjects(30/Site)

90 Subjects(30/Site)

Stdy rBCG30-3 Phase I US PPD+ Adults

Koch PhenGuinea Pig Study

30 Subjects

Stdy rBCG30-2 Phase I Africa PPD-

Adults

Go/NoGo

Stdy rBCG30/72f-1 Phase II S. Africa + 2 Other Sites Prime Boost 4-Arm Trial Neonates

648 Subjects(216/Site)

(1) BCG(2) rBCG30(3) BCG Prime + Mtb72fBoost(4) rBCG30 Prime + Mtb72f Boost

Site Development/Epidemiology/Infrastructure/Training

Fig 3 rBCG30 Prime + 72f BoostFig 3 rBCG30 Prime + 72f BoostSubject to a Later Supplemental RequestSubject to a Later Supplemental Request

Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr 7 Yr 8

Interim Analysis (POC)

(1) BCG(2) rBCG30(3) BCG Prime + Mtb72fBoost(4) rBCG30 Prime + Mtb72f Boost

Final Scale Up – Development & Manufacture 72f

Final Scale Up for Manufacturing rBCG30

Pivotal Phase III 3 Arm Study – Adolescents & Adults

Interim Analysis (POC)

(1) Placebo(2) Mtb72fBoost(3) rBCG30 Prime + Mtb72f

Boost

25,000 Subjects

Pivotal Phase III 4 Arm Study - Neonates

26,000 Subjects

Go/NoGo

Initial Safety

Initial Safety

Summary

• A moderately effective vaccine + drug control could eliminate the 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

• A new vaccine to prevent reactivation possible in 10-12 years