Washington Global Health Alliance Discovery Series Peter Hotez, MD, PhD June 9, 2008 'Innovation for the Control of Neglected Tropical Diseases'

1. Peter Hotez MD PhD Walter G. Ross Professor and Chair, Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University President, Sabin Vaccine Institute Director Human Hookworm Vaccine Initaitive Innovation in the Control of Neglected Tropical Diseases University of Washington Global Health HHVI Human Hookworm Vaccine Initiative

2. 1. Eradicate extreme poverty and hunger. 2. Achieve universal primary education. 3. Promote gender equality and empower women. 4. Reduce child mortality. 5. Improve maternal health. 6. Combat HIV/AIDS, malaria and other diseases. 7. Ensure environmental sustainability. 8. Develop a global partnership for development. Millennium Development Goals

3. The New Global Health Celebrities Global Fund $4.6 billion over 2 years PMI Expected to reach $135 million for 2007 PEPFAR $15 billion over 5 years (2003-2008)

4. AIDS TB Malaria Apparently there are only three diseases on that planet !

5. 1. Eradicate extreme poverty and hunger. 2. Achieve universal primary education. 3. Promote gender equality and empower women. 4. Reduce child mortality. 5. Improve maternal health. 6. Combat HIV/AIDS, malaria and other diseases . 7. Ensure environmental sustainability. 8. Develop a global partnership for development. Millennium Development Goals

8. NTDs are Chronic and Disfiguring Buruli Ulcer Leishmaniasis Leprosy (Hansen’s Disease) Property of the Global Network

9. Disabling “ It’s quite a problem for me when I have to stand at work for long periods.”

10. Impairment of child growth and development Hookworm leads to 40% reduction in future wage earnings Age (months) 0 3 6 9 12 15 18 21 24 27 17 16 15 14 13 9 12 11 10 8 7 6 5 4 3 2 PERCENTILES Treatment for 2 days Weight (kg) Property of the Global Network Children have the highest worm burdens

11. … and Stigmatizing “ People make fun of me. “

12. Global Burden of NTDs DALYs 91.4 million 84.5 million 67.3 million 62.0 million 58.6 million 56.6 million 49.2 million 46.5 million 34.7 million 38.7 million Per DALY Funding DISEASE Lower Respiratory Infections HIV/AIDS Unipolar Depression Diarrheal Disease Ischemic Heart Disease Neglected Tropical Diseases Cerebrovascular Diseases Malaria Road Traffic Accidents Tuberculosis $0.62

14. Malaria and the NTDs The “Perfect Storm” of Anemia Increased Susceptibility Geographic Overlap “ The Perfect Storm” of Anemia Brooker et al. Malaria Journal 2006; Hotez et al. PLoS Medicine 2006

16. Version 1.0 The Beginning of NTD Control

17. NTD Elimination Lymphatic filariasis – South Pacific Lymphatic filariasis - Zanzibar Trachoma - Morocco Schistosomiasis - Egypt

19. Current Pharmaceutical Commitments Pfizer – Azithromycin Donation 120 million doses provided since 1999 Pfizer – Azithromycin Donation 120 million doses provided since 1999 Over 600 million treatments provided since 1998 GlaxoSmithKline – Albendazole Donation Over 600 million treatments provided since 1998 GlaxoSmithKline – Albendazole Donation 50 million tablets in 2007 Johnson & Johnson – Mebendazole Donation 50 million tablets in 2007 Johnson & Johnson – Mebendazole Donation Over 539 million treatments provided since 1988 Merck & Co., Inc – Mectizan Donation Program Over 539 million treatments provided since 1988 Merck & Co., Inc – Mectizan Donation Program 200 million tablets 2008-2017. Merck KGaA – Praziquantel Donation

20. MDA Coverage 2005-07

21. Ascariasis Trichuriasis Hookworm Schistosomiasis Lymphatic Filariasis Onchocerciasis Trachoma

22. Version 2.0 Global Distribution of NTDs

24. Rapid Impact Package = Cost Effective Only $0.50 per person per year!

26. The U.S. – U.K. Partners of The Global Network for Neglected Tropical Diseases (GNNTDC)

31. Estimated gaps by medicine 2008-2012 Total funding gap for medicines = US$ 222 million 1,842 million tablets in US$ 147 million 95% 51% 3,805 million tablets in US$ 64 million 2,686 million tablets in US$ 11 million 37% 49% 63% 100% 5%

33. Drug Failure: Mebendazole for Hookworm

35. The Global Distribution of Human Hookworm Infection Necator americanus is the predominant species 576 million cases (25% of the poor); 50 million in LAC 22 million DALYs Wherever Rural Poverty and Adequate Climate Overlap

37. Pediatric Hookworm Disease Pallor and Anasarca Iron deficiency anemia Protein malnutrition Growth stunting Intellectual retardation Impairment in memory/cognition Reduction in school attendance Reduction in school performance 43% Reduction in future wage earning Impact on health, education and economic development

38. Anti-L3 Vaccines X-irradiated Larvae Anti-adult Blood-feeding Vaccines L3 Adult

39. Xir-L3 VACCINES OPERATE BY INHIBITING L3 TISSUE INVASION Reduction in Worm Burden + Egg Counts Inhibition of L3 penetration in vitro

40. ANTI-L3 ANTIBODIES INHIBITION OF L3 TISSUE PENETRATION (Somatic Migration ) REDUCED NUMBER OF ADULT HOOKWORMS REDUCTION IN HOST INTESTINAL BLOOD LOSS REDUCTION IN FECAL EGG COUNTS REDUCTION IN MALNUTRITION AND ANEMIA L3 Hookworm Vaccine: Proposed Mechanism

41. Ac -16 L3 Surface Protein: SAA-2 (“ Ac -16”) 65% Inhibition of L3 Invasion

43. 0 10 20 30 40 50 60 70 80 90 a-irL3 a-ASP-2 Control GROUP % reduction in L3 penetration ANTI ASP-2 ALSO INHIBITS L3 THROUGH TISSUE N = 5 9 12 Bethony et al. FASEB J 2005; 19: 1743-5 Goud et al. Vaccine 2005; 23: 4754-64

44. APR-1 (Blood-feeding Aspartic Protease) Anti-APR-1 Antibodies in Hookworm Gut Anti-APR-1 antibodies reduce host blood loss Reduce fecal egg counts Loukas et al. PLoS Medicine 2005; 2: e295

45. Fraunhofer USA CMB Rapid Expression of Green Fluorescent Protein and LicKM in Nicotiana benthamiana 24 hrs after infiltration 48 hrs after infiltration Green fluorescence is indicative of GFP expression LicKM 800mg/kg 1 2 3

48. Antigen Discovery Research & Development Process Development / Quality Control cGMP Manufacture Product Development Strategy Developing Recombinant Vaccines: The Process Phase 1 Clinical Trials Technology Transfer to cGMP Facility

49. Sabin-Brazil Technology Transfer D C V M N

51. A Multivalent Vaccine for Hookworm and Schistosomiasis?

52. TSP-2 discovered through genomic/proteomics approaches: Antibodies to TSP-2 bound outer tegument of adult S. mansoni X63 X252 Recent proteomics studies identified TSP-2 as an abundant tegument protein Braschi et al 2006 (biotinylation of worm surface) Van Balkon et al 2005  -thioredoxin  -thioredoxin teg nuc  -TSP-1  -TSP-2  -TSP-2 teg tub teg nuc tub teg teg nuc nuc a b c d e f membrane 1 2 3 4 C G C C C C G/A G/A E/Q E/Q G/A K G/A F/Y G C E/Q P W/F/Y EC-1 EC-2

53. Putative Resistant Low (1-99 epg) Medium (100-399 epg) Heavy (400+ epg) Patient Group anti-TSP-2 IgG1 IgG from putatively resistant individuals selectively recognises TSP-2 0.000 0.500 1.000 1.500 2.000 2.500 OD (492 nm) Patient Group 0.00 0.25 0.50 0.75 1.00 1.25 1.50 OD (492 nm) Putative Resistant Low (1-99 epg) Medium (100-399 epg) Heavy (400+ epg) anti-TSP-2 IgG3

55. Neglected Infections of Poverty in the U.S. Chagas Disease 3,000-1,000,000 (Hispanics) Congenital CMV 27,000 (50 X risk AfrAmer) Cong Toxoplasmosis 4,000 (Hispanics/Afr Amer) Trichomoniasis 884,000 (10 X risk AfrAmer) Cysticercosis 41,000-169,000 (Hispanics) Toxocariasis 1.3-2.8 million (>20% AfrAmer) Hotez PLoS NTDs 2008