WGHA Discovery Series: Peter Hotez

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Washington Global Health Alliance Discovery Series

Peter Hotez, MD, PhD
June 9, 2008
'Innovation for the Control of Neglected Tropical Diseases'

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WGHA Discovery Series: Peter Hotez

  1. 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. 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. 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. 4. AIDS TB Malaria Apparently there are only three diseases on that planet !
  5. 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
  6. 6. The Neglected Tropical Diseases Core Group <ul><li>Protozoan Infections </li></ul><ul><ul><li>Human African Trypanosomiasis </li></ul></ul><ul><ul><li>Chagas Disease </li></ul></ul><ul><ul><li>Leishmaniasis </li></ul></ul><ul><li>Bacterial & Viral Infections </li></ul><ul><ul><li>Buruli Ulcer </li></ul></ul><ul><ul><li>Dengue </li></ul></ul><ul><ul><li>Leprosy </li></ul></ul><ul><ul><li>Trachoma </li></ul></ul><ul><li>Helminth Infections </li></ul><ul><ul><li>Ascariasis </li></ul></ul><ul><ul><li>Hookworm infection </li></ul></ul><ul><ul><li>Trichuriasis </li></ul></ul><ul><ul><li>Schistsosomiasis </li></ul></ul><ul><ul><li>Lymphatic Filariasis </li></ul></ul><ul><ul><li>Onchocerciasis </li></ul></ul><ul><ul><li>Dracunculiasis </li></ul></ul>
  7. 7. Neglected Tropical Diseases (NTDs) <ul><li>Most prevalent infections of poor people </li></ul><ul><li>Over ONE BILLION people infected worldwide </li></ul><ul><li>Ascariasis 807 million </li></ul><ul><li>Trichuriasis 604 million </li></ul><ul><li>Hookworm 576 million </li></ul><ul><li>Schistosomiasis 207 million </li></ul><ul><li>Lymphatic Filariasis 120 million </li></ul><ul><li>Trachoma 84 million </li></ul><ul><li>Onchocerciasis 37 million </li></ul>Hotez PJ et al. N. Engl. J. Med. 2007; 357: 1018-27
  8. 8. NTDs are Chronic and Disfiguring Buruli Ulcer Leishmaniasis Leprosy (Hansen’s Disease) Property of the Global Network
  9. 9. Disabling “ It’s quite a problem for me when I have to stand at work for long periods.”
  10. 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. 11. … and Stigmatizing “ People make fun of me. “
  12. 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
  13. 13. NTDs and Poverty <ul><li>Impairment of intellectual and physical development in children </li></ul><ul><li>Adverse pregnancy outcome </li></ul><ul><li>Reduced productive capacity/worker productivity </li></ul>NTD’s PROMOTE POVERTY Property of the Global Network
  14. 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
  15. 15. <ul><li>VERSION 1.0 1970s </li></ul><ul><li>VERSION 2.0 2005 </li></ul><ul><li>VERSION 3.0 VISION FOR THE FUTURE </li></ul>Opportunities for NTD Control
  16. 16. Version 1.0 The Beginning of NTD Control
  17. 17. NTD Elimination Lymphatic filariasis – South Pacific Lymphatic filariasis - Zanzibar Trachoma - Morocco Schistosomiasis - Egypt
  18. 18. Version 1.0 World Health Assembly Resolution 54.19 <ul><li>Goal of attaining a minimum target of regular administration of chemotherapy to at least 75% and up to to 100% of all school-age children at risk of morbidity by 2010 </li></ul>Benzimidazoles Mebendazole Albendazole Praziquantel
  19. 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. 20. MDA Coverage 2005-07
  21. 21. Ascariasis Trichuriasis Hookworm Schistosomiasis Lymphatic Filariasis Onchocerciasis Trachoma
  22. 22. Version 2.0 Global Distribution of NTDs
  23. 23. Version 2: the Rapid Impact Package <ul><li>The Rapid </li></ul><ul><li>Impact </li></ul><ul><li>Package </li></ul><ul><ul><li>Albendazole (GSK) or Mebendazole (J&J) </li></ul></ul><ul><ul><li>Diethylcarbamazine or Ivermectin (Merck) </li></ul></ul><ul><ul><li>Praziquantel </li></ul></ul><ul><ul><li>Azithromycin (Pfizer) </li></ul></ul>BIG SEVEN NTDs Ascariasis Trichuriasis Hookworm Lymphatic Filariasis Onchocerciasis Schistosomiasis Trachoma <ul><li>Bonuses: </li></ul><ul><li>Strongyloidiasis </li></ul><ul><li>Trematodiases </li></ul><ul><li>Taeniasis </li></ul><ul><li>Scabies </li></ul>US $0.50 all inclusive DRUGS + delivery +equipment +health education materials +Training of personnel +Monitoring and Evaluation US $0.50 per person per year
  24. 24. Rapid Impact Package = Cost Effective Only $0.50 per person per year!
  25. 25. The Global Network <ul><li>Alliance of the major NTD partners </li></ul><ul><li>Treated 34 million people in 2007 </li></ul><ul><li>NTD Advocacy </li></ul><ul><li>Fills the funding gap </li></ul>
  26. 26. The U.S. – U.K. Partners of The Global Network for Neglected Tropical Diseases (GNNTDC)
  27. 27. The Buzz on NTDs <ul><li>“ The world is now paying attention to these [neglected] diseases and making progress in unprecedented ways, with ambitious goals, excellent interventions, and growing evidence of multiple benefits for health. The attention to long-neglected diseases is a positive sign that health is a responsibility shared by the international community.” </li></ul><ul><ul><li>Dr. Margaret Chan, Director-General of the WHO </li></ul></ul>“ Comprehensive, Africa-wide control of malaria and NTDs together would probably cost no more than $3 billion a year , or just two days of Pentagon spending . If each of the billion people in the rich world devoted the equivalent of one $3 coffee a year to the cause, several million children every year would be spared of death and debility, and world would be spared the grave risks when disease and despair run unchecked. A new Global Network for Neglected Tropical Disease Control is helping make this opportunity a reality .” - Jeffrey Sachs, Director of the Earth Institute, Scientific American January 2007 “ It quickly became clear that this story is not just about the staggering numbers of the world’s citizens overwhelmed by HIV, AIDS, TB, and malaria. And it’s not just the story about one billion people who are afflicted with disabling, oftentimes stigmatizing, neglected tropical diseases , such as human hookworm infection and elephantiasis… it’s all about the faces of dying children and sick mothers who haunt those who have seen them...What struck me, and what I think struck us all…that these challenges are all interconnected .” - Clinton Global Initiative, Closing Remarks The Brownback-Brown amendment provides a significant financial incentive for pharmaceutical companies to produce neglected tropical disease treatments by awarding them with a FDA priority review voucher for bringing to market such products. “ It is unacceptable that neglected diseases like leprosy, hookworm, and river blindness cause over 500,000 deaths annually. A total of 13 such diseases afflict the poor in Africa, Asia, and the Americas, and I am hopeful that this amendment will work toward reducing deaths and suffering from these diseases .&quot; -Senator Sam Brownback, May 2007
  28. 28. New Lead Ambassador: Alyssa Milano <ul><li>Made a personal donation of $250,000 to the NTD drug fund </li></ul><ul><li>Will stand as a spokesperson for NTD advocacy </li></ul><ul><li>“ Stop NTD” online campaign </li></ul>“ Words cannot fully express the devastation and horror caused by NTDs. Until now these diseases have been hidden in the shadows, but working with the GLOBAL NETWORK, I am focused on bringing this tragedy into the public eye” - Alyssa Milano, May 2007
  29. 30. <ul><li>White House announced $350 million </li></ul><ul><li>Leveraging into $1 billion fund at the G8 agenda </li></ul><ul><li>Structure of the fund </li></ul><ul><ul><li>WHO </li></ul></ul><ul><ul><li>Global Network </li></ul></ul><ul><ul><li>Carter Center </li></ul></ul><ul><ul><li>The Global Fund to Fight ATM </li></ul></ul><ul><ul><li>Gates Foundation </li></ul></ul><ul><ul><li>World Bank </li></ul></ul><ul><li>Harmonizing donation and distribution programs for maximum efficiency </li></ul><ul><li>Does Pharma have capacity </li></ul><ul><li>What about the other $1.5 billion </li></ul>A Global Fund for NTDs
  30. 31. Estimated gaps by medicine 2008-2012 Total funding gap for medicines = US$ 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%
  31. 32. Version 2.1: Linking NTD Control with Malaria and HIV Control “Roll back anemia” “Tropical disease no more” <ul><li>Geographic overlap and increased susceptibility </li></ul><ul><li>IPTi/IPTc and Rapid Impact Package </li></ul><ul><li>IPTp and Rapid Impact Package </li></ul><ul><li>LLITN and Onchocerciasis/LF </li></ul><ul><li>ART and Rapid Impact Package </li></ul><ul><li>Malaria and HIV Vaccines and Rapid Impact Package </li></ul><ul><ul><li>Vaccines do not work with hookworms and schistosomes </li></ul></ul>
  32. 33. Drug Failure: Mebendazole for Hookworm
  33. 34. NEW TOOLS FOR DISEASE CONTROL THE ANTIPOVERTY VACCINES <ul><li>Low efficacy of Mebendazole </li></ul><ul><li>Re-infection within 4-12 mos </li></ul><ul><li>Diminishing efficacy </li></ul>Hookworm Re-Infection Product Development Partnership Sabin Vaccine Institute George Washington University FIOCRUZ Instituto Butantan London School Hyg. Trop. Med. Queensland Inst. Med. Res HHVI Human Hookworm Vaccine Initiative
  34. 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
  35. 36. Adult worms injure their host by causing intestinal blood loss:   <ul><li>Anticoagulants: Factor Xa and Tissue Factor-VIIa Inhibitors </li></ul><ul><li>Hemolysins, and Hemoglobinases </li></ul><ul><li>Intestinal blood loss: 25 Necator worms = 1 ml blood loss </li></ul><ul><li>= 0.55 mg Fe = Child’s daily iron intake </li></ul><ul><li>Iron Deficiency Anemia and Protein Malnutrition </li></ul>Hookworm-Blood Loss
  36. 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
  37. 38. Anti-L3 Vaccines X-irradiated Larvae Anti-adult Blood-feeding Vaccines L3 Adult
  38. 39. Xir-L3 VACCINES OPERATE BY INHIBITING L3 TISSUE INVASION Reduction in Worm Burden + Egg Counts Inhibition of L3 penetration in vitro
  39. 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
  40. 41. Ac -16 L3 Surface Protein: SAA-2 (“ Ac -16”) 65% Inhibition of L3 Invasion
  41. 42. <ul><li>L3 secreted protein (21-22 kDa) </li></ul><ul><li>PRP (Pathogenesis related protein superfamily) </li></ul><ul><li>Immunodominant protein of X-ir L3 vaccines </li></ul><ul><li>Anti-ASP-2 antibodies inhibit larval invasion </li></ul><ul><li>Protective antigen in dogs ( A. caninum ) and in hamsters </li></ul><ul><li>( A. ceylanicum and N. americanus ) </li></ul><ul><li>6) Developed as a Pichia pastoris recombinant vaccine on Alhydrogel </li></ul>ASP-2 ASP - 2 ASP - 1 PR 1 PR1 PR1 MT MT MT SP SP c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c 45 kDa ASPs = Single and double PR - 1 domain Proteins 21-22 kDa Hotez et al. Immunol. Rev . 1999; Int J Parasitol 2003; PLoS Medicine 2005
  42. 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
  43. 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
  44. 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
  45. 46. Na -GST-1 Na -APR-1 fragment 5a Fuse Na- APR-1 fragment 5a to C-terminus of Na -GST-1 A multi-antigen adult fusion protein vaccine <ul><li>Na -APR-1 is an efficacious antigen but is difficult to express at high yield </li></ul><ul><li>Protection is thought to be mediated by antibodies that neutralize enzymatic function </li></ul><ul><li>neutralizing mAbs map to fragment 5a </li></ul><ul><li>fragment 5a is expressed in soluble form in E. coli as a GST-fusion protein </li></ul><ul><li>we are now fusing APR-1 fragment 5a to the C-terminus of N. americanus </li></ul><ul><li>Na- GST-1 to produce a chimeric antigen </li></ul>
  46. 47. Bivalent Strategy Adult Antigen + Larval Antigen Adult antigen L3 antigen ADCC Neutralizing antibodies <ul><li>Inhibit migration </li></ul><ul><li>Attenuate L3 </li></ul>Reduced host blood loss (Hookworm Disease) Neutralizing antibodies Inhibit Blood Feeding 1. Reduced worm burden 2. Reduced fecundity Larval Antigens Under development Na -ASP-2 Na -SAA-2 Adult antigens under development Na -APR-1 Na -GST-1
  47. 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
  48. 49. Sabin-Brazil Technology Transfer D C V M N
  49. 50. HHVI Field Site Development <ul><li>Americaninhas </li></ul><ul><li>68% Hookworm Prevalence </li></ul><ul><li>Phase 1/Phase 2 trials to take place in Minas Gerais, Brazil </li></ul>Americaninhas Minas Gerais
  50. 51. A Multivalent Vaccine for Hookworm and Schistosomiasis?
  51. 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
  52. 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
  53. 54. Future Trends in NTD Control <ul><li>The “Antipoverty Vaccines” </li></ul><ul><li>Fold them into existing structures, i.e., rapid impact package </li></ul><ul><li>Drugs + Vaccines in Integrated Framework </li></ul><ul><li>Human Vaccine-Linked Chemotherapy </li></ul><ul><li>Alternative Health Delivery Mechanisms </li></ul><ul><ul><li>School-based Health Systems and Child Health Days </li></ul></ul>
  54. 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
  55. 56. <ul><li>World’s first peer-reviewed, open-access journal devoted to the NTDs </li></ul><ul><li>Launch supported by Bill and Melinda Gates Foundation </li></ul><ul><li>Papers on pathology, epidemiology, treatment, control, prevention </li></ul><ul><li>Magazine section devoted to policy and advocacy </li></ul><ul><li>International editorial board—half of the Associate Editors are from endemic countries </li></ul><ul><li>Accepting submissions in early 2007 </li></ul>“ It is expected that the journal will be both catalytic and transformative in promoting science, policy, and advocacy for these diseases of the poor.” — Peter Hotez, Editor-in-Chief

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