Pediatric TB and HIV The Potential of New TB Vaccines

1. Pediatric TB and HIVThe Potential of New TB Vaccines Dr. Hoosen Coovadia Nelson Mandela School of Medicine, University of KwaZulu Natal Board of Directors, Aeras Global TB Vaccine Foundation Presentation to the CORE Group May 17, 2010

2. Estimated TB Incidence Rate, 2007 Estimated new TB cases (all forms) per 100 000 population No estimate 0-24 25-49 50-99 100-299 >= 300 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

3. HIV Prevalence Among TB Cases, 2007 Global estimate: about 1.4 million TB/HIV cases and 450,000 TB/HIV deaths a year HIV prevalence in TB cases, (%) No estimate 0–4 5–19 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 20–49 >= 50

4. + 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

5. 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

6. Global Health issues for children WHO, “World Health Statistics, 2010”

7. 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

8. 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.

9. 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) • Maternal TB/HIV important risk factor for pediatric TB and mortality (Pillay 2004; Khan 1999; Cotton 2008; Gupta 2007) Adapted from presentation by Amita Gupta, July 19, 209

10. WHO Estimated TB Cases by Age, 2006 Adapted from “Childhood TB” by AHesseling, PMusoke, AGupta, JSadoff

11. 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

12. 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.

13. 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

14. 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. As of November 2009

15. Aeras Global TB Vaccine Foundation Mission To 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

16. Induction of Immunity: Prime –Boost Infants BCG or rBCG IM or as an aerosol Capsids in bacteria or as an aerosol 24 Weeks 14 Weeks

17. Recombinant BCG (rBCG) - A Better BCG • 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

18. Summary of Aeras Candidates in Clinical Testing

19. Aeras Partnerships for Field Research St. John’s Research Institute Palamaner, India Cambodian Health Committee Svay Rieng, Cambodia Makerere University Kampala, Uganda KEMRI/CDC Kisumu, Kenya Manhica Health Research Centre Manhica, Mozambique SATVI/U of Cape Town Worcester, South Africa

20. 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

21. 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

22. 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

23. Activities in South Africa 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)

24. Activities in South Africa 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)

25. 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

26. TB Vaccine Development Timeline Costs associated with the development of a portfolio of TB vaccine candidates Field Site Preparation ($2-4 million per yr, per site) Manufacturing ($310 million to build and upgrade facilities; $10 million per year to maintain) Vaccine Discovery Pre-Clinical Testing Phase I Phase II Phase IIb Phase III Licensure 2.5 Years 3 Years 4 Years 1 - 2 Years 1 Year Costs related to the development of one TB vaccine candidate up to $265 million $3.5 million $3 million $18 million $48 million • 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.

27. Aeras gratefully acknowledges the support of the following major donors THE MARY LYNN RICHARDSON FUND Netherlands Ministry of Foreign Affairs