Advanced Development of MVA85A: A leading TB Vaccine Candidate

Dr Jacqui SheaGeneral Manager

Oxford-Emergent Tuberculosis Consortium

March 17 2011

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1) Tuberculosis (TB) Overview

2) Oxford-Emergent Tuberculosis Consortium (OETC)

3) Vaccine

1) BCG

2) MVA85A

4) Overview of MVA85A Development to Date

a) Summary of clinical trials

b) Summary of HIV clinical trials

5) MVA85A – Efficacy Studies

AgendaContent

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Tuberculosis Overview

• Approx 2 billion people – a third of the worlds population - latently infected with Mycobacterium tuberculosis

• Approx 9.2 million cases per year of active disease• Approx 500,000 cases of MDR TB each year• HIV/TB co-infection

– up to 80% of people with TB test positive for HIV– Globally approximately 30% of HIV-infected persons are estimated to have latent TB

infection– In 2008, there were an estimated 1.4 million new cases of TB among persons with

HIV infection– TB accounted for 23% of AIDS-related deaths

• Approx 2 million deaths per annum – mostly in developing world countries• Burden of disease in infants, adolescents and young adults and HIV positive

individuals

Estimated tuberculosis incidence rates 2008

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ACP Countries

• 8 of 22 high burden countries are ACP countries– 80% of the world’s TB cases are in these 22 countries– South Africa (480,000 cases), Zimbabwe (95,000 cases), Mozambique (94,000

cases), Democratic Republic of the Congo (250,000 cases), Ethiopia (300,000 cases), Kenya (130,000 cases), Uganda (98,000 cases), Nigeria (460,000 cases)

• 27 ACP countries have a TB incidence ≥300/100,000– Swaziland, South Africa, Zimbabwe, Namibia, Botswana, Lesotho, Djibouti, Sierra

Leone >600/100,000

Tuberculosis

Global Plan to Stop TB: 2006 - 2015

• Targets (from MDGs)– > 70% with infectious TB will be diagnosed– >85% of those will be cured– By 2015, global prevalence of TB will be reduced

to 50% of 1990 levels– By 2050, global incidence will be <1/million

population

• How?– Use of current tools

• DOTS; DOTS-plus; DOTS expansion– New tools

• New drugs• New diagnostics• New vaccines

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Oxford-Emergent Tuberculosis Consortium (OETC)

OETC• The Oxford-Emergent Tuberculosis Consortium “OETC” was formed

in July 2008

• OETC is a joint venture between the University of Oxford and Emergent BioSolutions

• Objective is to develop MVA85A – the world’s most clinically advanced TB vaccine - for both developed and developing world markets

• Key activities:

– Late stage (IIb/III) clinical trials in 3 separate indications

– Commercial manufacturing process (cell line)

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OETC Key Partners and Funders

• Aeras Global TB Vaccine Foundation, USA

– Trial sponsor and co-funder for infant Phase IIb efficacy study

– Responsibility for regulatory strategy for developing world countries

– OETC-Aeras Steering Committee

• Wellcome Trust, UK

– Historical funder and co-funder for infant Phase IIbefficacy study

– OETC-Aeras Steering Committee member and OETC Steering Committee member

• South African Tuberculosis Vaccine Initiative (SATVI), SA

– Infant Phase IIb efficacy study

– Worcester trial site

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OETC Key Partners and Funders (continued)

OETC• University of Cape Town

― Professor Robert Wilkinson, PI for Phase IIb study in HIV infected adults in South Africa

• Hopital Aristide Le Dantec, Senegal

― Professor Souleymane Mboup, PI for Phase IIb study in HIV infected adults in Senegal

• European & Developing Countries Clinical Trials Partnership (EDCTP)

― Funder of Phase IIb trial in HIV infected adults

• Medical Research Council, UK

— Funder of Phase I trials in the Gambia and PhIIb trial in HIV infected adults

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Bacille Calmette Guerin (BCG)

• Only approved vaccine for prevention of TB

• Derived from attenuated M. bovis

• Introduced in 1921

• Variable efficacy (0-80%)

• Given at birth – effective against disseminated forms of the

disease in infants

• Fails to protect against pulmonary disease

• WHO EPI schedule

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MVA85A

• A replication-deficient Modified Vaccinia Ankara (MVA) viral vector– Poxvirus– No replication in mammalian tissues– Good T-cell boosting vector– Excellent safety record

• M.tb antigen 85A– Mycolyl transferase– Major target antigen– Present in all environmental mycobacteria– Doesn’t interfere with new diagnostic tests

• MVA85A can improve BCG induced protection in mice, guinea pigs, non-human primates and cattle

• Clinically the most advanced new TB vaccine

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• 12 completed clinical studies - 8 Phase I, 4 Phase II • Over 1500 subjects have received MVA85A to date

MVA85A Clinical Trial Overview

Phase Population Health Status Country

I

Adults healthy/BCG vaccinated UKAdults healthy/BCG naïve UKAdults healthy/Latent M.tb positive UKAdults HIV positive UK

IIa

Adults healthy/BCG naïve and vaccinated GambiaAdultsAdolescents

healthy/BCG naïve and vaccinatedhealthy/BCG vaccinated SA

Children/Infants healthy/BCG vaccinated SAInfants healthy/BCG vaccinated Gambia

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• 5 ongoing clinical studies - 2 Phase I, 3 Phase II

MVA85A Clinical Trial Overview

Phase Population Health Status Country

IAdults HIV positive Senegal

Adults healthy/BCG vaccinated UK

IIa AdultsM.tb positiveHIV positiveM.tb and HIV positive

SA

IIb

Infants healthy/BCG vaccinated SA

AdultsHIV positivereceiving ART/not receiving ART – Clinical trial to start – Q2 2011

SA/Senegal

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Summary of MVA85A Clinical Trials

• MVA85A safe and immunogenic in all clinical trials to date including:– M.tb infected adults (UK and South Africa)

– HIV infected adults (UK, South Africa and Senegal)

– Infants (The Gambia and South Africa)

– Adolescents (South Africa)

• Well tolerated

• Mild local reactions common (>90%)

• Mild systemic side effects common

• No signs of immunopathology

• MVA85A induces highly polyfunctional CD4+ T cells, which proliferate and have a non-terminally differentiated phenotype; MVA85A induces IL-17+ and IFNγ+ CD4+ T cells, and induces CD8+ T cells

MVA85A

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MVA85A Phase IIb Efficacy Studies

• Phase IIb Efficacy Study in infants–Started 2009–South Africa

• Phase IIb Efficacy Study in HIV+ Adults–Commences in Q1 2011–Multi-site trial

• South Africa• Senegal

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Infant Phase IIb efficacy trial• Objectives:

– Safety– Immunogenicity– Efficacy (against disease & infection)– Immune correlates

• Design: – BCG vaccinated infants in Worcester, South Africa– Randomised at 18-26 weeks to receive either:

• MVA85A (1 x 108pfu)• placebo (Candin)

– Sample size = 2784 (1392/arm)• Cumulative TB incidence of 3%• 90% power to detect 60% improvement over BCG

alone• Status:

– Study sponsored by Aeras– Study commenced in April 09 – Dosing commenced 15th July 2009

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Phase IIb trial in HIV+ adults• Objectives:

– Safety– Immunogenicity– Efficacy (against disease & infection)– Immune correlates

• Design: – HIV-infected adults: +/- ARV– 1400 subjects randomized to receive either:

• 2 doses of MVA85A, 6-9 months apart or• Placebo (Candin)

– Annual incidence assumed to be 2.5%– 80% power to detect 60% improvement– Follow-up for 2 years

• Status:– Study to commence in Q2 2011