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Pediatric TB and HIVThe Potential of New TB Vaccines

Dr. Hoosen Coovadia

Nelson Mandela School of Medicine, University of KwaZulu NatalBoard of Directors, Aeras Global TB Vaccine Foundation

Presentation to the CORE GroupMay 17, 2010


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AERAS GLOBAL TB VACCINE FOUNDATION

Estimated TB Incidence Rate, 2007

Estimated new TB cases (allforms) per 100 000 population

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World HealthOrganization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.WHO 2009. All rights reserved

No estimate

0-24

50-99

>= 300

25-49

100-299


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No estimate

04

2049

>= 50

519

HIV prevalence inTB cases, (%)

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health

Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.WHO 2009. All rights reserved

HIV Prevalence Among TB Cases, 2007

Global estimate: about 1.4 million TB/HIV cases and 450,000 TB/HIV deaths a year


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HIV/AIDS and TB:A Deadly Combination

HIV suppresses the human immune system

TB suppresses the human immune system Each makes the other worse synergistically

The number of new cases of TB has more thandoubled in countries with high HIV prevalence in the

past 15 years

One in four HIV

deaths is linked toTB

+


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Drug Resistance WHO estimates 490,000 MDR-TB cases emerge every

year, with more than 110,000 deaths

E

xtensively drug-resistant (XDR) TB has been identifiedin 57 countries as of November 2009

In 2008, WHO reported that the highest rates of MDR TBever recorded, with peaks of up to 22% of new TB cases,were in some settings of the former Soviet Union. In thesame region, 1 in 10 cases of MDR-TB is XDR-TB

Treatment for drug-resistant TB is much longer, morecomplex and more expensive - with much lower successrates


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Global Health i

ssues

for children

WHO, WorldHealth Statistics, 2010


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Human Rights Issue No vaccine to provide long-term protection from

pulmonary TB

No HIV vaccine

No benefit from biomedical advances for people andcommunities affected by TB

TB exposure due to inadequate health systems poordelivery of INH prophylaxis

TB and HIV diagnostics inadequate for testing children

Poor pediatric tracking programs to measure incidence

Social circumstances lead to exposure poverty,malnutrition


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Maternal TB/HIV important risk factor forpediatric TB and mortality

Estimated TB rate:

-10 times higher in HIV-exposeduninfected children


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WHOEstimated TB Cases by Age, 2006

Country Total Cases Cases in Children < 15 % in Children

Myanmar 78,489 8,007 10.2

Nigeria 261,404 32,310 12.4

Pakistan 244,736 61,905 25.3

The Phillipines 230,217 12,167 5.3

Russian Fed. 183,373 7,778 4.2

South Africa 220,486 35,449 16.1

Thailand 85,928 2,317 2.7

Uganda 75,250 12,099 16.1

Tanzania 117,489 18,890 16.1

Viet Nam 143,023 7,559 5.3

Zimbabwe 76,296 12,267 16.1

Total 6,678,188 630,722 9.4

Adapted from Childhood TB by AHesseling, PMusoke, AGupta, JSadoff


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Existing TB Vaccine Ineffective BCG provides unreliable protection against

pulmonary TB, which accounts for most TBdisease worldwide

BCG is not know to protect against latent TB

BCG is not recommended for use in infantsinfected with HIV due to increased risk forsevere BCG-related complications

Despite wide use, particularly in high burden

countries, BCG has had no apparent impacton the growing global TB epidemic

BCG does reduce risk of severe pediatricTB disease, so it should continue to be useduntil a better TB vaccine is available

BCG introduced in 1921


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Tuberculosis: TB Vaccine Too Dangerous

for Babies With AIDS Virus, Study Says

July 2, 2009 The vaccine against tuberculosis that is

routinely given to 75 percent of the worlds infants is

too risky to give to those born infected with the AIDS

virus, says a new study published by the World HealthOrganization. It recommended that vaccination be

delayed until babies can be tested.


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Goals for Better TB Vaccines Eliminate TB as a public health

threat, in line with global targets(


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Global TB Vaccine Pipeline

Additional research at the discovery/early pre-clinical level: Bhagawan Mahavir Medical Research Center; Cardiff University; EpiVax, Inc.; ImmunoBiology Ltd.; Infectious Disease ResearchInstitute; Institute de Pharamacologie, Puso; Karolinska Institute; Malaysia-Finlay Institute, NIAID; NIH; Osaka University; Shanghai H&G Biotech; Sequella; UCLA; and, Vanderbilt University .

Vaccine Candidate Pre-Clinical Phase I Phase II Phase IIb Phase III

AE

RAS402/Crucell Ad35Crucell N.V./Aeras

MVA85A/AERAS-485OETC/Aeras

GSK M72GSK Biologicals/Aeras

Hybrid 1 SSI IC-31SSI, TBVI, Intercell

HyVac4/AERAS-404sanofi pasteur/SSI/Intercell/Aeras

VPM 1002Max Planck/Vakzine Projekt Management GmbH/TBVI

AdAg85AMcMaster University

RUTIArchivel Farma, S.I.

Hybrid 1 SSI CAF01SSI

AERAS-rBCGAeras

AERAS-CapsidAeras

Other rBCG rMtbAlbert Einstein S. of Med., Institute Pasteur, Univ. of Zaragoza, TBVI

AERAS-other virusAeras

Protein/PolysaccharidesInst. Pasteur de Lille/Inserm, Albert Einstein S. of Med., Aeras, Karolinska Instit.

As of November 2009


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Aeras Global TB Vaccine Foundation

MissionTo develop new, more effective TBvaccines and ensure their availability toall who need them

Goal A more effective, safe and affordable

TB vaccine by 2016

Method Collaborate with academic, biotech,

pharmaceutical and NGO partners todevelop and test new TB vaccines

Pursing a Prime-Boost strategy bydeveloping a modern replacement forBCG plus booster vaccines

Develops vaccines in its own lab and

manufacturing plant


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Safer in HIV infected infants orothers with immune-suppression

BCG or rBCG boosted with anotherTB vaccine is much better thaneither vaccine alone

Constructed to address each stageof the TB life cycle

Prevent infection and reactivation

A new vaccine candidate with all ofthese properties is expected toenter clinical trials in 2010

Recombinant BCG (rBCG) - A Better BCG


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Summary of Aeras Candidates in Clinical TestingSSI HyVac4 / AERAS-404 Status: Phase I

Recombinant protein vaccine intended to be a booster vaccine

Phase I clinical trials

Current trials in Finland, Sweden, South 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

EuropeCurrent trials in South Africa, the Gambia

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+ inSouth Africa

Current trials in South 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-conceptPhase IIb trial in infants

Previous clinical trials in the UK and Africa, including in HIV+

Awarded orphan drug status by EMEA

Current trial in South Africa


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Aeras Partnerships for Field Research

SATVI/U of Cape TownWorcester, South Africa

Makerere UniversityKampala, Uganda

KEMRI/CDCKisumu, Kenya

St. Johns Research InstitutePalamaner, India

Cambodian Health CommitteeSvay Rieng, Cambodia

Manhica Health Research CentreManhica, Mozambique


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Example of Site Development

South Africa Partnership with South African Tuberculosis Vaccine Initiative (SATVI)

Field site developed in Worcester (~120 km from Cape Town)

Infrastructure developed:

State-of-the-art immunology laboratory Highly skilled staff capable of performing the duties necessary to maintain the

infrastructure and execute clinical research

Clinical and office facilities

Professional Development Program (Siyantinga- Reach for the Stars) program initiated in 2001

Resource Center established in 2005


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Clinical Trials Field Site Development

Large-scale community-based clinicaltrials are conducted in high burdencountries

Aeras partners with local researchinstitutions to establish field sites andconduct clinical research

Build local infrastructure and health

care/research capacity to perform futureGood Clinical Practice (GCP) compliantPhase III clinical trials


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Activities in South Africa

Research Partner - South AfricanTuberculosis Vaccine Initiative (SATVI)

Conducting Phase I, II and IIb studies of

fourvaccine candidates Adult and infant enrollment

Over 230 staff trained since 2004

Most advanced site for large-scale TB

vaccine trials in the world Future infant studies planned of AERAS-

402/Crucell Ad35

Western Cape


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Research Partner University ofCape Town Lung Institute

Phase II clinical trial in adults with

active or previous TB (AERAS-402/Crucell Ad35 )

Cape Town

Future study of TB vaccine

candidate in HIV infected adultsplanned (part of multi-centerMVA85A/AERAS-485 study)


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Research Partner Aurum Institute Enrolling adults with HIV in Phase IIb trial Safety and efficacy of TB vaccine

(MVA85A/AERAS-485)

Klerksdorp, North West (mining area)


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Access and Availability Future access considered at every stage of vaccine

development Manufacturing

Guarantee by partners for sufficient production and affordableprices, or technology transfer

Manufactured by Aeras with partners in developing world Aeras will not consider vaccine candidates that will be costly to

manufacture on a large scale

Pricing Dual pricing for affordable distribution in resource-poor countries Cost plus purchase from partner Aeras provides at cost

Distribution Developing world governments International organizations (GAVI, UNICEF) Developing world partners


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TB Vaccine Development Timeline

Field Site Preparation ($2-4 million per yr, per site)

2.5 Years 3 Years 4 Years

Direct costs to develop one TB vaccine candidate could be as much as$340 million

Phase III licensure trials are complex and the most costly componentInfant trial - between $70 and $140 millionAdolescent and adult trial - between $130 and $265 million

Aeras has a broad pipeline of vaccine candidates, 4 of which are currentlyin clinical trials

With sufficient resources, a new TB vaccine could be ready in 7 10 years.

1 - 2 Years 1 Year

Vaccin

eDiscovery

Pre-

Clinical

Testing

Phase

I

Phase

II

Phase IIb Phase III

Manufacturing ($310 million to build and upgrade facilities; $10 million per year to maintain)

$3 million $18 million $48 million

Licensure

$3.5 million

Costs associated with thedevelopment of a portfolio ofTB vaccine candidates

Costs related to thedevelopment ofone TBvaccine candidate

up to $265million


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Aeras gratefully acknowledgesthesupportof

thefollowing majordonors

Netherlands Ministry of Foreign Affairs

THE MARY LYNNRICHARDSON

FUND

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