HIV/AIDS & TB

Jerald C. Sadoff M.D. “Journalist to Journalist” National Press Foundation Toronto, Canada August 9th 2006

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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

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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

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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)

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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

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The Tuberculosis (TB) Pandemic
• TB is the world’s 2nd 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.

Estimated new TB cases ('000s)
1000 1500 2000 500 0
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

AERAS GLOBAL TB 80% of all new 22 high-burden countries: VACCINE FOUNDATION TB cases

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Highest TB rates per capita are in Africa

per 100 000 population
< 10 10 to 24 25 to 49 50 to 99 100 to 299 300 or more No Estimate

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

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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

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HIV/AIDS and TB: A Deadly Combination
• 12 million people worldwide are coinfected 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

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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 coinfected 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

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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

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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

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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

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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

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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 2nd generation vaccines with improved product profiles and efficacy against latent TB in 9-15 years

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Invention of BCG Vaccine

By Calmette and Guérin, 19061921

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No New TB Vaccine in 85 Years
BCG developed in 1921

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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

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Variable Efficacy of BCG vs. Pulmonary TB
Vaccine Efficacy (%)
-900 -500 -300 -100

0 20

40

60 70

80

90

Population
British School Children British School Children British School Children N. American Indians USA (Chicago Infants) Puerto Rico (Gen. Pop.) S. India (Madanapalle) USA (Georgia & Alabama) S. India (Chingleput) USA (Georgia Children) Brazil (Sao Paolo) Argentina (Buenos Aires) Brazil (Belo Horizonte) Cameroon (Yaounde) Canada (Manitoba Indians) Indonesia (Jakarta) Surinam (Rangoon) Sri Lanka (Colombo) Colombia (Cali) Argentina (Santa Fe) Togo (Lome) Thailand

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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

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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 <0.2/106 serious complications Persists innocuously in vivo

• • • • •

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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

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Prime Boost Strategy for Infants

24 Weeks 14 Weeks

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Booster Strategy for Adolescents

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Aeras’ TB Vaccine Candidates Under Development
Vaccine rBCG30 AERAS 403 Source UCLA/Aeras Aeras Stage Phase I PreClinical Phase I Q2-07 Phase I Description
Recombinant BCG genetically modified to over express antigen 85B Recombinant BCG which over expresses antigens 85A, 85B and 10.4, rvwith endosome escape

M72

Aeras/GSK

Fusion molecule comprised of a protein from the PPE family (Rv1196), combined with an inactive serine protease Rv0125 to boost BCG Replication deficient adenovirus35 which expresses antigens 85A, 85B, and 10.4 to boost rBCG Recombinant Mtb antigens 85B and 10.4 combined with adjuvant IC31 to boost BCG

AERAS 402

Crucell/Aeras Pre-clinical Phase I Q3-06) SSI/Intercell Pre-clinical Aeras Phase I Q2 -07

HyVac 4 (AERAS 404)

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Proving New TB Vaccines Work
• Animal Challenge Models • Human immune responses • Clinical Trials

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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

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Humoral & Cellular Immunity
B - cell
Will CD4’s be Enough ? Do we need a balance of CD4 & CD8?

antibodies

CD 4 T cell
TH1 TH2

CD 8 T cell
TH1 TH2 What cytokine profile to we need?

DTP, Hib, Pneumococcus, Measles, Polio, Hep B, Rotavirus, HPV, Malaria

IFN-γ TNF-α IL-2 IL-4 TB, Malaria, HIV

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Timeline Aeras 403 prime Aeras 402 boost
2006 2007 2008 2009 2010 2011 2012 2013 2014

Is it safe in 2040 subjects in each age group ...

Is it safe in 200600 subjects: infants & adolescents ? ...
Phase II

Is it safe in 60009000 infants & 10000-15000 Adol ?

Will it be used ?

Phase I
Does it induce an immune response?

Phase III Infants Phase III Adolescents

License, Launch & Distribute

Does it induce an immune response & show some protection? (Confidence for Ph III)

Does it protect against TB at a licensure standard ? Can you consistently manufacture it?

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Global Plan 2006-2015 Resource Needs
Total needs by activities
Diagnostics $0.5 Vaccines $3.6 ACSM $2.9

Drugs $4.8

DOTS-Plus $5.8

DOTS Expansion $32.0

•$31 billion gap •$1 billion gap for vaccines • $187 M for scale up and manufacture •$341 M for clinical trials

TB/HIV $6.7

In $US billions
Global Plan to Stop TB 2006-2015, p. 59

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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

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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

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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.

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