pediatric tb and hiv the potential of new tb vaccines dr. hoosen coovadia nelson mandela school of...

Pediatric TB and HIVThe Potential of New TB Vaccines

Dr. Hoosen CoovadiaNelson Mandela School of Medicine, University of KwaZulu Natal

Board of Directors, Aeras Global TB Vaccine Foundation

Presentation to the CORE GroupMay 17, 2010

AERAS GLOBAL TB VACCINE FOUNDATION

Estimated TB Incidence Rate, 2007

Estimated new TB cases (all forms) 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 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

No estimate

0-24

50-99

>= 300

25-49

100-299


No estimate

0–4

20–49

>= 50

5–19

HIV prevalence in TB 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


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 than

doubled in countries with high HIV prevalence in the past 15 years

One in four HIV deaths is linked to TB

+


Drug Resistance

• WHO estimates 490,000 MDR-TB cases emerge every year, with more than 110,000 deaths

• Extensively drug-resistant (XDR) TB has been identified in 57 countries as of November 2009

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

• Treatment for drug-resistant TB is much longer, more complex and more expensive - with much lower success rates


Global Health issues for children

WHO, “World Health Statistics, 2010”


Human Rights Issue

• No vaccine to provide long-term protection from pulmonary TB

• No HIV vaccine• No benefit from biomedical advances for people and

communities affected by TB • TB exposure due to inadequate health systems – poor

delivery 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


Pediatric HIV• 2.1 million children were

living with HIV/AIDS, vast majority in sub-Saharan Africa.

• 1000 children get newly infected with HIV each day.

• Children acquire HIV from their HIV-infected mothers during pregnancy, birth or breastfeeding.

• PMTCT works, but needs broader rollout and accessibility to those who need it most.


Maternal TB/HIV important risk factor for pediatric TB and mortality

• Estimated TB rate:-10 times higher in HIV-exposed uninfected children <5 years than in non-HIV exposed-30 times higer in HIV-infected children<5 years than non-HIV exposed (Mukade 1997)-1596/100,000 pop. HIV+ infants ≤ 12 mo. vs 65.9/100,000 pop. In HIV-infants ≤ 12 mo. (Hesseling CID 2009)

Adapted from presentation by Amita Gupta, July 19, 209

• Maternal TB/HIV important risk factor for pediatric TB and mortality (Pillay 2004; Khan 1999; Cotton 2008; Gupta 2007)


WHO Estimated TB Cases by Age, 2006Country 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


Existing TB Vaccine Ineffective• BCG provides unreliable protection against

pulmonary TB, which accounts for most TB disease worldwide

• BCG is not know to protect against latent TB

• BCG is not recommended for use in infants infected with HIV due to increased risk for severe BCG-related complications

• Despite wide use, particularly in high burden countries, BCG has had no apparent impact on the growing global TB epidemic

• BCG does reduce risk of severe pediatric TB disease, so it should continue to be used until a better TB vaccine is available

BCG introduced in 1921


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 world’s infants is too risky to give to those born infected with the AIDS virus, says a new study published by the World Health Organization. It recommended that vaccination be delayed until babies can be tested.


Goals for Better TB Vaccines • Eliminate TB as a public health

threat, in line with global targets (<1 case/million), in conjunction with new drugs and diagnostics

• 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


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 Research Institute; 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 IIIAERAS402/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


Aeras Global TB Vaccine Foundation

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

Goal• A more effective, safe and affordable

TB vaccine by 2016

Method• Collaborate with academic, biotech,

pharmaceutical and NGO partners to develop and test new TB vaccines

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

• Develops vaccines in its own lab and manufacturing plant


Induction of Immunity: Prime –Boost Infants

14 Weeks

24 Weeks

BCG or rBCG

Capsids in bacteria or as an aerosol

IM or as an aerosol


• Safer in HIV infected infants or others with immune-suppression

• BCG or rBCG boosted with another TB vaccine is much better than either vaccine alone

• Constructed to address each stage of the TB life cycle

• Prevent infection and reactivation

• A new vaccine candidate with all of these properties is expected to enter clinical trials in 2010

Recombinant BCG (rBCG) - A Better BCG


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 Europe•Current 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+ in South 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-concept Phase 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


Aeras Partnerships for Field Research

SATVI/U of Cape TownWorcester, South Africa

Makerere UniversityKampala, Uganda

KEMRI/CDCKisumu, Kenya

St. John’s Research InstitutePalamaner, India

Cambodian Health CommitteeSvay Rieng, Cambodia

Manhica Health Research Centre Manhica, Mozambique


Example of Site DevelopmentSouth 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


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


Activities in South Africa

Research Partner - South African Tuberculosis Vaccine Initiative (SATVI)

• Conducting Phase I, II and IIb studies of four vaccine 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



Research Partner – University of Cape 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 adults planned (part of multi-center MVA85A/AERAS-485 study)



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)


Access and Availability• Future access considered at every stage of vaccine

development • Manufacturing

– Guarantee by partners for sufficient production and affordable prices, 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


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 component–Infant trial - between $70 and $140 million–Adolescent and adult trial - between $130 and $265 million

•Aeras has a broad pipeline of vaccine candidates, 4 of which are currently in clinical trials

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

1 - 2 Years 1 Year

Vaccine Discovery

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 the development of a portfolio of TB vaccine candidates

Costs related to the development of one TB vaccine candidate

up to $265 million


Aeras gratefully acknowledges the support of the following major donors

Netherlands Ministry of Foreign Affairs

THE MARY LYNN RICHARDSON

FUND

pediatric tb and hiv the potential of new tb vaccines dr. hoosen coovadia nelson mandela school of...

Documents

tb tb exposure

tb slide

pediatric tb

pulmonary tb

mdrtb cases

drugresistant tb

estimated new tb cases

tb incidence rate