1. HIV/AIDS & TB Jerald C. Sadoff M.D. “Journalist to Journalist” National Press Foundation Toronto, Canada August 9 th 2006

2. AERAS GLOBAL TB VACCINE FOUNDATION The HIV/AIDS Pandemic The World Health Organization (WHO) estimates that in 2005: –40.3 million people were living with HIV –4.9 million people were newly infected with HIV –3.1 million people died of AIDS

3. AERAS GLOBAL TB VACCINE FOUNDATION The HIV/AIDS Pandemic AIDS is the world’s most deadly infectious disease – more than 25 million people have died as a result of AIDS since the disease was first recognized in 1981 Despite years of research, there is still no cure or vaccine for HIV/AIDS

4. AERAS GLOBAL TB VACCINE FOUNDATION The Tuberculosis (TB) Pandemic The World Health Organization (WHO) estimates that in 2004: –8.9 million new cases of TB were diagnosed –1.7 million people died from TB –One out of three people in the world have been infected with TB (most do not develop disease)

5. AERAS GLOBAL TB VACCINE FOUNDATION The Tuberculosis (TB) Pandemic TB is spread from an infectious person to a vulnerable person through the air TB usually affects the lungs but can affect any part of an infected person

6. AERAS GLOBAL TB VACCINE FOUNDATION The Tuberculosis (TB) Pandemic TB is the world’s 2 nd most deadly infectious disease, after AIDS Although TB is curable, treatment is lengthy and costly– often spanning 6 months to a year – and is not easily accessible to all who need it.

7. AERAS GLOBAL TB VACCINE FOUNDATION 22 high-burden countries: 80% of all new TB cases 0 500 1000 1500 2000 India China Indonesia Bangladesh Nigeria Pakistan Philippines South Africa Russian Federation Ethiopia DR Congo Viet Nam Kenya UR Tanzania Brazil Thailand Myanmar Zimbabwe Uganda Cambodia Afghanistan Mozambique Estimated new TB cases ('000s)

8. AERAS GLOBAL TB VACCINE FOUNDATION Highest TB rates per capita are in Africa 25 to 49 50 to 99 100 to 299 < 10 10 to 24 300 or more No Estimate 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 2002

9. AERAS GLOBAL TB VACCINE FOUNDATION 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

10. AERAS GLOBAL TB VACCINE FOUNDATION HIV/AIDS and TB: A Deadly Combination 12 million people worldwide are co-infected with TB and HIV TB is the leading cause of death of HIV positive people. In fact, TB accelerates progression of HIV into AIDS People with HIV/AIDS are highly susceptible to TB disease – 50-100 times more so than people without HIV

11. AERAS GLOBAL TB VACCINE FOUNDATION HIV/AIDS and TB Co-Epidemic TB is hard to diagnose with the standard “sputum smear” test in people with HIV/AIDS Both TB and HIV drugs work in co-infected people, but, treating HIV and TB co-infection is complicated as there are troublesome drug-drug interactions Without proper treatment, 90% of HIV positive people die of TB within months of TB appearance

12. AERAS GLOBAL TB VACCINE FOUNDATION HIV/AIDS and TB Co-Epidemic Women of reproductive age are highly susceptible to TB disease and bear a very heavy burden of the HIV/AIDS and TB co-epidemic Access to care and treatment is least available in the developing world – where the co-epidemic is greatest

13. AERAS GLOBAL TB VACCINE FOUNDATION Turning the Tide: New Tools to Combat TB by PDPs New Diagnostics – FIND (Foundation for Innovative New Diagnostics) is focused on the development of rapid, accurate and affordable diagnostic tests to improve detection of TB –This is a critical need for PLWHA who are co- infected with TB

14. AERAS GLOBAL TB VACCINE FOUNDATION Turning the Tide: New Tools to Combat TB by PDPs New Treatments – The Global Alliance for TB Drugs is working to develop new, faster-acting and affordable TB medicines – The Consortium to Respond Effectively to the TB AIDS Epidemic (CREATE) is seeking ways to prevent TB disease in people living with HIV/AIDS

15. AERAS GLOBAL TB VACCINE FOUNDATION Turning the Tide: New Tools to Combat TB by PDPs New Vaccines Aeras Global TB Vaccine Foundation is working to develop a new, more effective TB vaccine – the first new vaccine in over 80 years

16. AERAS GLOBAL TB VACCINE FOUNDATION Developing a New TB Vaccine Goals of the Aeras Global TB Vaccine Foundation: - To obtain regulatory approval and ensure supply of a new TB vaccine regimen within 7-10 years - To introduce 2 nd generation vaccines with improved product profiles and efficacy against latent TB in 9-15 years

17. AERAS GLOBAL TB VACCINE FOUNDATION

18. By Calmette and Guérin, 1906-1921 Invention of BCG Vaccine

19. AERAS GLOBAL TB VACCINE FOUNDATION No New TB Vaccine in 85 Years BCG developed in 1921

20. AERAS GLOBAL TB VACCINE FOUNDATION Developing a New TB Vaccine BCG is the most widely used vaccine in the world - and not highly effective BCH may provide ~70% protection against severe TB in young children, so it will continue to be used until something better is available BCG provides little protection against childhood pulmonary TB and it is questionable if any protection later in life when it is given to infants

21. AERAS GLOBAL TB VACCINE FOUNDATION British School Children Variable Efficacy of BCG vs. Pulmonary TB British School Children S. India (Madanapalle) USA (Georgia & Alabama) S. India (Chingleput) USA (Georgia Children) USA (Chicago Infants) Puerto Rico (Gen. Pop.) N. American Indians Brazil (Sao Paolo) Argentina (Buenos Aires) Brazil (Belo Horizonte) Cameroon (Yaounde) Canada (Manitoba Indians) Surinam (Rangoon) Sri Lanka (Colombo) Colombia (Cali) Argentina (Santa Fe) Togo (Lome) Thailand Indonesia (Jakarta) Vaccine Efficacy (%) -900 -500 -300 -100 0 20 40 60 70 80 90 Population

22. AERAS GLOBAL TB VACCINE FOUNDATION Developing a New TB Vaccine Vaccines with a 50 – 90% efficacy rate could eliminate about 1/3 of TB disease and death Effective vaccines in combination with better diagnostics and antibiotics could: achieve global control of TB eliminate TB by 2050 (<1 case/million) A 75% effective vaccine is estimated to save $25 billion in medical costs worldwide

23. AERAS GLOBAL TB VACCINE FOUNDATION Advantages of BCG as basis for a new, improved TB vaccine BCG can be given at birth Can be administered orally >3 billion doses administered <0.2/10 6 serious complications Persists innocuously in vivo

24. AERAS GLOBAL TB VACCINE FOUNDATION Approach to a New TB Vaccine Improve BCG – make a recombinant rBCG Give booster vaccinations in infants Give booster vaccinations in adolescents who have received BCG at birth

25. AERAS GLOBAL TB VACCINE FOUNDATION Prime Boost Strategy for Infants 14 Weeks 24 Weeks

26. AERAS GLOBAL TB VACCINE FOUNDATION Booster Strategy for Adolescents

27. AERAS GLOBAL TB VACCINE FOUNDATION Aeras’ TB Vaccine Candidates Under Development VaccineSourceStageDescription rBCG30UCLA/AerasPhase I Recombinant BCG genetically modified to over express antigen 85B AERAS 403Aeras Pre-Clinical Phase I Q2-07 Recombinant BCG which over expresses antigens 85A, 85B and 10.4, rvwith endosome escape M72Aeras/GSKPhase I Fusion molecule comprised of a protein from the PPE family (Rv1196), combined with an inactive serine protease Rv0125 to boost BCG AERAS 402Crucell/Aeras Pre-clinical Phase I Q3-06) Replication deficient adenovirus35 which expresses antigens 85A, 85B, and 10.4 to boost rBCG HyVac 4 (AERAS 404) SSI/Intercell Aeras Pre-clinical Phase I Q2 -07 Recombinant Mtb antigens 85B and 10.4 combined with adjuvant IC31 to boost BCG AERAS X05Aeras Pre-clinical PhI Q2-07 Mtb antigens delivered by RNA capsid system to boost rBCG

28. AERAS GLOBAL TB VACCINE FOUNDATION Proving New TB Vaccines Work Animal Challenge Models Human immune responses Clinical Trials

29. AERAS GLOBAL TB VACCINE FOUNDATION rBCG better then BCG in Guinea pig Protection Guinea pigs Vaccinated with Sham, BCG or rBCG30 Challenged with Live aerosolized TB White arrows point to Granulomas seen at sacrifice

30. AERAS GLOBAL TB VACCINE FOUNDATION CD 4 T cell CD 8 T cell TH1 TH2 TH1 TH2 IFN-γ IL-2 TNF-α IL-4 B - cell antibodies DTP, Hib, Pneumococcus, Measles, Polio, Hep B, Rotavirus, HPV, Malaria Humoral & Cellular Immunity TB, Malaria, HIV Will CD4’s be Enough ? Do we need a balance of CD4 & CD8? What cytokine profile to we need?

31. AERAS GLOBAL TB VACCINE FOUNDATION 2011 201220132014 Phase III Infants Phase III Adolescents 2006 200720082009 2010 License, Launch & Distribute Timeline Aeras 403 prime Aeras 402 boost Phase I Is it safe in 20- 40 subjects in each age group... Phase II Does it induce an immune response? Is it safe in 200- 600 subjects: infants & adolescents ?... Does it induce an immune response & show some protection? (Confidence for Ph III) Is it safe in 6000- 9000 infants & 10000-15000 Adol ? Does it protect against TB at a licensure standard ? Can you consistently manufacture it? Will it be used ?

32. AERAS GLOBAL TB VACCINE FOUNDATION Global Plan 2006-2015 Resource Needs $31 billion gap $1 billion gap for vaccines $187 M for scale up and manufacture $341 M for clinical trials In $US billions Total needs by activities Global Plan to Stop TB 2006-2015, p. 59

33. AERAS GLOBAL TB VACCINE FOUNDATION Resources Needed Additional funding to support research, planning and product development for new tools More research and clinical trials to demonstrate whether new tools are effective and appropriate

34. AERAS GLOBAL TB VACCINE FOUNDATION Resources Needed Policies to guarantee that people in developing countries can afford the tools and regulatory processes to ensure quality Successful partnerships among private corporations, the global health community, and governments of affected nations

35. AERAS GLOBAL TB VACCINE FOUNDATION Summary TB and HIV/AIDS are terrible pandemics in and of themselves – together they are deadly Vaccines that are safe and effective used with new diagnostics and drugs are the only way to control HIV and TB Without vaccines HIV and TB will not be controlled A TB vaccine would prevent undue suffering and death among those at high risk, and would save billions of dollars in health costs.