Hope in the TB Vaccine Pipeline Sebastian Gelderbloem Aeras Global TB Vaccine Foundation 25 January 2011.

Hope in the TB Vaccine Pipeline

Sebastian GelderbloemAeras Global TB Vaccine Foundation

25 January 2011

AERAS GLOBAL TB VACCINE FOUNDATION

Aeras Global TB Vaccine Foundation

MissionTo develop new, more effective TB vaccines and ensure their availability to all who need them

Method• Non-profit PDP; collaborate with

academic, biotech, pharma and NGO partners to develop and test new TB vaccines

• Pursue a Prime-Boost strategy by developing a modern replacement for BCG plus booster vaccines

• Develop vaccines in our own lab and manufacturing plant


Existing TB Vaccine IneffectiveBCG introduced in 1921


WHO 2007 Recommendations on BCG

• Children with HIV infection regardless of symptoms should not be BCG vaccinated

• All high risk infants need HIV screening – Maternal antibody masks antibody

tests – Detection of virus required– Very difficult to implement in many

places

• Disseminated BCG in HIV infected infants recently (2009) estimated to be 992 per 100,000 (Hesseling, et al)

AERAS GLOBAL TB VACCINE FOUNDATIONPredicted Impact of 50% Effective New TB vaccine

0

50

100

150

200

250

2010 2020 2030 2040 2050

TB

in

cid

en

ce/1

00 0

0/y

r

neonatal

no intervention

mass vaccination (post-exposure)

mass vaccination(pre-exposure)

A

mass vaccination(dual action)

0

50

100

150

200

250

2010 2020 2030 2040 2050

no intervention

drug treatment

mass vaccination (dual action) + drug treatment

B

mass vaccination(dual action)

periodic mass vaccination (dual action) + drug treatment

Young and Dye Cell 2006


Goals for Better TB Vaccines

• Eliminate TB as a public health threat

• Safe and effective in preventing TB in children, adolescents and adults, including people with HIV (for whom BCG is unsafe)

• Protect against all forms of TB – including MDR and XDR

AERAS GLOBAL TB VACCINE FOUNDATIONTB Vaccine Pipeline

VPM 1002Max Planck, Vakzine Projekt Mgmt, TBVI

rBCG30*UCLA, NIH, NIAID, Aeras

AdAg85AMcMaster University

Hybrid-I+CAF01SSI

Hyvac 4/ AERAS-404SSI, Sanofi-Pasteur, Aeras, Intercell

RUTIArchivel Farma

M smegmatis*

Hybrid-I+IC31SSI, TBVI, Intercell

M72GSK, Aeras

MVA85A/AERAS-485Oxford-Emergent Tuberculosis Consortium (OETC), Aeras

AERAS-402/ Crucell Ad35Crucell, Aeras

M vaccae*Immodulon, NIH

Preclinical Phase II Phase IIIPhase IIbPhase I

*indicates candidates that have been in clinical trials in the past, but are not currently being tested in clinical trials

Source: Tuberculosis Vaccine Candidates – 2009; Stop TB Partnership Working Group on New TB Vaccines

As of November 2009

AERAS-422Aeras

Mtb [∆lysA ∆panCD ∆secA2] Albert Einstein College of Medicine

MTBVAC01 [∆phoP, ∆fad D26] University of Zaragoza, Institute Pasteur, TuBerculosis Vaccine Initiative (TBVI)

HBHAInstitute Pasteur of Lille, INSERM, TBVI

Hybrid 56Statens Serum Institute (SSI), Aeras, Intercell, TBVI

HG85 A/BShanghai H&G Biotech

Prime

Boost

Post-infection

Immunotherapy

Preclinical vaccine candidates are not yet in clinical trials, but have been manufactured under Good Manufacturing Practice (GMP) for clinical use and have undergone some preclinical testing that meets regulatory standards.


• 12 candidates have entered clinical trials; 9 currently being tested; 10th will enter trials this year

• Robust pipeline of candidates in preclinical development

• Capacity and infrastructure developed or being developed at several sites

• Manufacturing capacity being developed and agreements explored, with particular emphasis on emerging economies

• Regulatory pathways and market/economic impact research laying groundwork to accelerate adoption and uptake of new TB vaccines

Progress in TB Vaccine Development


Approach to a New TB Vaccine

• Improve BCG – make a recombinant rBCG

• Prime-Boost regimen

• Give booster vaccinations in infants

• Give booster vaccinations in adolescents who have received BCG at birth

Aeras TB Vaccine Candidates in Clinical Trials Potential Boost Vaccines

SSI HyVac4 / AERAS-404 Status: Phase I

•Recombinant protein vaccine intended to be a booster vaccine •Phase I clinical trials being conducted in Europe and Africa

GSK M72 Status: Phase II

•Recombinant protein vaccine intended to be a booster vaccine •Phase I and II trials conducted in Europe, Africa and Asia, including a Phase I trial in HIV+ in Europe

AERAS-402 / Crucell Ad35 Status: Phase IIb•Viral vectored vaccine utilizing adenovirus 35; intended to be a booster vaccine •Phase I and II trials conducted in North America and Africa; Phase IIb recently initiated in HIV+ in S. Africa

MVA85A / AERAS-485 Status: Phase IIb•Viral vectored vaccine utilizing modified vaccinia Ankara; intended to be a booster vaccine •The most clinically-advanced booster vaccine for tuberculosis with an ongoing proof-of-concept Phase IIb trial in infants•Previous clinical trials in the UK and Africa, including in HIV+•Awarded orphan drug status by EMEA

AERAS-422 rBCG Status: Phase I

• Recombinant BCG• Phase I conducted in the US


Clinical Trials: Field Site Development

• Large-scale community-based clinical trials are conducted in high burden countries

• Aeras partners with local research institutions to establish field sites and conduct clinical research

• Build local infrastructure and health care/research capacity to perform future Good Clinical Practice (GCP) compliant Phase III clinical trials


SATVI/University of Cape TownSouth Africa

Makerere UniversityUganda

KEMRI/CDC Kenya

St John’s Research Institute

India

Aeras Partnerships in Clinical Development –Africa and Asia

Manhiça Health Research Center

Mozambique

Le DantecDakar

Senegal

CHC/GHCCambodia

AURUMJohannesburgSouth Africa

AERAS GLOBAL TB VACCINE FOUNDATIONSite DevelopmentSouth Africa

• Partnership with South African Tuberculosis Vaccine Initiative (SATVI) and AURUM

• Field site developed in Worcester (~120 km from Cape Town); most advanced site in the world for TB vaccine trials

• Infrastructure developed both for clinical and laboratory work

AERAS GLOBAL TB VACCINE FOUNDATIONAeras-Sponsored Trials in South Africa

• SATVI is conducting Phase I, II and IIb studies of four vaccine candidates in Worcester

• CIDRI will be conducting a Phase IIb in HIV positive adults in Kayalisha

• UCT Lung Institute conducted a Phase II clinical trial in adults with active or previous TB in Cape Town

• Aurum Institute is enrolling adults living with HIV in Phase IIb trial in Klerksdorp (mining community)

AERAS GLOBAL TB VACCINE FOUNDATIONKey Accomplishments at Other Partner Sites

• State-of-the-art immunology and mycobacteriology laboratory established in South Africa and India

• GeneXeprt role-out for vaccine trials in South Africa, Mozambique, Uganda and Inida

• Mycobacterial and Immunology lab capacity is completed in Kenya and Uganda

• Local staff trained in clinical research in Kenya, Uganda and India

• Epidemiological cohort studies in Cambodia and Kenya

• Quality management and data management infrastructure developed in Kenya , India and Uganda

• New state-of-the-art Clinical Research Center established at a District Hospital in western Kenya

• First multicenter TB vaccine clinical trial initiated in Kenya


Local Benefits of Clinical Research

• Retain local talent and expertise• Raise awareness about TB in the community• Support and enhance local clinical research capacity• Community health and education• Infrastructure remains in the community• Leverage investment in infrastructure to use for clinical trials of

other diseases


Drivers of Future Uptake

• Wide recognition that TB is serious and neglected problem; MDR-TB threat

• Widespread dissatisfaction with current BCG• Likely demand for partially effective vaccine

better than BCG• Willingness to commit to rapid introduction• FDA or EMEA approval will speed adoption• Willingness to spend money out of existing

budgets for prime-boost; private sector


Barriers to Future Uptake

• Clarify expected benefits (20-30 years)

• Fatalism about TB – competing priorities, e.g., HIV/AIDS

• Funding

• Waiting for strong efficacy data

• Some resistance to adolescent boosting (transient populations)

• Some skepticism about aerosol delivery


Lessons Learned

• Heterogeneity of responses within and between countries

• Strong efficacy data will be a critical success factor for introduction, including in-country data

• Cost, if kept low, not likely to be major issue; not an issue in private markets

• Education and preparation will be necessary, but raising awareness and expectations too high needs to be avoided

AERAS GLOBAL TB VACCINE FOUNDATIONAeras gratefully acknowledges the support of the following major donors but

also acknowledges the need for Government support to effectively fight

TB

Netherlands Ministry of Foreign Affairs

US Food and Drug Administration


Thank You!

For more information:

www.aeras.org

[email protected]

Hope in the TB Vaccine Pipeline Sebastian Gelderbloem Aeras Global TB Vaccine Foundation 25 January 2011.

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