BVGH Global Health Primer

October 2007 Building Biotech Solutions for Diseases of the Developing World

BVGH Global Health Primer
October 2007 Building Biotech Solutions for Diseases of the Developing World

Contents
Message to Readers . . . . . . . . . . . . . . . . . . . . . . . . . . 5 List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . 6 Global Burden of Disease: Fact Sheet . . . . . . . . . . . 7 Disease Burden vs . Health Care Investment . . . . . 8 New Funding and Incentives . . . . . . . . . . . . . . . . . . 9 Neglected Diseases: A Call to Action . . . . . . . . . . 10 2006–2007 Global Health Milestones . . . . . . . . . . . 11 Key Global Health Players . . . . . . . . . . . . . . . . . . . . 12 Select Companies Working in Global Health . . . . 18 Biotech Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Disease Sheets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 African Trypanosomiasis . . . . . . . . . . . . . . . . . . 24 Chagas Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Cholera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Dengue Fever (DF) . . . . . . . . . . . . . . . . . . . . . . . . 32 Enterotoxigenic E. coli (ETEC) . . . . . . . . . . . . . . 35 Human Immunodeficiency Virus (HIV) . . . . . . 38 Japanese Encephalitis (JE) . . . . . . . . . . . . . . . . . 42 Leishmaniasis . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Lymphatic Filariasis (LF) . . . . . . . . . . . . . . . . . . 48 Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . 56 Shigellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Tuberculosis (TB) . . . . . . . . . . . . . . . . . . . . . . . . 62 About BVGH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Founded
2004

Supporters
Bill & Melinda Gates Foundation Biotechnology Industry Organization The Rockefeller Foundation Industry Leaders

Management
Christopher D. Earl, PhD President & CEO Wendy Taylor Founder, Vice President, Strategy & Operations Julie S. Klim Vice President, Business Development

Board of Directors
Robert B. Chess, Chairman Chairman, Nektar Therapeutics Christopher D. Earl, PhD President & CEO, BIO Ventures for Global Health Carl B. Feldbaum President Emeritus, Biotechnology Industry Organization (BIO) James C. Greenwood President, BIO Vaughn M. Kailian General Partner, MPM Capital Melinda Moree, PhD Former Director, Malaria Vaccine Initiative J. Leighton Read, MD General Partner, Alloy Ventures George Rupp, PhD President & CEO, The International Rescue Committee

MeSSaGe tO ReaDeRS

Dear Reader: As our knowledge expands, our world becomes smaller. We are increasingly aware of the challenges faced by the world’s poorest citizens. Each year infectious diseases—many of them potentially preventable or treatable—ravage families throughout the developing world. Some lose their ability to work, many lose their loved ones, and others lose their lives. We are in a unique position to help by introducing new medical products to prevent, diagnose, and treat infectious diseases. These challenges can be overcome and are our communal responsibility. By working together, major strides are being made in producing innovative health care interventions. However, to ensure that the next generation of products enters the development pipeline, it is essential that we commit an unprecedented investment in new product discovery. Otherwise we may never see the day when poor families, particularly children, can escape the effects of disease. We have created this primer to serve as a reference tool for those interested in understanding the major challenges and opportunities in global health. It summarizes the infectious diseases that cause the greatest burden of disease, outlines the technologies currently available, and points out gaps in our armamentarium. It also describes the existing pipelines of emerging medicines and highlights areas where innovation is required. Finally, it identifies many of the major players in global health, including international non-governmental organizations, governments, academia and industry, who are working together to accelerate global health research and development. The information contained in this document was compiled from various sources including, but not limited to, the World Health Organization, the Centers for Disease Control and Prevention, product development partnerships, and biopharmaceutical companies. We have highlighted additional references throughout the document where you can obtain further information. BIO Ventures for Global Health fosters collaboration among groups and individuals working to ensure that new medicines are introduced in the developing world. We are working to build incentives that will draw the best of biopharmaceutical industry resources and expertise to this fight. We hope this document will motivate many to seek innovative solutions for the devastating diseases described in the following pages. Collectively, we have the ability to create a better world for millions of people. Sincerely yours,

Christopher D. Earl, PhD President and CEO BIO Ventures for Global Health

BVGH Global Health Primer 

List of abbreviations
ACT . . . . . . . . . . . . . . . . . . . Aeras . . . . . . . . . . . . . . . . . . AMC. . . . . . . . . . . . . . . . . . . BCG . . . . . . . . . . . . . . . . . . . BIO . . . . . . . . . . . . . . . . . . . BVGH . . . . . . . . . . . . . . . . . . CDC . . . . . . . . . . . . . . . . . . . CPDD . . . . . . . . . . . . . . . . . . DALY . . . . . . . . . . . . . . . . . . DFID . . . . . . . . . . . . . . . . . . DNDi . . . . . . . . . . . . . . . . . . EMEA . . . . . . . . . . . . . . . . . . EPI . . . . . . . . . . . . . . . . . . . . ETEC . . . . . . . . . . . . . . . . . . FIND . . . . . . . . . . . . . . . . . . FDA . . . . . . . . . . . . . . . . . . . FNIH . . . . . . . . . . . . . . . . . . GAVI Alliance . . . . . . . . . . . Global Fund . . . . . . . . . . . . . IAVI . . . . . . . . . . . . . . . . . . . ICDDR,B . . . . . . . . . . . . . . . IDRI . . . . . . . . . . . . . . . . . . . IFFIm . . . . . . . . . . . . . . . . . . IOWH . . . . . . . . . . . . . . . . . IPM . . . . . . . . . . . . . . . . . . . IVI . . . . . . . . . . . . . . . . . . . . MDR-TB . . . . . . . . . . . . . . . . MMV . . . . . . . . . . . . . . . . . . MVI . . . . . . . . . . . . . . . . . . . NGO . . . . . . . . . . . . . . . . . . NIAID . . . . . . . . . . . . . . . . . NIH . . . . . . . . . . . . . . . . . . . OECD . . . . . . . . . . . . . . . . . PAHO. . . . . . . . . . . . . . . . . . PATH . . . . . . . . . . . . . . . . . . PDP . . . . . . . . . . . . . . . . . . . PEPFAR . . . . . . . . . . . . . . . . PMI . . . . . . . . . . . . . . . . . . . R&D. . . . . . . . . . . . . . . . . . . SBRI . . . . . . . . . . . . . . . . . . . TB Alliance . . . . . . . . . . . . . . TDR . . . . . . . . . . . . . . . . . . . UNDP . . . . . . . . . . . . . . . . . UNICEF . . . . . . . . . . . . . . . . USAID . . . . . . . . . . . . . . . . . WHO . . . . . . . . . . . . . . . . . . XDR-TB . . . . . . . . . . . . . . . . artemisinin-based combination therapy Aeras Global TB Vaccine Foundation Advance Market Commitment Bacille Calmette-Guerin tuberculosis vaccine Biotechnology Industry Organization BIO Ventures for Global Health Centers for Disease Control and Prevention (United States) Consortium for Parasitic Drug Development Disability Adjusted Life Year Department for International Development (United Kingdom) Drugs for Neglected Diseases Initiative European Medicines Agency Expanded Program on Immunization (WHO) enterotoxigenic Escherichia coli Foundation for Innovative Diagnostics Food and Drug Administration (United States) Foundation for the National Institutes of Health (United States) Formerly Global Alliance for Vaccines and Immunisation The Global Fund to Fight AIDS, TB and Malaria International AIDS Vaccine Initiative International Center for Diarrheal Disease Research, Bangladesh Infectious Disease Research Institute International Financing Facility for Immunization Institute for OneWorld Health International Partnership for Microbicides International Vaccine Institute multidrug-resistant tuberculosis Medicines for Malaria Venture Malaria Vaccine Initiative non-governmental organization National Institute for Allergy and Infectious Diseases (United States) National Institutes of Health (United States) Organisation for Economic Co-operation and Development Pan American Health Organization Formerly Program for Appropriate Technology in Health product development partnership President’s Emergency Plan for AIDS Relief (United States) President’s Malaria Initiative (United States) research and development Seattle Biomedical Research Institute Global Alliance for TB Drug Development Special Programme for Research and Training in Tropical Diseases United Nations Development Program United Nations Children’s Fund United States Agency for International Development World Health Organization extensively drug-resistant tuberculosis 

BVGH Global Health Primer

Global Burden of Disease: Fact Sheet
Devastating infectious diseases cause widespread death with millions more at risk
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More than 10 million children under age five die yearly from preventable or treatable diseases. Respiratory infections and diarrheal diseases together kill as many people as AIDS, tuberculosis, and malaria combined. Serious pneumococcal diseases are the number one vaccine-preventable cause of death in children under age five. The WHO estimates that pneumococcal diseases claim the lives of up to one million children under five each year. Between two million and three million children in the developing world die each year from acute diarrheal illnesses (ADI) including rotavirus, enterotoxigenic E. coli (ETEC) and shigella. Some 60 percent of the deaths from diarrhea occur in 10 developing countries. Nearly 40 million people (including 2.3 million children) are currently living with HIV/AIDS—63 percent of whom live in Africa. In 2006, there were an estimated 4.3 million new infections worldwide.

The WHO has found multidrug-resistant strains of TB (MDR-TB) in every country worldwide. MDR-TB is resistant to at least isoniazid and rifampicin, the two principal first-line drugs. Seventy-nine percent of MDR-TB cases detected now show resistance to three or more drugs. Extensively drug-resistant TB (XDR-TB), which is resistant to two first-line drugs and at least one secondline drug, has gained attention as it spreads rapidly through HIV-positive populations in South Africa. More than 2.4 billion people (40 percent of the global population) in over 100 countries are at risk for malaria. There are between 300 million and 500 million cases of acute malaria each year. Between 75 percent and 90 percent of those affected are in sub-Saharan Africa. Climate change could result in the expansion of this disease range. In malaria-endemic countries, infections account for between 30 percent and 50 percent of all inpatient admissions and up to 50 percent of outpatient clinic visits.

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Leading Causes of Mortality and Disease Burden from Infectious Diseases (2002)
Deaths (millions) Respiratory Infections Diarrheal Diseases HIV/AIDS Tuberculosis Malaria
Source: WHO Death & DALY Estimates Report for 2002

DALYs* (millions) 94.60 61.97 84.46 34.74 46.49

3.96 1.80 2.78 1.57 1.27

* DALYs – Disability adjusted life years: The sum of the years of life lost due to premature mortality and disability. 

BVGH Global Health Primer

Chronic infections slow the economic development of afflicted countries
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Disease Burden vs. Health Care Investment
Limited developing world health care expenditures highlight global inequities
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Chronic infections debilitate working adults and place undue burdens on countries. Studies show that chronic lymphatic filariasis patients lost one out of five of their productive working days each year. One-third of South Africa’s workforce is HIV-positive. Repeated bouts of childhood diarrheal infections are associated with malnutrition and growth stunting in children. Young children may suffer bouts of severe diarrhea 10 times a year, delaying and diminishing mental development.

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The burden of disease in developing countries outstrips budgets for health care. Despite a pressing global burden, R&D spending on neglected diseases is far less than for Western diseases with similar mortality and morbidity profiles.

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Percentage distribution of population, DALYs and total health expenditure by WHO region and OECD membership (2004)
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Disease Burden of Chronic Infectious Diseases (2002)
Annual DALYs (millions) Lymphatic filariasis (elephantiasis, hydrocoele) Leishmaniasis Schistosomiasis Human African trypanosomiasis (African sleeping sickness) Chagas disease Onchocerciasis (river blindness) 5.8 Global Prevalence (millions) 120 Population at Risk (millions) 1300 % of world total

80 60 40 20

Population as % of world Number of DALYs as % of world Total health expenditure as % of world

2.1 1.7 1.5

12 207 0.3

350 779 60 0 AFR AMR EMR EUR SEAR WRP OECD

0.7 0.5

8–9 37

25 90

AFR, African; AMR, Americas; EMR, Eastern Mediterranean; EUR, European; SEAR, South-East Asia; WPR, Western Pacific. Note: Totals for the following regions calculated after subtracting the 30 OECD members: Americas, European and Western Pacific. DALYs are from 2002. Source: WHO National Health Accounts, 2007

Sources: WHO World Health Report, 2004 and Hotez, PJ, et al. Control of neglected tropical diseases. NEJM 357:10 (2007)

R&D Spending per DALY (2002)
200 180 160 140 (In US Dollars) 120 100 80 60 40 20 0 $24 $11 $6 $102 $93 $63 $191

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r S gue ula /AID asc Den HIV iov ard C

TB

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Source: Lewison, G, et al. Outputs and expenditures on health research in eight disease areas, 1996-2001. Global Forum for Health Research Forum 8, Mexico City, November 2004 

BVGH Global Health Primer

New Funding and Incentives
Led by the Bill & Melinda Gates Foundation and the major industrialized countries, funding has grown rapidly for health care delivery and R&D
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Major donors are investing in “pull” incentives to attract industry investment Priority Review Voucher n The FDA Amendments Act, enacted in the United States in September 2007, creates a transferable priority review voucher for companies that obtain approval for drugs or vaccines for neglected tropical diseases.
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The Gates Foundation has made major commitments to purchase new medicines and to fund R&D for HIV/AIDS, tuberculosis, and malaria, as well as other neglected diseases. Sustained and growing purchases of vaccines and drugs by the Global Fund, PEPFAR, GAVI Alliance, and others provide a growing market to attract biopharmaceutical investment. Malaria prevention and treatment has been brought to the forefront in recent years by organizations such as PMI, the World Bank’s Malaria Program, and the Global Fund. Combined, these groups have committed over $4 billion to the fight against malaria since 2005.
Funds Available (in US $billions) $1.5 per year, with $900 million for global health $1.6 per year by 2009 $1.7 since inception $4.0 over 10 years through 2015 $15.0 from 2003-2008 $30.0 from 2008-2013 $7.7 spent to date $1.2 over 5 years

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The voucher, which is transferable and can be sold, entitles the bearer to a priority review for another drug or biologic product. When the FDA grants priority review, the agency agrees to review and act on an application within six months of receipt; standard approval times can be 12 months or longer. Hastening approval by six months or more could be worth several hundred million dollars to a sponsor— potentially sufficient incentive to move forward with an independent R&D program for neglected diseases.

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Funding Source The Bill & Melinda Gates Foundation Warren Buffett’s contribution to the Gates Foundation Global Alliance for Vaccines and Immunization (GAVI Alliance) International Financing Facility for Immunization (IFFIm) President’s Emergency Plan for AIDS Relief (PEPFAR) Global Fund for AIDS, TB & Malaria (Global Fund) President’s Malaria Initiative (PMI)

Advance Market Commitments (AMCs) n An AMC is an innovative financing mechanism in which major donors guarantee a market as incentive for industry to supply the developing world’s demand for vaccines targeting neglected diseases.
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A pilot $1.5 billion AMC program for pneumococcal vaccines was launched in February 2007 funded by Italy, the United Kingdom, Canada, Russia, Norway, and the Gates Foundation. The AMC will supplement the vaccine market in target countries by subsidizing the purchase of vaccines at an agreed-upon price that makes them affordable to the world’s poorest countries. When the $1.5 billion AMC is exhausted, all companies that have benefited from the enhanced market must provide the vaccine at a reduced price to low-income countries to ensure that the vaccines remain accessible.

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Important Papers n BIO Ventures for Global Health. Advance Market Commitments to Stimulate Industry Investment in Global Health Product Development (2006) ~ http://bvgh.org/documents/BVGH_AMCReport_Complete_000.pdf n Center for Global Development. Making Markets for Vaccines–Ideas to Action (2005) ~ www.cgdev.org/section/initiatives/_active/vaccinedevelopment n Ridley, DB, et al. Developing Drugs for Developing Countries. Health Affairs 25:313-324 (2006) n Tremonti, G. Ministero dell’Economia e delle Finanze. Advanced Market Commitments for vaccines–A new tool in the fight against disease and poverty. Report to the G8 Finance Ministers (2005)
BVGH Global Health Primer 

Neglected Diseases: a Call to action
New health care products have begun to address the burden of neglected diseases
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Rotavirus vaccines licensed in the past two years from both AVANT Immunotherapeutics/GlaxoSmithKline (GSK) and Merck have the potential to save 1,400 lives per day by preventing deadly diarrheal disease in children. More than any other cancer, cervical cancer reflects striking global health inequity. More than 80 percent of the 300,000 worldwide deaths from this devastating disease occur in developing countries. Human papillomavirus (HPV) vaccines produced by Merck and GSK, using MedImmune technology, stand to substantially reduce this burden and efforts are under way to make these vaccines affordable in the developing world. Four drugs—albendazole, ivermectin, azithromycin, and praziquantel—delivered annually at a cost of $0.50 per person, would address seven diseases afflicting one billion people: schistosomiasis, trachoma, lymphatic filariasis, onchocerciasis, hookworm, trichuriasis, and ascariasis. Miltefosine, a drug originally in development for cancer by Æterna Zentaris, has been approved for treatment of leishmaniasis in India, Colombia, and Germany. Rapid, point-of-care diagnostics for HIV have been approved, including ChemBio’s HIV Stat-Pak®, which is now being purchased for PEPFAR programs in Africa.

Researchers have sequenced, assembled, and annotated the genomes of the pathogens that cause malaria, tuberculosis, and other tropical diseases. This wealth of information, combined with molecular genetics, biochemical assays, and validated targets, offers new insights into the pathogens’ biology and provides a foundation for new drug discovery. The biotechnology industry has raised $400 billion of equity in the past 25 years. This infrastructure and expertise can be used to further neglected disease product R&D. Drug discovery platforms focused on targets such as proteases, kinases, and cell motility factors that control diseases such as cancer and cardiovascular disease can be applied to analogous targets in neglected diseases.

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Select companies investing in neglected disease R&D
AstraZeneca: Tuberculosis AVANT Immunotherapeutics and IOMAI: ETEC Genzyme: Malaria, African trypanosomiasis GlaxoSmithKline: Malaria, Tuberculosis Novartis: Malaria, Tuberculosis, Dengue Vertex Pharmaceuticals: Tuberculosis

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Organizations in developing countries are increasingly able to contribute to innovation for global health
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The biopharmaceutical industry can capitalize on scientific advances and leading-edge discovery engines to create new vaccines, drugs, and therapeutics
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Developing countries with economies emerging from poverty continue to have populations afflicted by neglected diseases, but their governments are increasingly able to purchase better health care for the poor. For example, China is the fourth-largest market for vaccines worldwide ($388 million) and is expected to grow at 15 percent or more annually. Countries with emerging economies, such as India, China, and Brazil, that also have academic and commercial capabilities in biomedical technology, are becoming attractive partners for discovery, development, and manufacturing of new global health interventions. Public and private sector innovators in global health are increasingly seeking R&D and manufacturing partners in these countries to make new global health products as affordable as possible. New incentives for investment in R&D are just as important to companies in developing countries as they are for competitors in the industrialized world.

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With over 1,400 biotech companies in the United States alone, over 200 approved products on the market, and exceptionally diverse high-tech platforms for drug discovery, the biotechnology industry has the resources, capability, and maturity to take on the challenges of global health. Leading biotech and pharmaceutical companies are already devoting resources to neglected diseases. Far more companies could participate if market, funding, and information barriers fell.
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2006–2007 Global Health Milestones
Market Incentives n In February 2007, five countries belonging to the Organisation for Economic Co-operation and Development (OECD) and the Gates Foundation launched a $1.5 billion pilot Advance Market Commitment to fund the purchase of novel vaccines against pneumococcal disease for developing countries. n In September 2007, the United States enacted the FDA Amendments Act with an amendment that creates a transferable priority review voucher for companies that obtain approval for drugs or vaccines targeting neglected diseases. Global Facilities for Delivering Medicines n Total contributions to the Global Fund in 2007 are expected to be $2.5 billion, with $750 million of that amount coming from the United States. n The GAVI Alliance will distribute $1 billion of funds raised by the International Financing Facility for Immunization (IFFIm) for vaccine purchase in 2007. n The President’s Malaria Initiative funding in 2007 was $135 million and is budgeted to rise to $300 million per year in fiscal years 2008 and 2009. Product Development Advances n In 2006, the Institute for One World Health announced that paromomycin, used to treat leishmaniasis, was approved for sale in India. n In 2007, Drugs for Neglected Diseases Initiative (DNDi) and Sanofi-Aventis launched a new drug combination, artesunate-amodiaquine (ASAQ), in Africa to treat malaria. n Also in 2007, the Medicines for Malaria Venture (MMV) initiated Phase III clinical trials for PYRAMAX®, pyronaridine-artesunate, a new artemisinin-based combination therapy (ACT) for malaria. n The TB Alliance plans to launch Phase III trials of moxifloxacin in combination in late 2007. But there have also been disappointments… n In January 2007, researchers stopped two clinical trials of the microbicide UsherCell (cellulose sulphate) when the Phase III trial showed higher, not lower rates of HIV transmission. n Sponsors of the STEP study, testing Merck’s MRK-Ad5 HIV vaccine candidate, announced in September 2007 that they have discontinued the Phase IIb trial based on an interim analysis that demonstrated the product was not efficacious. New Support for R&D n In 2006, the Gates Foundation committed $104 million over five years to the TB Alliance. The TB Alliance also received an $11 million commitment from the Irish government in the same year. n Also in 2006, The Netherlands committed €30 million to TB research with funds going to Aeras, the TB Alliance, and the Foundation for Innovative Diagnostics (FIND). n In late 2006, the Gates Foundation committed $29.3 million to a partnership between the Malaria Vaccine Initiative (MVI) and Sanaria to develop a novel, whole-parasite vaccine. n In 2007, the Gates Foundation made a new commitment of $280 million for TB R&D, including $200 million for vaccine research at Aeras and $62 million for TB diagnostics work at FIND.

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Key Global Health Players

PRODuC t De VeLOPMeNt Pa RtNeR SHIPS (PDPS)
Aeras Global TB Vaccine Foundation — Aeras
WWW.aeRaS.ORG

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Focus: Vaccines for tuberculosis n

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Leads the effort to develop a new vaccine for tuberculosis; working on both improved live attenuated vaccines and subunit vaccines; lead products entering Phase I Partnering with GlaxoSmithKline, Crucell, Intercell and Statens Serum Institute for both second-generation BCG and novel TB vaccines Working with the University of Cape Town and St. John’s Medical College, Bangalore, to develop clinical trials facilities in South Africa and southern India, respectively Has received over $100 million in funding, principally from the Gates Foundation with a new $200 million grant announced in September 2007 In 2006, opened a new vaccine research and production facility in Rockville, MD Formed in 2003 by leaders from Medecins Sans Frontieres (MSF) with support from multiple NGOs and governments Focuses primarily on trypanosomal diseases and malaria; portfolio includes a range of discovery, preclinical, and clinical projects Launched its first product in March 2007, a new antimalaria formulation, artesunate-amodiaquine (ASAQ), in collaboration with Sanofi-Aventis Has received $48.2 million in funding from MSF and the British and French governments The only PDP to focus on diagnostics—initial focus on TB expanded to malaria and human African trypanosomiasis Partnering with Cepheid, ImmPORT, Proteome Systems, Hain Lifesciences, Roche Diagnostics, Becton, Dickinson and Company (BD), Cellestis, and the government of Lesotho In September 2007, announced funding of $62 million over five years for TB diagnostics Leading developer of new drugs for TB; founded in 2000 Announced Phase III trials of moxifloxacin in combination with other drugs; a new compound, PA-824, has completed Phase I trials; several discovery projects in early pipeline Partnering with Bayer, GlaxoSmithKline, Novartis, BG Medicine, Cumbre, and the Institute of Materia Medica in China Has raised over $193 million, principally from the Gates Foundation and European governments Leading global partnership for developing an HIV/AIDS vaccine; founded in 1996 Pipeline includes six vaccine candidates currently in clinical trials Partnering with Targeted Genetics, Biosciences UK, and Becton, Dickinson and Company. Has received $340 million in contributions since 1997; current annual budget nearly $100 million

Drugs for Neglected Diseases Initiative — DNDi
WWW.DNDI.ORG

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Focus: Drugs for leishmaniasis, african trypanosomiasis, Chagas disease, and malaria

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Foundation for Innovative New Diagnostics — FIND
WWW.FINDDIaGNOStICS.ORG

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Focus: Diagnostics for tuberculosis and other diseases n

Global Alliance for TB Drug Development — TB Alliance
WWW.tBaLLIaNCe.ORG

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Focus: Drugs for tuberculosis

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International AIDS Vaccine Initiative — IAVI
WWW.IaVI.ORG

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Focus: Vaccines for HIV/aIDS n

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BVGH Global Health Primer

Key GLOBaL HeaLtH PLayeRS

International Partnership for Microbicides — IPM
WWW.IPM-MICROBICIDeS.ORG

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Focus: Microbicides for prevention of HIV/aIDS transmission

Leading partnership to develop vaginal microbicides to prevent transmission of HIV Has two products currently in clinical trials Partnering with Gilead Sciences, Merck, and Imquest Biosciences Has raised $215 million from the Gates Foundation, the Rockefeller Foundation, the UN Population Fund, multiple European countries, and the United States Independent not-for-profit focused on several neglected diseases Lead product is paromomycin for visceral leishmaniasis, approved in India in 2006 Developing microbial process for synthesizing artemisinin through a groundbreaking, $33 million partnership with Amyris Biotechnologies Has obtained grants of over $130 million, principally from the Gates Foundation Leading organization developing new drugs and combination treatments for malaria Lead product is PYRAMAX®, pyronaridine-artesunate, currently in Phase III trials; has a broad portfolio of projects from discovery through Phase III trials Partnering with GlaxoSmithKline and Novartis on the discovery of new antimalarials Has received $113 million in funding from the Gates Foundation and other sources, with an additional $30 million of “in-kind” contributions An independent unit of PATH created in 1999; leader in malaria vaccine development The most advanced candidate, RTS,S, partnered with GlaxoSmithKline, is entering Phase III clinical trials; also partnering with Sanaria, Shanghai Wanxing Bio-Pharmaceuticals Co., Walter Reed Army Institute of Research (WRAIR), and GenVec, among others Has raised nearly $260 million in funding, principally from the Gates Foundation Largest of the Gates-funded philanthropies; founded in 1977 Developing medical devices, diagnostics, and vaccines that are appropriate for developing countries; also working to improve health care delivery Responsible for over 30 products that have helped solve global health problems, including single-use syringes, malaria tests, and chemically active stickers that detect heat-damaged vaccines Piloting introduction of cervical cancer vaccines and meningococcal vaccines into the developing world Has received nearly $900 million; 2007 budget is $168 million

Institute for OneWorld Health — IOWH
WWW.IOWH.ORG

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Focus: Drugs for visceral leishmaniasis, malaria, and diarrheal diseases

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Medicines for Malaria Venture — MMV
WWW.MMV.ORG

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Focus: Drugs for malaria n

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Malaria Vaccine Initiative — MVI
WWW.MaLaRIaVaCCINe.ORG

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Focus: Vaccines for malaria

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Formerly Program for Appropriate Technology in Health — PATH
WWW.PatH.ORG

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Focus: Sustainable, culturally relevant solutions to improve health and well-being in the developing world n n

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Key GLOBaL HeaLtH PLayeRS

I N t e R N at I O N a L a N D Mu Lt I L at e R a L O R G a N I z at I O N S a N D I N I t I at I V e S
Bill & Melinda Gates Foundation
WWW.GateSFOuNDatION.ORG

Launched in 2000 with an endowment of $29.1 billion, the foundation supports work in the areas of global health, global development, and improving public schools in the United States. Grant commitments to date total $13.6 billion with average annual commitments of $1.5 billion. By 2009, the foundation will begin to disburse an additional $1.6 billion a year from the 2006 bequest of $31 billion from Warren Buffett. The government of the United Kingdom aid and development arm, DFID aims to reduce world poverty through long-term programs that tackle its underlying causes. DFID is a major supporter of Advanced Market Commitments (AMCs) and other programs to improve health in the developing world. Its annual budget is roughly $6 billion. Founded in 1996, FNIH was established by the NIH as a flexible funding organization to support pioneering biomedical research. Along with the Gates Foundation, FNIH administers the Gates Grand Challenges within the Global Health Program. ICDDR,B is an international health research institution that conducts research, training, and program-based activities in collaboration with partners from academic and research institutions throughout the world. In 2006, the organization received almost $24 million with large portions from USAID, the United Kingdom’s Department for International Development, and the government of Bangladesh. IFFIm is a financing facility backed by several European governments to finance vaccine commitments. These commitments will be floated on the international bond market in order to “front-load” predictable funding to GAVI for enhanced vaccination programs. IFFIm provided $800 million, or 90 percent, of GAVI’s 2007 expenditures. The IVI, established by the United Nations Development Program with the support of 35 countries and the WHO, supports collaborative research to accelerate the introduction of new vaccines into developing countries. IVI’s focus includes basic and applied laboratory research, product development, training, and technical assistance. An alliance between the public and private sector, GAVI has raised more than $3.3 billion for the purchase and distribution of vaccines to children in the developing world. GAVI’s funding comes from national governments and a 15year, $1.5 billion grant from the Gates Foundation. GAVI estimates its efforts have saved the lives of 2.3 million children. Since 2002, the Global Fund has directed global financing of interventions against HIV, tuberculosis, and malaria. The Global Fund has committed $7.7 billion in 136 countries to prevention and treatment, and has developed innovative systems to measure its success.

Department for International Development — DFID
WWW.DFID.GOV.uK

Foundation for the National Institutes of Health — FNIH
WWW.FNIH.ORG

International Center for Diarrheal Disease Research, Bangladesh — ICDDR,B
WWW.ICDDRB.ORG

International Financing Facility for Immunization — IFFIm
WWW.IFFIM.COM

International Vaccine Institute (UN Program hosted by Korea) — IVI
WWW.IVI.ORG

Formerly Global Alliance for Vaccines and Immunisation — GAVI Alliance
WWW.VaCCINeaLLIaNCe.ORG

The Global Fund to Fight AIDS, TB and Malaria — Global Fund
WWW.tHeGLOBaLFuND.ORG

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BVGH Global Health Primer

Key GLOBaL HeaLtH PLayeRS

National Institute for Allergy and Infectious Diseases — NIAID
WWW.NIaID.NIH.GOV

Part of the NIH, NIAID provides support for research into infectious, immunologic, and allergic diseases. NIAID is the leading arm of the United States government promoting research into preventions and cures for HIV/AIDS, influenza, and infectious diseases of the developing world. PAHO is an international public health agency working to improve health and living standards of the countries of the Americas. It serves as the WHO’s Latin America regional office and is the main purchaser of vaccines in Latin America. A $15 billion, five-year plan announced by President Bush in 2003, PEPFAR aims to dramatically scale up HIV/AIDS prevention, diagnosis and treatment in 15 target countries. The president recently announced a plan to renew PEPFAR and double its funding to $30 billion for 2008-2013. Begun in 2005, the PMI will increase malaria funding by $1.2 billion over five years with the goal of reducing deaths from malaria by 50 percent in 15 African countries. The PMI is working with multiple public and private sector partners in programs to distribute bed nets, drugs and insecticides. Established in 1913, the foundation has $3.4 billion in assets that support programs in health, globalization, arts and culture, agriculture, housing, and education. Many of today’s largest product development partnerships (PDPs) were founded with seed financing from the foundation. TDR, an independent program established by WHO, supports research and development to combat 10 of the most devastating tropical diseases through grants and partnerships. It coordinates worldwide efforts in discovery research for neglected diseases. The UNDP is the United Nation’s principal provider of advice, advocacy, and grant support to foster development initiatives.

Pan American Health Organization — PAHO
WWW.PaHO.ORG

President’s Emergency Plan for AIDS Relief — PEPFAR
WWW.PePFaR.GOV

President’s Malaria Initiative — PMI
WWW.PMI.GOV

The Rockefeller Foundation
WWW.ROCKFOuND.ORG

Special Programme for Research and Training in Tropical Diseases — TDR
WWW.WHO.INt/tDR

United Nations Development Program — UNDP
WWW.uNDP.ORG

United Nations Children’s Fund — UNICEF
WWW.uNICeF.ORG

UNICEF provides long-term humanitarian and developmental assistance to children and mothers in developing countries. UNICEF is the global leader in vaccine supply, reaching 40 percent of the world’s children. In 2002, UNICEF procured two billion vaccine doses. USAID is the United States government’s foreign aid and development organization. The population, health, and nutrition sector works to stabilize world population and protect human health. USAID administers PEPFAR and other disease-targeted programs.

United States Agency for International Development — USAID
WWW.uSaID.GOV

BVGH Global Health Primer

1

Key GLOBaL HeaLtH PLayeRS

The Wellcome Trust
WWW.WeLLCOMe.aC.uK

The Wellcome Trust is the largest funder of biomedical research in the United Kingdom. The Trust has a strong interest in infectious disease and has focused significant funding in neglected diseases. The Trust is increasingly funding “translational” efforts to invent new therapeutics based on fundamental discoveries made in academic laboratories—the organization is unusual in its willingness to fund private sector R&D. Wellcome Trust funding helped to produce the malaria treatment artemisinin. WHO is the agency of the United Nations that acts as a coordinating authority on international public health. WHO’s major aim is to combat disease, especially infectious diseases, and to promote the general health of the peoples of the world.

World Health Organization — WHO
WWW.WHO.INt/eN

1

BVGH Global Health Primer

Key GLOBaL HeaLtH PLayeRS

N O ta B L e aC a D e MI C G RO uP S a ND R e Se a RC H INS t I t u t I O NS
The Broad Institute of MIT and Harvard
WWW.BROaD.MIt.eDu

n n

A biomedical research institute researching all aspects of human disease; founded with $100 million from Eli and Edythe Broad Collaborating with MMV and Genzyme to identify new malaria therapeutics

Focus: Malaria and tuberculosis

Infectious Disease Research Institute — IDRI
WWW.IDRI.ORG

n

n n

Focus: Leishmaniasis, tuberculosis, leprosy, Chagas disease, chlamydia, Buruli ulcer

Leading independent research institute focused on developing treatments and vaccines for infectious diseases Lead program is a vaccine for leishmaniasis Funded by the Gates Foundation, GlaxoSmithKline, the NIH, and American Leprosy Missions; actively seeks industrial partnerships

Sabin Vaccine Institute
WWW.SaBIN.ORG

n

Focus: Neglected diseases

n

Funds the Hookworm Vaccine Initiative and the Center for Neglected Tropical Disease Control and Elimination Budget of $14 million in 2007 Leading independent research institution, funded by grants, with a strong focus on neglected diseases, particularly malaria and tuberculosis Created a genetically attenuated whole-organism malaria vaccine that conferred protection in a rodent model Annual budget of approximately $25 million

Seattle Biomedical Research Institute — SBRI
WWW.SBRI.ORG

n

n

Focus: Malaria, tuberculosis, HIV/aIDS, trypanosomal diseases, toxoplasmosis, and H. influenzae associated diseases n

UCSF Sandler Center
WWW.uCSF.eDu/MCKeRROW/ SLIDe.HtML

n

n

Focus: Parasitic diseases n

Combines academic groups and resources to simulate a pharmaceutical R&D division Maintains open-access “Low Hanging Fruit” database; a set of FDA-approved drugs that have shown promise against T. brucei and Leishmania Building compound libraries for drug screening A translational research center targeting human African trypanosomiasis (sleeping sickness), Chagas disease, and leishmaniasis With funding from the British government and the Wellcome Trust, the center is building drug discovery capabilities that would deliver at least one drug candidate in preclinical development by 2011 Developing pafuramidine, an oral drug currently in Phase III clinical trials, for the treatment of sleeping sickness Consortium members include the University of North Carolina, Georgia State University, Swiss Tropical Institute, London School of Hygiene and Tropical Medicine, Ohio State University, University of South Florida, University of Glasgow, Gorgas Memorial Institute (Panama), Kenya Agricultural Research Institute, and Immtech Pharmaceuticals Has received grant funding of $15.1 million from the Gates Foundation

University of Dundee Tropical Disease Initiative
WWW.DRuGDISCOVeRy.DuNDee. aC.uK/tROPICaL/OVeRVIeW

n

n

Focus: Parasitic diseases

University of North Carolina Consortium for Parasitic Drug Development — CPDD
Focus: Human african trypanosomiasis (sleeping sickness) and leishmaniasis

n

n

n

BVGH Global Health Primer

1

Select Companies Working in Global Health
Recent Examples of Companies and PDPs Working Together on Global Health R&D
Company AstraZeneca Abbott Acambis Æterna Zentaris AlphaVax Amyris Biotechnologies Anaspec AnorMED Antigenics AVANT Immunotherapeutics Bavarian Nordic Bayer Becton Dickinson Bharat Biotech Biosante Pharmaceuticals Bioption AB Biotec Laboratories Bristol-Myers Squibb Cambridge Biostability Celera Genomics Cellegy Cellestis Cepheid ChemBio Diagnostics Chemogen Cobra Biomanufacture Crucell CSL Cumbre Cytokinetics Dictagene Eli Lilly Emergent BioSolutions Enzo Biochem FIT Biotech GenVec Genzyme Gilead GlaxoSmithKline GroPep Hain Lifescience Hoffman-La Roche Aeras, IAVI, MMV, MVI, TB Alliance MVI FIND MMV MVI DNDi, MMV FIND IAVI Aeras, IAVI MVI TB Alliance FIND FIND IOWH IAVI FIND, MMV MMV TB Alliance IAVI, FIND MVI IOWH IAVI PDP-Partner Company Holleykin Pharmaceutical Hollis-Eden IDM Pharma IDT GmbH ImmPORT Immtech Immune Response Indevus Pharmaceuticals Intercell InterMune IOMAI Lupin Pharmaceuticals Maxygen MedImmune Medmira Merck Novartis OraSure Technologies Oxxon PanBio Paratek Pevion Biotech Pfizer Proteome Systems Ranbaxy Salubris Sanaria Sanofi-Aventis Sciclone Scynexis Sequella Shanghai Wanxing Shin Poong Sigma Tau Starpharma Targeted Genetics Therion Biologics Corps United Biotech Valeant Pharmaceuticals Vertex Pharmaceuticals Vical Wyeth IAVI TDR IAVI IAVI MVI MMV MMV DNDi MMV, TDR FIND MMV FIND MVI DNDi MMV MVI, IAVI MMV, TB Alliance TDR IAVI Aeras IAVI FIND MMV PDP-Partner MMV

1

BVGH Global Health Primer

Biotech Solutions

SMaLL MOLeCuLe tHeR aPeutICS Problem: There is a critical need for novel, safe, and affordable therapeutics to treat infectious diseases of the developing world. For diseases for which treatments exist, such as TB and malaria, improvements are sought in treatment efficacy, safety, cost, and activity against drug-resistant organisms. For diseases such as sleeping sickness and Chagas disease, current drugs are inadequate, and there is an urgent need for new therapeutic options. Potential small molecule solutions include: n Unique approaches to therapeutic compound generation n Use of rational drug design and high-throughput screening to identify inhibitors of targets specific to the infectious agents that cause major tropical diseases n Use of chemogenomics to identify targets in a range of infectious organisms Innovative small molecule approaches include: n PA-824, a nitroimidazole antibiotic with significant activity against tuberculosis bacteria in pre-clinical tests; originally developed by Pathogenesis (subsequently acquired by Chiron) and licensed to the TB Alliance; now in Phase II clinical trials n Impavido® (miltefosine) an oral alkylphospholipid developed by Æterna Zentaris and recently approved in India for leishmaniasis

VaCCINeS Problem: Vaccines are the most sought-after intervention in the developing world because they provide long-term protection in areas where patients’ access to medical treatment may be infrequent or inadequate. Vaccines protecting against smallpox and polio have been among the most important public health success stories in both industrialized and developing countries. Vaccines are still needed for the infectious diseases that primarily affect the developing world, including HIV/AIDS and other sexuallytransmitted diseases, malaria, TB, enteric pathogens, trypanosomes, and nematodes. Biotech companies can improve existing vaccines and create new vaccines against infectious agents: n Genetically engineered “live attenuated” vaccines with greater safety, specificity, and efficacy n Recombinant bacterial or viral vectors incorporating multiple immunogens in a single vaccine n Recombinant subunit vaccines engineered to maximize both Tand B- cell responses n Molecular identification of the most immunogenic and conserved antigens that can be used in new vaccines Innovative vaccine approaches include: n Rotarix®, a live attenuated oral vaccine for rotavirus, developed by AVANT Immunotherapeutics/GlaxoSmithKline and approved in 90 worldwide markets, including the European Union n Japanese encephalitis vaccine, a purified, inactivated vaccine in Phase III development by Intercell in partnership with Novartis; the vaccine is planned for a 2008 release n ChimeriVax™-Dengue, a live attenuated vaccine for all serotypes of dengue fever, in Phase II development by Acambis and its partner Sanofi Pasteur n DNA/MVA prophylactic vaccine for HIV, in Phase II development by Oxford BioMedica in conjunction with IAVI

BVGH Global Health Primer

1

BIOteCH SOLutIONS

MOLeCuL aR DIaGNOStICS Problem: Most neglected diseases are underdiagnosed, and there is a profound unmet need for simple, affordable diagnostics designed for the hospital, clinic and point-of-care settings in developing countries. Many diagnostic techniques commonly used in the developed world are far too complex and expensive to be suitable for low-resource settings in tropical climates. The challenges are to adapt appropriate technologies to neglected diseases and to generate new technologies that allow treatment decisions to be made quickly, reliably, and inexpensively. Potential molecular diagnostics solutions include: n Improved techniques for generating biomarkers for disease characterization n Improved sampling methods that increase test sensitivity n Novel materials and reagents that do not require refrigeration n Simple “dip stick”-type assays with easily understood colorimetric readout n New “lab on a chip” methods that allow multiple conditions and diseases to be monitored in a single test Innovative diagnostic approaches include: n Proteome Systems’ rapid diagnostic test that was developed to identify TB biomarkers for use in TB diagnostic tests n Rapid HIV tests from ChemBio n UBI MAGIWEL™ trypanosomiasis (Chagas) qualitative, an ELISA test developed by United Biotech that provides an easy method for detecting Chagas antibodies (IgG) in human serum or plasma

VaCCINe a ND DRuG DeLIVeRy Problem: Current methods of vaccine and drug delivery rely on refrigeration, trained personnel and disposable needles. Alternatives to injections, frequent dosing and refrigeration could increase safe access to drugs and vaccines, saving millions of lives. Potential vaccine and drug delivery method solutions include: n Alternatives to injections, such as powdered, oral, edible, and transdermally administered vaccines and topical drugs n Combination formulations and controlled-release formulations to replace the need for multiple doses, increasing the likelihood that patients will improve compliance n Development of novel adjuvants to increase the immunogenicity of vaccine antigens Innovative vaccine approaches include: n Emergent BioSolutions’ live attenuated typhoid vaccine, now in Phase II trials, designed to be administered in a single, drinkable dose prior to travel to countries where typhoid is endemic n An ETEC vaccine patch in Phase II development by IOMAI, using its proprietary transcutaneous immunization platform technology

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BVGH Global Health Primer

BIOteCH SOLutIONS

ReSeaRCH PRODuCtS Problem: Scientists in developing countries carrying out research on endemic infectious diseases are hampered in their ability to perform molecular biology because of problems related to refrigeration (exacerbated by electricity supply problems) and the high costs of shipping research reagents from developed countries, particularly enzymes that require shipment on dry ice. Potential research approaches include: n Development of low-cost preservatives that allow enzymes to be stored at room temperature for extended periods n Development of new methods that allow inexpensive production of research reagents with minimal equipment and chemicals n Innovative research equipment to reduce laboratory infrastructure costs Innovative approaches include: n Bolivian researcher Nataniel Mamani’s “blenderfuge,” a microcentrifuge built from a cannibalized blender, and his laboratory shaker assembled from a record turntable

BVGH Global Health Primer

21

Disease Sheets

BVGH Global Health Primer

23

african trypanosomiasis
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is African Trypanosomiasis?
Human African trypanosomiasis (HAT), also known as sleeping sickness, is caused by a single-celled parasitic protozoan called a trypanosome and is transmitted by tsetse flies . The disease progresses from fever and fatigue to severe neurological conditions . Untreated HAT results in death .

Global Burden
There are 60 million people at risk worldwide, with an estimated 300,000 new cases and 50,000 deaths annually .

Geographic Distribution
HAT is found in 36 countries in sub-Saharan Africa .

Causative Agent/Transmission
HAT is caused by Trypanosoma brucei, a protozoan parasite transmitted to humans by the bite of an infected tsetse fly . There are several subspecies of T. brucei; T.b. gambiense, found in Central and West Africa, causes chronic disease, and T.b. rhodesiense, present in South and East Africa, causes acute disease .

Presentation
T. brucei parasites first develop in the blood, lymph, and peripheral organs (Stage One) and then cross the bloodbrain barrier and enter the central nervous system (Stage Two) . Stage Two is characterized by severe neurological disorders including extreme fatigue, major disturbances to patients’ sleep cycle (hence “sleeping sickness”), and coma . Without treatment, the disease is always fatal .

Trends
By the 1960s, aggressive surveillance and programs to eradicate tsetse flies resulted in the near disappearance of the disease . Subsequently, control measures were relaxed, tsetse populations recovered, and HAT rebounded .

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BVGH Global Health Primer

aFRICaN tRyPaNOSOMIaSIS

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
Current treatments are only minimally effective, are prohibitive to deliver (all are delivered intravenously), and can be highly toxic.
n

Vaccines
None

Diagnostics
typically patients are not diagnosed until the late stage of the disease. there are no molecular diagnostic methods currently available.
n

PEntamIdInE

casE dEtEctIon

– treats early-stage T.b. gambiense (ineffective against late-stage disease) – Side effects are rare
n

suramIn

– treats early-stage T.b. rhodesiense (ineffective against late-stage disease) – Side effects can be severe
n

– Blood smear for T.b. rhodesiense (sensitive) or T.b. gambiense (less sensitive) – Card indirect agglutination test (Catt) for T.b. gambiense
n

stagIng

– Microscopy on cerebral spinal fluid

mElarsoProl (arsEnIc dErIvatIvE)

– treats late-stage disease (first-line treatment) – Side effects are frequent and severe; results in reactive encephalopathies in five to ten percent of treated cases – Showing evidence of resistance
n

EflornIthInE (dfmo)

– treats late-stage T.b. gambiense (first- or second-line treatment) – Side effects are numerous and can be severe – Requires hospital administration – Highly effective, but costs are high and supply is unreliable

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n

Vaccines
n

Diagnostics
n

n

Less toxic Oral or injectable treatments can be effective; injectable is preferable for patients in coma Crosses blood-brain barrier in order to eliminate CNS infection in late-stage disease

Offers long-term protection against infection

n

n

n

Molecular diagnostic capable of early detection for prevention of severe disease Detects disease stage (treatment choice depends on whether there is CNS involvement) Less invasive methods for staging (current method is lumbar puncture) affordable

BVGH Global Health Primer

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aFRICaN tRyPaNOSOMIaSIS

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
Immtech Pharmaceuticals/university of North Carolina (DB 289; pafuramidine) DNDi/Bayer/tDR (Nifurtimox-eflornithine) DNDi/Dundee university (trypanothione reductase inhibitors) DNDi (Novel nitroheterocycles) DNDi/Sandler Center (Cysteine protease inhibitors) DNDi (ascofuranone) DNDi (DHFR inhibitors) DNDi (Nitroimidazoles) DNDi (Microtubule inhibitors) DNDi/Genzyme (screening)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n

Primarily a disease of impoverished rural communities and will require donor support to encourage innovation .

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
eradication of CNS infection is difficult to confirm (only a few residual organisms are needed for infection to recur)

Vaccines
T. brucei undergo extensive antigenic variation, which presents significant obstacles to vaccine development

Diagnostics
No serum biomarkers yet identified to diagnose late-stage disease

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/topics/trypanosomiasis_african/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/trypanosomiasis

Key Organizations
Drugs for Neglected Diseases Initiative (DNDi) ~ www .dndi .org n University of Dundee, Tropical Disease Initiative ~ www .drugdiscovery .dundee .ac .uk/tropical/overview/ n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr
n

Important Papers
Berriman, M et al . The genome of the African trypanosome Trypanosoma brucei . Science 309:416-422 (2005) El-Sayed, NM et al . Comparative genomics of trypanosomatid parasitic protozoa . Science 309:404-409 (2005) n Legros, D et al . Treatment of human African trypanosomiasis–present situation and needs for research and development . Lancet Infectious Diseases 2:437-440 (2002) n Renslo, AR, and McKerrow, JH . Drug discovery and development for neglected parasitic diseases . Nature Chemical Biology 2:701-710 (2006)
n n

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BVGH Global Health Primer

Chagas Disease
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Chagas Disease?
Chagas disease, also called American trypanosomiasis, is a parasitic disease that over time causes damage to the nervous system, digestive tract, and the heart . Chagas disease is caused by a trypanosome that is related to the parasites that cause human African trypanosomiasis and leishmaniasis . Humans contract the disease when the infected feces of the insect vector enter the body, typically through scratching the bite wound .

Global Burden
It is estimated that eight million to nine million people are currently infected, with 750,000 new cases and 14,000 deaths occurring each year . An additional 25 million people are at risk of infection .

Geographic Distribution
Chagas disease is prevalent in 18 countries within the Americas, ranging from Mexico to Argentina .

Causative Agent/Transmission
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. It is transmitted to humans through the feces of blood-sucking insects known as triatomine bugs (also known as “assassin” or “kissing” bugs) . Transmission may also occur congenitally or via breast milk or blood transfusion . In its human host, the parasites invade and replicate inside many types of cells . Pet dogs are an alternate mammalian host, a situation that has impeded efforts to break the chain of transmission . Chagas disease is most prevalent in rural areas and is linked to substandard housing . Thatched roofs and mud walls are especially prone to infestation by the insect vector .

Presentation
Both phases of Chagas disease, acute and chronic, can be either asymptomatic or life-threatening . The acute phase of the disease begins several days after infection . Most acute infections are asymptomatic . However, this phase can have fever and swelling of the lymph nodes, spleen, liver, and the site of infection . The hallmark of acute Chagas disease is the swelling of the eyelids or the side of the face near the bite wound . This is called Romaña’s sign . The chronic phase can last from months to decades and may also remain asymptomatic for long periods of time . Damage can eventually occur to the nervous system, the digestive system, and the heart . Cardiomyopathy, or damage to the heart’s muscle structure, is the leading cause of death .

Trends
The number of deaths per year has decreased slightly in recent years . The WHO launched a major campaign in 2007 to seek eradication of the disease .

BVGH Global Health Primer

2

CHaGaS DISeaSe

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
there is no treatment for long-term, chronic infections.
n

Vaccines
n

Diagnostics
there are no diagnostics that can reliably detect chronic disease.
n

None

nIfurtImox & BEnznIdazolE

tcf-ElIsa

– Cures at least 50 percent of acute and short-term chronic infections principally in children, but little to no impact on long-term chronic infections – Frequently causes side effects, which can be severe – Limited access – High cost of treatment – Shows signs of resistance

– Sensitive and specific – Low occurrence of leishmaniasis cross-reactions
n

uBI magIWEl™ ElIsa

– Detects T. cruzi antibodies (IgG) in human serum or plasma
n

chEmBIo chagas stat-Pak™

– Detects T. cruzi antibodies – Rapid test and does not require special equipment or refrigeration

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n n n

Vaccines
n

Diagnostics
n n

effective against chronic disease Oral formulation Short course of therapy affordable

n

Preventive: long-term protection against infection therapeutic: treat the chronic phase

n

Molecular diagnostic able to differentially diagnose the presence and stage of disease affordable

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
DNDi (Ravucnazole) DNDi/eisai (Benzofuroxan compounds) DNDi/Dundee university (trypanothione reductase inhibitors) DNDi (DHFR inhibitors) DNDi/Sanofi-aventis/Roche/Novartis ItD/alkem (Nitroimidazoles) IVIC/Schering-Plough Research Institute (Posaconazole)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnn nnnnnnnnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n

This is primarily a disease of the very poor and will require donor support to encourage innovation .

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

n

Clinical trials are likely to be complicated by the slow progression of the disease In the chronic stage, organisms are difficult to detect and damage occurs over many (>15) years

Clinical trials are likely to be complicated by the slow progression of the disease

n

No biomarkers exist to detect chronic disease troponin, a marker for cardiac damage that is elevated in latechronic stage disease, cannot differentiate between “no disease” and the early chronic stage

2

BVGH Global Health Primer

CHaGaS DISeaSe

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/topics/chagas_disease/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/chagasdisease

Key Organizations
n n

Drugs for Neglected Diseases Initiative (DNDi) ~ www .dndi .org Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr

Important Papers
De Souza, W . From the cell biology to the development of new chemotherapeutic approaches against trypanosomatids: dreams and reality . Kinetoplastid Biology and Disease 1:3 (2002) n El-Sayed, NM, et al . The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease . Science 309:409-415 (2005) n El-Sayed, NM, et al . Comparative genomics of trypanosomatid parasitic protozoa . Science 309:404-409 (2005) n Hucke, O, et al . The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease . J Med Chem 48:5415-5418 (2005)
n

BVGH Global Health Primer

2

Cholera
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Cholera?
Cholera is an acute bacterial intestinal infection with a very short incubation period, typically one to five days . Cholera causes watery diarrhea and vomiting that can lead to severe dehydration and death in less than 24 hours if not treated promptly . In areas where cholera is endemic, the disease mainly affects children .

Global Burden
In 2004, the WHO reported that 101,383 cases of cholera occurred in 56 countries resulting in 2,345 deaths . Case-fatality rates in epidemic conditions can exceed 40 percent, making cholera prevention a major public health objective .

Geographic Distribution
The majority of cases currently occur in sub–Saharan Africa and Southeast Asia, but distribution varies . During 2004, major outbreaks occurred in Cameroon, Chad, Guinea, Mali, Niger, Senegal, and Zambia .

Causative Agent/Transmission
Cholera is caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae . Most sudden, large outbreaks are linked to a contaminated water supply . Rarely, cholera can be transmitted by direct person-to-person contact . Until 1992, the only known cholera agent was Vibrio cholerae O1, but in that year a new serogroup, O139, was observed and found to be the cause of several epidemics in Asia .

Presentation
V. cholerae produces an enterotoxin that induces the intestine to release fluid, causing abundant, watery diarrhea that can quickly lead to severe dehydration . Frequent vomiting can exacerbate dehydration . If the dehydration is not addressed, cholera can be fatal . Most healthy people have the ability to fight a cholera infection without manifesting symptoms; however, about 10 percent of those infected develop severe disease .

Trends
The number of cholera deaths and the case-fatality rate have increased significantly in high-risk areas such as subSaharan Africa . Cholera remains a global threat and one of the key indicators of low development level . It is a particularly dangerous problem in places with limited access to clean water . Most developing countries are at risk for cholera outbreaks . Current vaccines do not protect against O139 . Institut Pasteur cautioned in 2003 that this new strain “may well become the origin of an eighth cholera pandemic .”

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

PallIatIvE carE

fIrst-gEnEratIon vaccInEs (IncludIng dukoral®)

raPId dIagnostIc dIPstIck tEst

− Oral rehydration therapy can be used to treat symptoms − antibiotics and intravenous (IV) fluids are sometimes given in severe cases, where available

− Oral delivery − Protection ranges from three months to two years − Some require multiple doses for efficacy; efficacy can be as low as 61 percent − Licensed in some countries but mainly available to travelers − Ineffective against O139 strain

− uses immunochromatography to detect the presence of O1 and O139 lipopolysaccharides

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BVGH Global Health Primer

CHOLeRa

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n

Vaccines
n

Diagnostics
n

High-potency antibiotic affordable

n n n n

Live attenuated, or killed bacterial (the latter for use in areas with high HIV-positive populations) Single, oral dose thermostable Bivalent against O1 and O139 cholera Long-term protection (>2 years) to infants and young children

n

ability to differentiate between other diarrheal pathogens Rapid test to ensure quick response in an epidemic

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Vaccines
National Institute of Cholera & enteric Diseases/IVI (VaI-3; oral, killed, bivalent) aVaNt Immunotherapeutics/BioSidus (CholeraGarde® ; live attenuated) Nha-trang, Vietnam (oral, live attenuated) Finlay Institute, Cuba (oral, live attenuated) university of Maryland (live attenuated O139 strains) Institut Pasteur (conjugate O139)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n

Potential commercial opportunities for vaccines through military and travelers’ applications .

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n n n

Diagnostics

Need to overcome antibiotic resistance

Single-dose oral vaccine Difficulties in conjugate development Specifications for travelers’ and military markets may differ from endemic markets

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/topics/cholera/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dbmd/diseaseinfo/cholera_g .htm

Key Organizations
n n

WHO Initiative for Vaccine Research (IVR) ~ www .who .int/vaccine_research/en ICDDR,B: Centre for Health and Population Research ~ www .icddrb .org/pub

Important Papers
n n

Lucas, MES, et al . Effectiveness of mass oral cholera vaccination in Beria, Mozambique . NEJM 352:757-767 (2005) Sack, DA, et al . Cholera . The Lancet 363:223-233 (2004)

BVGH Global Health Primer

31

Dengue Fever (DF)
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Dengue?
Dengue fever (DF) is a viral, mosquito-borne disease that can cause severe, flu-like symptoms with high fever and extreme muscle and joint pain . Dengue hemorrhagic fever (DHF), a more severe form of the disease associated with increased blood vessel permeability, can be fatal .

Global Burden
There are an estimated 50 million new dengue infections each year, and more than 2 .5 billion people are at risk for the disease . Approximately 500,000 cases of DHF require hospitalization each year, the majority of whom are children, resulting in more than 20,000 deaths . Without proper treatment, DHF case fatality rates can exceed 20 percent .

Geographic Distribution
DF is endemic in 100 countries throughout the Americas, Southeast Asia, the Western Pacific Islands, Africa, and the eastern Mediterranean . Southeast Asia and the Western Pacific are most seriously affected . Dengue cases have also been reported in Hawaii and Puerto Rico .

Causative Agent/Transmission
The dengue virus is a member of the family Flaviviridae, which includes the viruses that cause yellow fever, Japanese encephalitis, and West Nile disease . There are four known serotypes . The viruses are transmitted by Aedes aegypti mosquitoes, subgenus Stegomyi.

Presentation
DF is a severe, incapacitating, flu-like illness that affects infants, young children, and adults, but seldom causes death . In older children and adults, DF symptoms include sudden onset of high fever, severe headache, muscle and joint pain, and rash . With palliative care, these symptoms typically resolve within weeks, but complete convalescence may require additional time . Less than one percent of patients infected with dengue develop DHF, which is characterized by low platelet counts and blood iron imbalance that may be accompanied by bleeding, enlarged liver, and circulatory failure . Without proper treatment, DHF case fatality rates can exceed 20 percent . However, with modern intensive supportive therapy such as intravenous fluid replacement, case fatality rates can be reduced to less than one percent . Exposure to one dengue serotype provides permanent immunity against that serotype, but subsequent infections by a different serotype increase the likelihood that the patient will develop DHF .

Trends
Due to the deforestation, development, and urbanization of tropical regions, breeding grounds for A. aegypti have expanded . As a result, human-vector contact has increased, and infection rates are on the rise . The A. aegypti habitat is not limited to the developing world, and dengue cases have recently occurred in Puerto Rico, Singapore, Hawaii, and the southern United States . A dengue epidemic in Paraguay that started in early 2007 is ongoing and has spread to both Argentina and Brazil, with an estimated number of cases above 100,000 . Cases are on the rise in India as well .

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BVGH Global Health Primer

DeNGue FeVeR (DF)

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

PallIatIvE carE

None

PanBIo raPId tEsts

– Intravenous fluid replacement can be used for rehydration − acetaminophen can be used to manage pain and fever

− Dengue Duo Cassette and Dengue Duo IgM and IgG Rapid Strip test (For differentiation between primary and secondary dengue infection)
n

PanBIo ElIsas

− Dengue IgG Indirect eLISa (For detecting past/active dengue infection) − Dengue IgM and IgG Capture eLISas (For diagnosis of active and secondary dengue infection, respectively)

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n n n

Vaccines
n n n n

Diagnostics
n n

Oral formulation Rapid-acting ameliorates symptoms Prevents DHF

Single or two-dose tetravalent Provides extended protection Safe and effective in small children effective against all four serotypes

Rapid test ability to diagnose in initial stage of disease, to distinguish between serotypes and to distinguish from other fevers

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
united therapeutics (ut-231B) Novartis
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnn nnnnnnnnnn nnn nnnn

Vaccines
acambis/Sanofi Pasteur (ChimeriVax-Dengue; live chimeric tetravalent) GlaxoSmithKline (attenuated tetravalent) Sanofi-aventis (La tetravalent; development halted) Bavarian Nordic (MVa-BN®; live recombinant viral vector) GenPhar (tetravalent candidate) Hawaii Biotech (tetravalent viral proteins) InViragen (tetravalent, live attenuated chimeric)

research & discovery

Preclinical

clinicalPhase I

clinicalPhase II

clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Potential markets for travelers to endemic regions and for people living in developed world areas where A. aegypti can be found . The range of dengue is expanding into areas such as Singapore and the southern United States . n Military market; biodefense vaccines can qualify for FDA fast-track approval . n Largest market for dengue vaccines is in the endemic areas of the tropics (over four billion people at risk in Latin America, Asia, and perhaps Middle East/Africa) .
n

BVGH Global Health Primer

33

DeNGue FeVeR (DF)

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

Developing an antiviral that is effective once infection has occurred

Developing a tetravalent vaccine effective against all four serotypes

Current tests only detect antibodies to dengue late in infection

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/topics/dengue/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dvbid/dengue

Key Organizations
Genome Institute of Singapore and Novartis Institute for Tropical Diseases ~ www .dengueinfo .org/NITD Pediatric Dengue Vaccine Initiative (PDVI) ~ www .pdvi .org n WHO Initiative for Vaccine Research (IVR) ~ www .who .int/vaccine_research/en n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr
n n

Important Papers
Blaney, JE, Jr, et al . Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus monkeys . J Virol 79:5516-5528 (2005) n Edelman, R . Dengue and dengue vaccines . J Infect Dis 191:650-653 (2005) n Guirakhoo, F, et al . Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax™-DEN2) vaccine: Phase I clinical trial for safety and immunogenicity: effect of yellow fever pre-immunity in induction of broad neutralizing antibody responses to all 4 dengue serotypes . Human Vaccines 2:60-67 (2006) n Wilder-Smith, A, and Schwartz, E . Dengue in travelers . NEJM 353:924-932 (2005)
n

34

BVGH Global Health Primer

enterotoxigenic E. coli (eteC)
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is ETEC?
ETEC, a virulent strain of the bacterium Escherichia coli, is a major cause of severe diarrhea leading to hospitalization . Infection by this bacterium is a leading killer of children in the developing world .

Global Burden
Each year an estimated 300 million to 400 million new infections of ETEC result in between 400,000 and 500,000 deaths . Ninety percent of these deaths occur in lower income countries . ETEC is a major cause of childhood diarrhea; most fatal cases occur in children under the age of two . ETEC is also the leading cause of travelers’ diarrhea .

Geographic Distribution
ETEC cases are reported worldwide; incidence rates are highest in Central and South America, Africa, and Southeast Asia .

Causative Agent/Transmission
E. coli is a bacterium with numerous serotypes, most of which normally inhabit the human intestinal tract with little ill effect . Several strains, however, secrete toxins that act on the intestinal lining and cause disease . E. coli that cause diarrheal illness can be broken down into four categories based on virulence mechanism: enterotoxigenic (ETEC), enteropathogenic (EPEC), enteroinvasive (EIEC), and enteroaggregative (EAggEC) . ETEC is transmitted through food or water contaminated with human or animal feces .

Presentation
Toxins released by gut-colonizing ETEC cause water and salts to be lost into the intestine, resulting in watery diarrhea, abdominal cramping, fever, and vomiting . Death is caused by extreme dehydration .

Trends
The disease burden associated with diarrheal infections remains enormous across all developing countries . ETEC is also a concern for travelers visiting the developing world . Although ETEC can be treated with antibiotics, the most effective drugs are prohibitively expensive . Misuse of antibiotics has led to drug-resistant ETEC strains .

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

PallIatIvE carE

− Oral rehydration therapy can be used to treat symptoms − antibiotics and IV fluids are sometimes given in severe cases, where available

n

Dukoral® is a cholera vaccine that has shown 60 percent short-term efficacy against travelers’ diarrhea No product exists to vaccinate people in endemic regions

None

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n

Vaccines
n n n n

Diagnostics
n

High potency antibiotic affordable

Oral delivery extended protection Multivalent acceptable side effects

ability to differentiate between eteC and other gut infections such as other diarrheagenic E. coli and protozoan diseases

BVGH Global Health Primer

3

eNteROtOxIGeNIC E. coli (eteC)

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Vaccines
IOMaI (Lt+CS6 transcutaneous patch) university of Maryland/Center for Vaccine Development (CVD 1208: oral, attenuated Shigella expressing eteC antigens) ace BioSciences/Cambridge Biostability/acambis (HolaVax-eteC: live, attenuated E. coli expressing LtB) Berna Biotech/Crucell (Hybrid Orochol vector: attenuated CVD103HgR cholera expressing eteC antigen and CtB) NICHD/Robbins (O-Lt/St: Lt-St toxoid conjugated to O antigen) MIDRP (SC608: attenuated S. flex w/eteC Cfab component of CFa/i and Ltb) emergent europe (Spi-VeC eteC: S. typhi vector expressing LtB) Göteborg university (Killed, whole cell eteC expressing CFa/I, CS1-5 and rCtB-CF) aVaNt (attenuated cholera expressing CtB and eteC antigen CFa/I) MIDRP (Fimbrial tip adhesion antigens)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn

nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn

nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn

nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn

nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Surveys indicate that individuals across low- and middle-income countries would be willing to pay one-half to one day’s wage for a vaccine on the private market . n Moderate financial case for investment – Market may be sufficient to attract innovators (nearly $400 million peak annual) – Market driven by travelers, military and middle-income populations – More robust travelers’ market could boost revenue > $200 million/year
n

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics

Need to overcome antibiotic resistance

n

n

n

n

Multiple strains make it difficult to design a multivalent vaccine with sufficient coverage Certain major cell-surface markers are not immunogenic, making them poor candidates for vaccines Specifications for travelers’ and military markets may differ from endemic markets Implementation in field conditions must be easy Cost must be low in comparison to alternative therapies/other vaccines

3

BVGH Global Health Primer

eNteROtOxIGeNIC E. coli (eteC)

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/vaccine_research/diseases/e_e_coli/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dbmd/diseaseinfo/etec_g .htm

Key Organizations
n

International Centre for Diarrheal Disease Research, Bangladesh (ICDDR,B): ~ www .icddrb .org/pub

Important Papers
Qadri, F, et al . Reduced doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine is safe and immunogenic in Bangladeshi infants 6-17 months of age: Dosing studies in different age groups . Vaccine 24:1726-1733 (2006) n Qadri, F, et al . Enterotoxigenic Escherichia coli in developing countries: epidemiology, microbiology, clinical features, treatment, and prevention . Clin Microbiol Rev 18:465-483 (2005) n Walker, RI . Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in children in developing countries . Vaccine 23:3369-3385 (2005)
n

BVGH Global Health Primer

3

Human Immunodeficiency Virus (HIV)
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is HIV?
HIV is a retrovirus that causes acquired immunodeficiency syndrome (AIDS), a syndrome characterized by progressive deterioration of the immune system . HIV/AIDS patients are at risk for opportunistic infections because of their diminished immune function, which may eventually lead to their death .

Global Burden
In 2006, it was estimated that 39 .4 million people worldwide were infected with HIV . There were approximately 2 .9 million AIDS deaths, and another 4 .3 million people were newly infected with HIV . Young people between the ages of 15 and 24 now account for almost half of all the new infections . Young women are especially vulnerable, with prevalence rates being as much as four times those found in young men of the same age .

Geographic Distribution
HIV/AIDS is a worldwide pandemic . Nearly two-thirds of those living with HIV/AIDS are located in sub-Saharan Africa . Southern Africa has been hardest hit; in several countries, the prevalence of HIV exceeds 30 percent of the adult population . Although the prevalence of HIV in South and Southeast Asia is much lower than in Africa, the huge population of this region makes it second to Africa in terms of the total number of individuals infected .

Causative Agent/Transmission
HIV is spread by exposure to infected body fluids including blood, semen, and breast milk . The major routes of transmission are sexual contact, contaminated needles, and from infected mother to child in utero, at birth or through breastfeeding . HIV mutates rapidly, and today patients are infected by many different strains of virus . Most broadly, HIV can be divided into two types: HIV-1 and HIV-2 . HIV-1 is more virulent than HIV-2 and causes the majority of human infections . HIV-1 itself can be divided into several distinct groups, which are themselves divided into subtypes, or clades, which display distinct geographic infection patterns . Treatment is more complicated in regions where more than one clade is circulating because hybrids of multiple clades can appear .

Presentation
Clinical diagnosis of HIV infection is complicated by the lack of specific symptoms . Two to four weeks after becoming infected, patients may display flu-like symptoms, accompanied by a rash and fever . However, many patients are asymptomatic upon initial infection . Although the incubation period between infection and onset of AIDS is often cited at seven to ten years, disease course is accelerated in low- and middle-income countries, due to environmental factors including burden of disease and nutrition . Once a patient develops AIDS (as defined as a CD4 lymphocyte count of <200 cells/µL), the disease is characterized by decreased immune functioning and an extreme susceptibility to opportunistic infections .

Trends
The HIV/AIDS epidemic has spread rapidly and is now considered a pandemic . While a majority of current and new HIV infections occur in sub-Saharan Africa, emerging crises are developing in Eastern Europe, Central Asia and East Asia . More than 95 percent of all new infections occur in people living in low- and middle-income countries . Resistance to antiretrovirals (ARV) is common and develops against all classes of ARVs, usually after prolonged use . Transmission of HIV strains resistant to one or multiple drugs has been documented and appears to be increasing .

3

BVGH Global Health Primer

HuMaN IMMuNODeFICIeNCy VIRuS (HIV)

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
Current technologies do not provide an inexpensive point-of-care test by which to direct treatment.
n

comBInatIon and hIghly actIvE antIrEtrovIral thEraPy (haart)

None

− Composed of a combination of anti-HIV drugs − there are three major groups of anti-HIV drugs, consisting of more than 20 approved medications − Side effects and drug resistance can be significant issues − although older, less expensive antiretrovirals are increasingly available, the latest treatments remain out of reach for many in the developing world − Current drugs reduce viral load, but do not cure the disease and must be taken indefinitely

hIv EnzymE Immunoassay & WEstErn Blot assay

− Detects HIV antibodies in serum, plasma, oral fluid, dried blood, or urine
n

oraQuIck® advancE™ hIv1/2 antIBody tEst

− First oral fluid rapid HIV test − Can be used on oral fluid, plasma, fingerstick, and venipuncture whole blood specimens
n

chEmBIo stat-Pak™ & surE chEck® assays and dIPstIck tEsts

− Simple, sensitive and specific − Room-temperature storage

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n n

Vaccines
n

Diagnostics
n

n

Fixed-dose combinations Specific pediatric formulations Low-cost, effective, easy-to-use first- and second-line treatments Combinations that could be used for pre-exposure prophylaxis

n

n

Induce several types of immunity: humoral, cell-mediated, mucosal Offer long-term protection against multiple clades Formulation and cost suitable for developing world use

n

Point-of-care test that quantifies viral load and CD4 count able to indicate when to start treatment and when to switch treatment in children and adults

BVGH Global Health Primer

3

HuMaN IMMuNODeFICIeNCy VIRuS (HIV)

P I P E l I n E * nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Vaccines
Sanofi-aventis (LIPO-5/aLVaC-canary pox vector) Merck (MRK-ad5 trivalent vaccine) Discontinued 09/2007 Oxford Biomedica/Oxford university/IaVI (DNa/MVa) Vical/VRC (HIV B gag/pol/nef, HIV a, C env) targeted Genetics/IaVI (tgaaC09) NIaID/VRC/IaVI (HIV-1 DNa plasmid + ad5) Bavarian Nordic (MVa-nef) aVaNt (LFn-p24-therapore) GSK (DNa antiviral-825780) GSK (Recombinant prophylaxis) CytRx (DP6-001) aaron Diamond aIDS Research Center/IaVI (aDMVa) Bavarian Nordic/NIaID/Pharmexa therion Biologics/IaVI (tBC-M4) GenPhar (multivalent HIV-1; therapeutic vaccine) Oxford Biomedica (Hi-8™ PrimeBoost™) alphaVax (multigene) Bavarian Nordic (MVa-BN® multiantigen) (MVa-BN® polytope)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn n nnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn n nnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn n nnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn n nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnn nnnn

targeted Genetics/IaVI (aaV-2) Novavax (VLP HIV-1)

Microbicides
Indevus Pharma (PRO 2000) Population Council (Carraguard®/PC-515) Cellegy/Biosyn (Savvy®1% C31G) ReProtect (BufferGel™) International Partnership for Microbicides (tMC120)

research & discovery

Preclinical

clinicalPhase I

clinicalPhase II

clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn

* This is not an exhaustive listing of all HIV vaccines and microbicides currently in development or clinical trials and excludes HIV drugs .

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
The worldwide market for HIV/AIDS products is rising because of several factors including increasing HIV prevalence, drug-resistance, and poor patient compliance with existing regimens . n Efficacious HIV drugs and vaccines, especially if affordable, will find markets in both the developed and developing worlds . By one estimate, annual sales of HIV/AIDS drugs are expected to grow from $7 .1 billion in 2005 to more than $10 .6 billion by 2015 . n Donor commitment to fighting HIV/AIDS includes the President’s Emergency Plan for AIDS Relief (PEPFAR), funded at $15 billion for 2003-2008 and $30 billion for 2008-2015 .
n

40

BVGH Global Health Primer

HuMaN IMMuNODeFICIeNCy VIRuS (HIV)

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

n

Continued need for highpotency, less-costly drugs Resistance is a growing issue

Vaccines need to overcome wide variability of virus strains, both in single patients and across populations

cd4 and vIral load dIagnostIcs

− Need to be accessible to developing world − Need to develop a rapid, quantitative test

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
World Health Organization (WHO) ~ www .who .int/topics/hiv_infections/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/hiv n National Institute for Allergy and Infectious Diseases (NIAID) ~ www .niaid .nih .gov/factsheets/hivinf .htm
n n

Key Organizations
n n n n n n n

AIDS Vaccine Advocacy Coalition (AVAC) ~ www .avac .org Alliance for Microbicide Development ~ www .microbicide .org Global Fund to Fight AIDS, Tuberculosis & Malaria ~ www .theglobalfund .org/en HIV Vaccine Trials Network (HVTN) ~ www .hvtn .org HIV InSite ~ www .hivinsite .ucsf .edu/InSite International AIDS Vaccine Initiative (IAVI) ~ www .iavi .org International Partnership for Microbicides ~ www .ipm-microbicides .org

Important Papers
AIDS Epidemic Update 2006 ~ http://data .unaids .org/pub/EpiReport/2006/2006_EpiUpdate_en .pdf Duerr, A, et al . HIV vaccines: new frontiers in vaccine development . Clin Infect Dis 43:500-511 (2006) n Gallo, RC . The end or the beginning of the drive to an HIV-preventive vaccine: a view from over 20 years . Lancet 366:1894-1898 (2005) n Lederman, MM, et al . Microbicides and other topical strategies to prevent vaginal transmission of HIV . Nat Rev Immunol 6:371-82 (2006) n Markel, H . The search for effective HIV vaccines . NEJM 353:753-757 (2005)
n n

BVGH Global Health Primer

41

Japanese encephalitis (Je)
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Japanese Encephalitis?
JE is a viral disease transmitted by mosquitoes, causing fever and flu-like symptoms . In severe cases, JE results in inflammation of the brain (encephalitis) . Death may result if the symptoms are not treated .

Global Burden
JE is the leading cause of viral encephalitis and neurological infection in Asia . The disease is severely unreported; 50,000 new cases are recorded annually that result in 15,000 deaths and a 75 percent JE-related disability rate . Over three billion people live in areas endemic for JE .

Geographic Distribution
JE is endemic in Asia, ranging from the islands of the Western Pacific in the east to the Pakistani border in the west, and from Korea in the north to Papua New Guinea in the south . JE distribution is linked to irrigated rice production combined with pig rearing .

Causative Agent/Transmission
The JE virus belongs to the family Flaviviridae. The viruses responsible for dengue fever, yellow fever, and West Nile disease are also flaviviruses . Mosquitoes belonging to the Culex tritaeniorhynchus and Culex vishnui groups, which breed in flooded rice fields, transmit JE . The virus circulates in birds and pigs, and tends to spill over into human populations only when Culex populations increase dramatically over a short period of time, as Culex mosquitoes prefer to feed on animals .

Presentation
Most JE virus infections are mild (fever and headache) or lack apparent symptoms . Approximately 1 in 200 infections results in severe disease characterized by rapid onset of high fever, headache, neck stiffness, disorientation, coma, seizures, spastic paralysis, and death . In these cases, JE affects the brain or the membranes around the brain (meninges) . Of those who survive severe JE, 30 percent suffer lasting damage to the central nervous system . In areas where the JE virus is common, encephalitis occurs mainly in young children because older children and adults have acquired immunity through prior exposure .

Trends
Large outbreaks of JE in India and Nepal have highlighted the continuing expansion of the geographic range of the disease in recent years .

42

BVGH Global Health Primer

JaPaNeSe eNCePHaLItIS (Je)

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
an inexpensive, field-ready technology (Mac Dot) has been developed but not commercialized.
n

PallIatIvE carE

kIllEd vaccInE (JE-vax)

− Intravenous fluid replacement can be used for rehydration − acetaminophen can be used to manage pain and fever

− − − −

expensive Requires three doses Offers short-term protection Reports of neurological and hypersensitivity reactions after vaccination
lIvE-attEnuatEd vaccInE

PlaQuE rEductIon nEutralIzatIon assay (Prnt)

− time intensive and costly − High biosafety-level requirements
n

n

hEmagglutInatIon InhIBItIon (hI)

− Inexpensive − used in China, but not available elsewhere − Currently being developed under improved GMP conditions

− Low specificity − High level of cross-reactivity with other flaviviruses
n

ElIsa

− Simple and sensitive − Some cross-reactivity with other flaviviruses − Not suitable for point-of-care testing

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n n n

Drug therapy not targeted

sEcond-gEnEratIon vaccInE

− Safer − Requires fewer doses − Should be compatible with the WHO expanded Program on Immunization (ePI) schedule

Simple Sensitive Low cross-reactivity with other flaviviruses

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Vaccines
Intercell/Novartis (Inactivated Vero cell-grown Sa14-14-2 strain) Biken, Kaketsuken (Inactivated Vero cell-grown Beijing strain) acambis/Sanofi Pasteur (ChimeriVax-Je Live, Sa14-14-2) Bavarian Nordic (Live MVa-BN® recombinant)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n n

Significant opportunity in travelers’ and military markets . One company estimates a global market of over $300 million .

BVGH Global Health Primer

43

JaPaNeSe eNCePHaLItIS (Je)

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

Difficult to develop therapeutic antivirals

n

evaluation of efficacy of Je vaccines against all four virus strains Immunity to fewer strains could increase susceptibility to DHF in the vaccinated when exposed to a new strain

Important to detect disease in early stages of infection, when intervention may be beneficial

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/vaccine_research/diseases/japanese_encephalitis/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dvbid/jencephalitis

Key Organizations
n

WHO Initiative for Vaccine Research (IVR) ~ www .who .int/vaccine_research/en

Important Papers
Anonymous . RNA sequence restrains fatal encephalitis . Focus Online (2006) Konstantin, V, et al . Chimeric vaccines against Japanese encephalitis, dengue and West Nile . New Generation Vaccines, 3rd ed . Chapter 47 . Eds . M Levine, JB Kapper, R Rappuoli, MA Liu, and MF Good . New York and Basel: Marcel Dekker (2004) n Monath, TP, et al . Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): Phase II clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen . JID 188:1213-1230 (2003) n Solomon, T. Flavivirus encephalitis. NEJM 351:370-378 (2004)
n n

44

BVGH Global Health Primer

Leishmaniasis
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Leishmaniasis?
Leishmaniasis is a widespread parasitic disease that affects the skin, mucosa, or internal organs, resulting in severe disfigurement, disability or death . Leishmania parasites are a genus of protozoa related to the trypanosomes that cause human African trypanosomiasis and Chagas disease .

Global Burden
Worldwide there are 12 million people infected with Leishmania. An estimated 350 million people are at risk for infection . There are an estimated 1 .7 million new cases and 45,000 deaths each year .

Geographic Distribution
Leishmaniasis is found in 88 countries, 72 of which are low-income countries . More than 90 percent of all cutaneous leishmaniasis cases, the most common form of the disease, are found in Afghanistan, Brazil, Iran, Peru, Saudi Arabia, and Syria . Approximately 90 percent of all visceral leishmaniasis cases, a less common but deadlier form of the disease, occur in Bangladesh, India, Nepal, Sudan, and Brazil .

Causative Agent/Transmission
The leishmaniases are caused by approximately 20 different species of protozoa that belong to the genus Leishmania. The parasites are transmitted by the bite of the female phlebotomine sandfly . Within the vertebrate host, parasites invade and replicate inside white blood cells such as macrophages and dendritic cells .

Presentation
Leishmania diseases can be classified into one of four forms: (1) visceral leishmaniasis (VL), commonly known as Kala-azar, is fatal if left untreated; (2) cutaneous leishmaniasis (CL), the most common form, is marked by a proliferation of self-healing skin lesions that produce significant scarring; (3) mucocutaneous leishmaniasis (MCL) is an ulcerative Leishmania infection that results in destruction of the mucosal membranes of the nose and mouth; and (4) diffuse cutaneous leishmaniasis (DCL), the most difficult Leishmania manifestation to treat, causes chronic ulcers and skin lesions resulting in severe disfigurement .

Trends
There is a profound need for safe, effective therapeutics and vaccines to combat the leishmaniases . Indeed, over the last 10 years, regions endemic for leishmaniasis have been growing, and there has been a sharp increase in the number of recorded cases of the disease . It is likely that a substantial number of cases are never recorded because declaration is compulsory in only 32 of the 88 countries affected by the disease .

BVGH Global Health Primer

4

LeISHMaNIaSIS

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
there are no modern vaccines against leishmaniasis. n In some endemic areas, a controlled lesion is created in an area of the skin normally covered by clothing, via inoculation of live parasite. While this lesion is active, the individual is protected from lesions on more visible parts of the body. this process, called leishmanization, is used to protect children from future lesions on the exposed parts of the body. this only protects against CL.

Diagnostics
n

mIltEfosInE (ImPavIdo®)

dIrEct agglutInatIon tEst (dat) WIth frEEzE-drIEd antIgEn

− approved in 2003 for use in India for VL, and in 2005 for use in Colombia for CL − Has shown a 95 percent response rate when used against VL − Currently the only effective oral treatment − Contraindicated in pregnancy
n

− First-line diagnostic − Highly sensitive and specific − Does not require special equipment
n

dIPstIcks k39/k26

ParomomycIn (amInosIdInE, humatIn®)

− K39 for serological diagnosis − Based on a recombinant antigen of L. chagasi − Requires cold storage
n

− approved in 2006 for use in India for VL − Granted “orphan drug” status − Injected
n

katEx (latEx agglutInatIon tEst)

PEntosam (ssg), amPhotErIcIn B, kEtoconazolE, PEntamIdInE, and antImony

− used to detect L. donovani antigen in urine samples − Requires cold storage

− Shows up to 60 percent resistance rates − Frequently have severe adverse events (up to nine percent of patients have fatal adverse reactions to antimony)

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n n n

Vaccines
n

Diagnostics
n

Oral formulation Short course of treatment Safer than current treatments High efficacy against all forms of the parasite, including drug-resistant ones

n

Highly efficacious subunit vaccine with lasting protection effective in preventing establishment of new infections, particularly on the face

n

Detection of early-stage, systemic disease thermostable

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
DNDi (Paromomycin) DNDi (Imiquimod topical cream) GSK/WRaIR (Sitamaquine) BioDelivery Sciences (amphotericin B) Lica Pharmaceuticals (Licochalcone a) DNDi (NPC116B/8-aminoquinoline)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

Vaccines
Razi Institute tehran, Iran (Killed Promastigote l. major with BCG and alum) Infectious Disease Research Institute (leish-111f + MPL-Se)

research & discovery

Preclinical

clinicalPhase I

clinicalPhase II

clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn

4

BVGH Global Health Primer

LeISHMaNIaSIS

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n

Potential military market; CL has been reported in hundreds of troops stationed in Iraq . The problem has become widespread enough that the CDC has advised soldiers returning from Iraq to wait a year before donating blood to prevent the spread of the parasite .

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

Scientific feasibility not an issue

Leishmanization suggests vaccination is possible but longlasting immunity may be difficult to achieve with a recombinant vaccine

thermostability may be difficult to achieve using antibody-based diagnostics

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/topics/leishmaniasis/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/leishmania

Key Organizations
Drugs for Neglected Diseases Initiative (DNDi) ~ www .dndi .org Institute for OneWorld Health (IOWH) ~ www .oneworldhealth .org n WHO Initiative for Vaccine Research (IVR) ~ www .who .int/vaccine_research/en n Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr
n n

Important Papers
n n n n n n

Coler, RN, and Reed, SG . Second-generation vaccines against leishmaniasis . Trends in Parasitol 21:244-249 (2005) Davies, CR, et al . Leishmaniasis: new approaches to disease control . BMJ 2003;v326:377-382 El-Sayed, NM, et al . Comparative genomics of trypanosomatid parasitic protozoa . Science 309:404-409 (2005) Hailu, A, et al . Visceral leishmaniasis: new health tools are needed . PLoS Med 2:e211 (2005) Ivens, AC, et al . The genome of the kinetoplastid parasite, Leishmania major. Science 309:436-442 (2005) Peacock, CS, et al . Comparative genomic analysis of three Leishmania species that cause diverse human disease . Nature Genetics 39:839-47 (2007)

BVGH Global Health Primer

4

Lymphatic Filariasis (LF)
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Lymphatic Filariasis?
Lymphatic filariasis (LF), also known as elephantiasis, is caused by parasitic worms and leads to severe disfigurement of the extremities . While not directly life-threatening, LF is among the world’s leading causes of permanent and long-term disability . Those infected are disabled in their most productive stage of life, resulting in an economic and psychosocial burden on afflicted individuals, families, and communities .

Global Burden
More than 120 million people are infected with LF; over 40 million are seriously disfigured by the disease . It is estimated that 1 .3 billion people are at risk for the disease .

Geographic Distribution
LF is endemic in 83 countries . One-third of the people infected with LF live in India and one-third live in Africa . Most of the remaining cases are distributed throughout South Asia, the Pacific, and the Americas .

Causative Agent/Transmission
Thread-like, parasitic filarial worms Wuchereria bancrofti and Brugia malayi cause lymphatic filariasis . These worms lodge in the lymphatic system, where they live for four to six years and produce millions of immature microfilariae (minute larvae) that circulate in the blood . Mosquitoes transmit the disease .

Presentation
The worst symptoms of the chronic disease generally appear in adults . Elephantiasis of an entire leg, arm, the vulva, or the breast—swelling up to several times normal size—is common . In endemic communities, some 10 to 50 percent of men suffer from genital damage, especially hydrocoele (fluid-filled balloon-like enlargement of the sacs around the testes) and elephantiasis of the penis and scrotum . Once hydrocoele formation has begun, the most effective way to deal with it is generally surgery, but this solution is too expensive for the majority of people affected by the disease .

Trends
In tropical and subtropical areas where lymphatic filariasis is well established, the prevalence of infection is continuing to increase . A primary cause of this increase is the rapid and unplanned growth of cities, which creates numerous breeding sites for the mosquitoes that transmit the disease .

4

BVGH Global Health Primer

LyMPHatIC FILaRIaSIS (LF)

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

comBInatIon trEatmEnt— alBEndazolE WIth dIEthylcarBamazInE (dEc) or IvErmEctIn

None

mIcroscoPy

− use of single doses of two drugs administered concurrently is 99 percent effective in removing microfilariae from the blood for a full year after treatment − Current standard of care is to treat children annually to prevent disease and break the chain of infection − treatment with DeC can cause serious side effects if certain other diseases are co-endemic to the region, as occurs in africa; ivermectin is used as an alternative in these regions

− Difficult because the parasites have a “nocturnal periodicity” that restricts their appearance in the blood to only the hours around midnight − Inexpensive reagents
n

antIgEn-dEtEctIon “Ict” tEst

− Simple, very sensitive, and specific − Detects circulating parasite antigens without the need for laboratory facilities − uses only finger-prick blood droplets taken anytime of the day
n

noW® fIlarIasIs tEst

− Rapid immunodiagnostic test − Detects antigens in whole blood, serum, or plasma − expensive to use except to identify populations at risk

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

n

Kills adult worms (macrofilaricidal) and reduces swelling Decreases necessity of repeated, annual treatment; inhibits microfilariae production

Prevents establishment of infection by microfilariae

n

n

n

Further development of diagnostics for Brugia malayi Less expensive point-of-care diagnostics would allow assessment of more at-risk individuals Increased monitoring and surveillance ability adapt existing serologic assays to work with oral fluids or urine

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
Regimens of tetracyclines, rifampicin, and combinations of antibiotics and conventional antifilarial drugs anti-Wolbachia treatments Moxidectin
research & discovery
nnn nnnn nnn nnnn nnn nnnn

Preclinical

clinicalPhase I

clinicalPhase II

clinicalPhase III

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
The critical issues for LF are delivery into remote, endemic areas and maintenance of treatment over many years to reduce adult disease and break the chain of infection . Currently, all drugs used to treat LF are donated . n Many current LF treatments are also effective against other diseases common in the developing world; new drugs might likewise have multiple markets .
n

BVGH Global Health Primer

4

LyMPHatIC FILaRIaSIS (LF)

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

n

Drugs and drug combinations should avoid interactions with other tropical diseases Recent evidence suggests (June 2007) that ivermectin resistance is emerging in other diseases; this emphasizes the need for new drugs in the event resistance appears

n

n

Lack of an in vitro culture system for filariae absence of tools for easy genetic manipulation Need for advances in animal model development

n

n

the major challenge is to reduce cost of diagnostics below $1 Maintain the current standard of tests that can be done at any time, day or night High sensitivity

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/topics/filariasis/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/lymphaticfilariasis

Key Organizations
n

The Global Alliance to Eliminate Lymphatic Filariasis ~ www .filariasis .org

Important Papers
Summary of immediate needs and opportunities for research on lymphatic filariasis . Supplement to AJTMH 71 (2004) n Molyneaux, D . Lymphatic filariasis (elephantiasis) elimination: a public health success and development opportunity . Filaria Journal 2:13 (2003) n Tan, JZG . The elimination of lymphatic filariasis: a strategy for poverty alleviation and sustainable development – perspectives from the Philippines . Filaria Journal 2:12 (2003)
n 

0

BVGH Global Health Primer

Malaria
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn ` nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Malaria?
Malaria is a parasitic disease transmitted by infected mosquitoes . It can be categorized as either uncomplicated or severe . Symptoms of uncomplicated malaria include fever, chills, body aches, nausea, headache, vomiting, and diarrhea . Severe disease can cause anemia, acute respiratory distress syndrome, coma, and death .

Global Burden
Over 40 percent of the world’s population is estimated to be at risk for malaria . Each year, there are between 300 million and 500 million new cases and one million deaths . Over 70 percent of malaria deaths occur in children under the age of five . In Africa, malaria has been estimated to result in more than $12 billion in lost annual GDP; malaria control would cost a fraction of this sum .

Geographic Distribution
Malaria is endemic in more than 100 countries in tropical and subtropical regions of Africa, Asia, and Central and South America . An estimated 90 percent of deaths occur in sub-Saharan Africa .

Causative Agent/Transmission
Malaria is caused by four species of protozoa of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum causes the most severe and deadly form of the disease . P. vivax is less deadly, but worldwide, is the most prevalent Plasmodium parasite and is the cause of the most morbidity . Transmission of all species occurs via the bite of an infected female Anopheles mosquito .

Presentation
Once in the bloodstream, parasites migrate to the liver, invade hepatocytes, and undergo multiple rounds of replication . Following this asymptomatic period (which lasts anywhere from a week to months depending on the species of Plasmodium), parasites are released from the hepatocyte and infect red blood cells (RBCs) . During this erythrocytic stage, parasites replicate several times inside the RBCs, eventually causing them to burst and thereby freeing the parasites to infect new RBCs . The symptoms of uncomplicated disease are associated with the erythrocytic stage . The destruction of RBCs may also cause jaundice and anemia . Severe disease may result in kidney failure, seizures, or coma .

Trends
Increasingly, Plasmodium are resistant to existing antimalarials . Use of combination therapies and the development of new drugs and vaccines are strategies being pursued to guard against drug resistance . Several of the 10 significant Anopheles vector species are exhibiting pesticide resistance, even to the powerful pesticide DDT .

BVGH Global Health Primer 

1

MaLaRIa

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
the leading drugs used in the developing world, chloroquine and Fansidar®, are increasingly ineffective across wide areas because of resistant parasites. New artemisinin-based combination therapies (aCts) are currently the best treatments but are ten times as costly. Other more expensive drugs are available in the developed world.
n

Vaccines
n

Diagnostics
n

None

lIght mIcroscoPy

− Labor-intensive and requires skill to read slides − High sensitivity and specificity when used by well-trained staff, but this is rare in the field
n

raPId dIagnostIc tEsts (rdts)

chloroQuInE

− affordable and widely available − Now ineffective in most endemic areas due to resistance
n

sulfadoxInE-PyrImEthamInE (sP/fansIdar®)

− Resistance increasing rapidly
n

− More expensive than microscopy − Vulnerable to high temperatures and humidity − Can be highly sensitive and specific − Cannot distinguish severe disease, active disease, and background parasite from one another − Binax NOW® test is the only rapid test approved in the united States

artEmIsInIn-BasEd comBInatIon thEraPIEs (acts)

− Currently the best treatment − Not licensed for use in the united States but often found overseas − More expensive than chloroquine or SP

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n n n

Vaccines
n

Diagnostics
n n n n n

n

Inexpensive (in tens of cents) easy to manufacture Significant shelf life Simple, regular, and short dosing regimen (one to three days) effective against all four species of Plasmodium

n n

n n

Vaccine for infants with delivery tied to ePI schedules effective for at least two years Demonstrated non-interference with ePI vaccines thermostable Need to boost immunogenicity and duration of effect

Quick and non-invasive Field appropriate affordable Requires minimal training Distinguishes severe disease from uncomplicated disease 

2

BVGH Global Health Primer

MaLaRIa

P I P E l I n E ( s E l E c t I t E m s o n l y ) nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
Sanofi-aventis/DNDi (artesunate-amodiaquine) Registered 3/07 DNDi (artesunate-mefloquine) GSK/MMV (Chlorproguanil-dapsone artesunate) university of Iowa/Shin Poong Pharma/MMV (Pyronaridine-artesunate/PyRaMax®) Sigma-tau/Chongqing Holley/Holleykin/Oxford university/ Mahidol university/MMV (Dihydroartemisinin piperaquine) Pfizer (zithromax® - chloroquine) Novartis/MMV (pediatric Coartem®) GSK (tafenoquine/8-aminoquinoline) Immtech Pharmaceuticals (Pafuramidine maleate/DB289) Jomaa Pharma Gmbh (Fosmidomycin-clindamycin/Fosclin) Sanofi-aventis (Ferroquine) GSK/MMV (4[1H]- pyridones) GSK/MMV (Isoquine) Sanofi-aventis (SaR 97276) Sanofi-aventis (SaR 116242) topotarget/WHO-tDR (HDaC inhibitor) ut Southwestern/university of Washington/MMV (Dihydroorotate dehydrogenase inhibitor) amyris/IOWH (synthetic artemisinin) university of Nebraska/Monash university/MMV (Next generation synthetic peroxide) GSK/MMV (4(1H) pyridones back-ups) GSK/uCSF/MMV (falcipain cysteine protease) Biotec/LSHtM/Monash university/MMV (DHFR) GSK/MMV (Pf enoyl-aCP reductase/FabI) Novartis ItD/MMV (9 discovery projects) Broad Institute/Genzyme/MMV (5 discovery projects)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

nnn nnnn nnn nnnn

nnn nnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn nnn nnnn

BVGH Global Health Primer 

3

MaLaRIa

Vaccines
GSK/MVI (RtS,S/aS02a/aS01B) Oxford BioMedica/Wellcome trust (Fowlpox-9 + CSP, LSa-1/MVa +CSP + LSa-1) Pevion Biotech (PeviPRO™ - PeV3a) WRaIR/NIH/uSaID (aMa1/aSO2a/FMP1) Sanaria/MVI (radiation attenuated sporozoites) ICGeB/MVI (Duffy Binding Protein) Shanghai-Wanxing/MVI/WHO (MSP-1 19/aMa-1 chimera (PfCP2.9) P. pastoris exp.) Latrobe university/GroPep/MVI (MSP2) Crucell (Recomb ad35 adenovirus vector) GenVec/MVI (multivalent - adenovirus vectors) Monash university/MVI (MSP4 & MSP5) NIH/NIaID/MVI (MSP1-42 & aMa-1) GSK/WRaIR/MVI (LSa-1) Sanofi-aventis (preventive)

research & discovery

Preclinical

clinicalPhase I

clinicalPhase II

clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
A highly efficacious vaccine, marketed to travelers and the military as well as to the developing world, could yield a positive return on investment (ROI) for its developer provided the public sector is willing to support the purchase for resource-poor countries . n Because malaria is such an overwhelming burden to African societies, donor funding for malaria prevention and treatment can be expected to be a priority for many years to come and is likely to support the development, manufacture, and delivery of a highly efficacious vaccine .
n

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n n n

Diagnostics
n

Resistance may make new drugs obsolete quickly

Needs to overcome antigenic variation No correlates of protection No predictive animal models

Differentially diagnose malaria from acute febrile illness 

4

BVGH Global Health Primer

MaLaRIa

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n

World Health Organization (WHO) ~ www .who .int/topics/malaria/en

Key Organizations
n n n n n n

Medicines for Malaria Venture (MMV) ~ www .mmv .org PATH Malaria Vaccine Initiative (MVI) ~ www .malariavaccine .org Multilateral Initiative on Malaria (MIM) ~ www .who .int/tdr/diseases/malaria Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr Roll Back Malaria ~ www .rbm .who .int Global Fund to Fight AIDS, Tuberculosis & Malaria ~ www .theglobalfund .org/en

Important Papers
n

n n n n

Alonso, PL, et al . Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial . Lancet 366:2012-8 (2005) Alonso, PL, et al . Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial . Lancet 364:1411-20 (2004) Gardner, MJ, et al . Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419:498-511 (2002) Greenwood, BM, et al . Malaria . Lancet 365:1487-1498 (2005) Touré, YT, et al . Disease watch – focus: malaria . Nature Rev: Microbiol 2:276-277 (2004)

BVGH Global Health Primer 

Schistosomiasis
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Schistosomiasis?
Parasitic worms that infect blood vessels cause schistosomiasis . Symptoms of early infection include blood in urine or stool . Over time the infection leads to urinary tract or liver damage . Death often results from internal hemorrhage .

Global Burden
The disease is endemic in 74 developing countries, infecting more than 200 million people in rural agricultural and peri-urban areas . Approximately 120 million are thought to experience chronic debilitating symptoms . Twenty million suffer more severe consequences from the disease . An estimated 779 million people worldwide are at risk for the disease . Children under 14 are especially vulnerable to infection leading to progressive disease and early death .

Geographic Distribution
More than 80 percent of people infected with schistosomiasis live in sub-Saharan Africa . The disease is also prevalent in the Middle East and can be found in parts of Southeast Asia and Latin America .

Causative Agent/Transmission
Schistosomiasis is caused by trematode flatworms of the genus Schistosoma. Infected individuals expel Schistosoma eggs in their feces or urine . When humans come in contact with contaminated water, schistosome larvae, which initially develop in freshwater snails, penetrate the skin and enter the bloodstream . The parasites migrate through the lungs to the liver where they mature, mate, and migrate together to blood vessels near either the intestine (S. mansoni) or bladder (S. haematobium). Over the next five years, the female lays anywhere from 200 to 2,000 eggs per day . About half the eggs produced are excreted in the feces or urine; the remainder becomes trapped in body tissues and organs, where they can cause severe damage, particularly to the liver . The parasite itself causes little damage to the human body; it is the eggs that bring about harmful symptoms .

Presentation
Schistosomiasis can take two forms–urinary and intestinal . In urinary schistosomiasis, urination becomes painful and urine turns blood red . There is progressive damage to the bladder, ureters and then kidneys . In intestinal schistosomiasis, there is progressive enlargement of the liver and spleen and hypertension of the abdominal blood vessels . Eggs breaking through from blood vessels into the intestine leads to blood in stools . In advanced cases, the functioning of organs such as liver, spleen, and kidneys becomes impaired . Death can result from bladder cancer (urinary schistosomiasis) or to bleeding from varicose veins in the esophagus or gastrointestinal tract .

Trends
Original estimates of the burden of schistosomiasis failed to adequately take into account the symptoms, sequelae, and chronic nature of the disease . Subsequent analysis revealed that it is among the most serious tropical diseases . Countries such as Nigeria are concerned that the unrecognized schistosomiasis problem may come to the forefront of their health-care issues . 

BVGH Global Health Primer

SCHIStOSOMIaSIS

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

PrazIQuantEl (dIstocId®, BIltrIcIdE®)

None

dIPstIck mIcroscoPy

− Standard of care − Safe and highly effective in curing an infected patient − Does not prevent reinfection − Off patent and inexpensive; costs as low as $0.20/dose
n

− Detection of blood in urine
n

− Most practical method for diagnosis − Inefficient; requires laboratory, multiple analyses − Does not catch early infections
n

othErs - oxamnIQuInE, mEtrIfonatE

antIBody dEtEctIon ElIsa

− Difficult to obtain − Do not work on all forms of the disease

− Sensitivity and specificity vary widely
n

− Highly sensitive; species can be determined by immunoblot

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n n

Vaccines
n n n n

Diagnostics
n n n

affordable effective against multiple species Long-lasting

Requires few doses extended protection thermostable High immunogenicity

Simple; appropriate for field-use Sensitive Detects all stages of disease

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
uCSF Sandler Center (K11777 cysteine protease inhibitor)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnn nnnnnnnnnn

Vaccines
Institute Pasteur (S. Haematobium 28kD GSt subunit) Bachem/uSaID/SVDP (S. mansoni paramyosin + tPI multiepitope) FioCruz (S. mansoni Sm14)

research & discovery

Preclinical

clinicalPhase I

clinicalPhase II

clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n

This is primarily a disease of the very poor . Donor support will be required to encourage innovation .

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
−n

Diagnostics
n

Current therapy is adequate

Need for further research into target antigens

Diagnostic tests need to be adapted to affordable, point-of-care formats

BVGH Global Health Primer 

SCHIStOSOMIaSIS

a d d I t I o n a l I n f o r m a t I o n nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
General Disease Links
n n

World Health Organization (WHO) ~ www .who .int/topics/schistosomiasis/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/ncidod/dpd/parasites/schistosomiasis

Key Organizations
Schistosomiasis Control Initiative (SCI) ~ www .schisto .org Special Programme for Research and Training in Tropical Diseases (TDR) ~ www .who .int/tdr n WHO Initiative for Vaccine Research (IVR) ~ www .who .int/vaccine_research/en
n n

Important Papers
Chitsulo, L, et al . Disease watch – focus: schistosomiasis . Nature Rev: Microbiol 12:12-13 (2004) Fenwick, A . New initiatives against Africa’s worms . Trans . Royal Soc Trop Med Hyg 100: 200-207 (2006) n Pearce, EJ . Progress towards a vaccine for schistosomiasis . Acta Tropica 86:309-313 (2003)
n n 

BVGH Global Health Primer

Shigellosis
B a c k g r o u n d nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
What Is Shigellosis?
Shigellosis is an infection by bacteria of the genus Shigella that causes severe abdominal symptoms including diarrhea, dysentery, abdominal cramps, fever, and rectal pain . Shigellosis can result in death . The disease is more dangerous than other gut pathogens because it can penetrate the lining of the intestine and cause severe inflammation of the intestine and systemic complications .

Global Burden
Worldwide there are approximately 165 million cases of shigellosis annually, causing over 1 .1 million deaths . Nearly 70 percent of all episodes and approximately 60 percent of all deaths attributable to shigellosis involve children under five years old .

Geographic Distribution
Distribution of Shigella serotypes varies by geography: S. sonnei and S. flexneri are prevalent in the United States, S. boydii in Middle East, Africa, and South Asia . The most severe form, S. dysenteriae, is primarily found in South Asia and sub-Saharan Africa .

Causative Agent/Transmission
Shigellosis is caused by bacterial infection by one of four species of Shigella: S. dysenteriae, S. flexneri, S. boydii and S. sonnei . Transmission occurs via consumption of water contaminated by human waste .

Presentation
Shigella multiply within the epithelial cells of the colon, cause cell death, and spread laterally to infect and kill adjacent epithelial cells, causing mucosal ulceration, inflammation and bleeding . Shigella dysenteriae type 1 produces severe disease and may be associated with life-threatening complications . Symptoms of shigellosis include diarrhea and/or dysentery with frequent mucoid bloody stools, abdominal cramps, and tenesmus . In some children, shigellosis causes seizure . Adults can experience Reiter’s Syndrome as a result of the disease, leading to eye and joint inflammation and reactive arthritis .

Trends
Diarrheal diseases represent an enormous disease burden across all developing countries . Shigellosis is also a concern for travelers . Although shigellosis can be treated with antibiotics, the most effective antibiotics are expensive . Their misuse has led to the emergence of drug-resistant Shigella strains .

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
there is no way to differentiate, at the diarrheal stage, between shigellosis and several other parasitic or bacterial infections. n Standard clinical microbiology n No molecular tests available

PallIatIvE carE

None

− Oral rehydration therapy can be used to treat symptoms − antibiotics and IV fluids are sometimes given in severe cases, where available

BVGH Global Health Primer 

SHIGeLLOSIS

t a r g E t P r o d u c t P r o f I l E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n n

Vaccines
n n n n n

Diagnostics
n

affordable, high-potency antibiotic Improved oral rehydration therapy

Single or two-dose Oral delivery effective for at least two years Multivalent acceptable side effects

ability to differentiate between Shigella and other gut infections such as eteC and protozoa

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Vaccines
NICHD/Robbins (O-specific polysaccharide conjugate) Institut Pasteur/WRaIR/IVI (SC602; S. flexneri 2a) WRaIR (S. flexneri 2a Invaplex 50) Institut Pasteur (SC599; live attenuated S. dysenteriae) emergent Biosolutions (activax) university of Maryland CVD (Hybrid CVD 1208; Shigella + eteC) university of Maryland CVD (Hybrid CVD 1208S; Shigella + eteC) MIDRP/Hale (WR Ss1, Sd1; live attenuated S. sonnei and S. dysenteriae) aridis (live attenuated, typhoid vector expressing S. sonnei, S. dysenteriae, and S. flexneri 2a O-PS) aVaNt (Live attenuated cholera vector (Peru 15) expressing S. sonnei O-PS) IVI (Shigella ribosomes) MIDRP (Hybrid SC 608; live attenuated S. flexneri 2a expressing eteC CfaB andLtB) endobiologics (O-specific polysaccharide) Vital Probes/DaRPa (bacterial ghosts)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnn

nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn

m a r k E t o P P o r t u n I t I E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
n

Potential opportunity in travelers’ and military markets may improve global market opportunity .

d E v E l o P m E n t I s s u E s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
n

Vaccines
n

Diagnostics
n

antibiotic resistance

n

n

Multiple strains make it difficult to design a multivalent vaccine with sufficient coverage Certain major cell-surface markers are not immunogenic, making them poor candidates for vaccines Specifications for travelers’ and military markets may differ from endemic markets

Key issue is the rapid identification of all serotypes 

0

BVGH Global Health Primer

SHIGeLLOSIS

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General Disease Links
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World Health Organization (WHO) ~ http://www .who .int/vaccine_research/diseases/diarrhoeal/en/index6 .html Centers for Disease Control & Prevention (CDC) ~ http://www .cdc .gov/ncidod/dbmd/diseaseinfo/ shigellosis_g .htm

Key Organizations
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International Center for Diarrheal Disease Research, Bangladesh (ICDDR,B): ~ www .icddrb .org/pub

Important Papers
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Walker, RI . Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in children in developing countries . Vaccine 23:3369-3385 (2005)

BVGH Global Health Primer 

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tuberculosis (tB)
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What Is Tuberculosis?
TB is a pandemic bacterial infection that most commonly affects the lungs (pulmonary TB) . In otherwise healthy individuals, most infections remain latent and are asymptomatic . About 10 percent of people infected with TB will develop disease . In immunocompromised patients such as those with HIV, active TB disease is extremely common .

Global Burden
One-third of the global population – two billion people – is infected with TB; between five and ten percent of those infected will develop active TB disease . WHO estimates that each year close to nine million people become sick with TB and two million die . TB is the leading killer of HIV-positive patients .

Geographic Distribution
TB is a worldwide problem . Eighty percent of the global burden is borne by only 22 countries, and one-third of those infected live in India and China . TB case numbers in 2005, by WHO region, were as follows: Africa (3,773,000), the Americas (448,000), Eastern Mediterranean (881,000), Europe (525,000), Southeast Asia (4,809,000), and the Western Pacific (3,616,000) .

Causative Agent/Transmission
TB is caused by Mycobacterium tuberculosis (MTB) and is spread via an aerosol route; when persons with active pulmonary TB exhale, cough, sneeze, or talk, they release tiny droplets containing bacteria that can be inhaled by others . Once inside the lung, MTB invades and replicate within macrophages . The host’s immune response may result in the formation of granulomas that contains the infection . Alternatively, MTB may escape control by the granuloma and replicate within the lung and/or disseminate to tissues throughout the body . In contrast to many bacteria, MTB is extremely slow-growing (~20–24 hour doubling time in log phase), a fact that has important implications on course of treatment .

Presentation
Symptoms of active pulmonary TB include a cough lasting more than two weeks, coughing up blood, fatigue, fever, chills, night sweats, and weight and appetite loss . Latent TB is neither contagious nor symptomatic . If a carrier’s immune system is compromised, the chance that he or she will develop active TB increases dramatically .

Trends
TB is a leading cause of death in the developing world . The recent increase in TB deaths stems from a multitude of factors including pandemic HIV, drug resistance, war and increasing poverty (which reduce treatment compliance) . The incidence of multidrug-resistant TB (MDR-TB) is rising at an alarming rate (~425,000 cases in 2004) and is not restricted to the developing world . Moreover, recent WHO data has revealed the existence of “super strains” of MDRTB: 79 percent of such MDR-TB strains are resistant to three of the four first-line drugs . MDR-TB that is also resistant to certain second-line drugs is known as Extensively drug-resistant TB (XDR-TB) and has recently been identified in HIV-positive populations and others . Active TB is the primary cause of HIV-related death in Africa . 

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BVGH Global Health Primer

tuBeRCuLOSIS (tB)

E x I s t I n g P r o d u c t s nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
Current tB therapies are delivered as combinations of multiple antibiotics over six to nine months. Serious problems of efficacy and toxicity reduce compliance and increase the generation of resistant bacteria.
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Vaccines
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Diagnostics
there are no rapid, point-of-care diagnostics to distinguish latent from active disease; tuberculin tests do not work in HIV-positive patients.
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Bcg (BacIllE calmEttE-guErIn)

rIfamPIcIn IsonIazId, PyrazInamIdE, strEPtomycIn & EthamButol

− Introduced in 1963
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− Introduced in 1940s-60s − Most frequently used in threeand four-drug combinations − treatment often causes toxic side effects
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EthIonamIdE, Para-amIno salIcylatE (Pas), cyclosErInE, amIkacIn, kanamycIn, fluoroQuInolonEs

− Most commonly administered vaccine in the world − Safe and inexpensive − targeted at newborn infants only, per WHO − Not used in the united States, Canada, or parts of europe, but common in the developing world − Variable and limited efficacy − appears to reduce risk of severe childhood tB disease, but, when given to infants, it may provide limited or no protection against pulmonary tB in adults or adolescents; this subject is controversial with numerous studies providing conflicting results

staInEd sPutum smEar

− Microscopic first indicator of the presence of mycobacteria − Provides physician with a preliminary confirmation of the diagnosis
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PurIfIEd ProtEIn dErIvatIvE (PPd) skIn tEst, a.k.a. mantoux tEst

− used to diagnose LtBI − Nonspecific
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culturE

− Gold standard for diagnosis, needed for drug susceptibility testing to diagnose MDR- and xDR-tB
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molEcular amPlIfIcatIon

− Second-line drugs − Generally less potent and more toxic (except fluoroquinolones) − used to treat drug-resistant tB

− Rapid, sensitive − too expensive for use in developing countries
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QuantIfEron-tB gold & tsPot.tB antIgEn tEsts

− antigens are not present in nontuberculosis mycobacteria or in BCG

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Drugs
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Vaccines
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Diagnostics
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Rapid acting (courses of two months or less) Can be co-administered with antiretrovirals Safer than existing treatments effective against MDR-tB Highly potent easily used in the field

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Safe to administer to HIV-positive infants and to adolescents at least 70 percent efficacy against tB disease at least as safe as BCG

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Rapid and easily performed Specific and sensitive (to replace existing skin test) Safe and effective in HIVpositive patients able to distinguish latent tB from active disease unaffected by prior BCG inoculation

BVGH Global Health Primer 

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tuBeRCuLOSIS (tB)

P I P E l I n E nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn
Drugs
OFLOtuB consortium/eC/WHO tDR/Lupin (Gatifloxacin) Bayer/tB alliance/Johns Hopkins university (Moxifloxacin) tibotec/Johnson & Johnson (tMC 207 Diarylquinolines) Novartis/tB alliance (Pa-824 Nitroimidazole) Otsuka (OPC-67683 Nitroimidazole) Sequella/NIH (Diamine SQ-109) Lupin Pharmaceuticals (LL-3858) FaSgen (Synthase Inhibitor FaS200313) Sankyo/Sequella (Capuromycins) university of auckland/Novartis ItD/NIaID/tB alliance (Nitroimidazole analogs) KRICt/yonsei university/tB alliance (Quinolones) Cumbre/tB alliance (Multi-functional molecules) GSK/tB alliance (Bacterial topoisomerase inhibitor) GSK/tB alliance (Inha inhibitors) GSK/tB alliance (Pleuromutilins) GSK/tB alliance (Focused screening – 2 projects) GSK/Rockefeller university/texas a&M (Malate synthase inhibitor) Institute of Materia Medica/BtttRI/tB alliance (Riminophenazines) astrazeneca (Screening and target Identification) Sequella (dipiperidine SQ609) Immtech/university of Illinois-Chicago (dication screening) Cornell university (Proteasome inhibitors) Summit (Nat)
research & discovery Preclinical clinicalPhase I clinicalPhase II clinicalPhase III

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BVGH Global Health Primer

tuBeRCuLOSIS (tB)

Vaccines
Oxford university (MVa-85a) GSK/aeras (72f (M72)) SSI/Intercell (Hybrid 1) Crucell/aeras (aeras 402) SSI/Intercell/aeras (HyVac 4) aeras (Shigella RNa capsids) aeras (aeras x03) Institut Pasteur (BCG::RD1) Vakzine Projekt Management/Max Planck Institute (rBCG:ΔureC-Hly) albert einstein College of Medicine (6020 & 6030 attenuated Mtb) Institut Pasteur/tB-VaC (ΔphoP/R) uCLa (RBCG30 expressing human IFN-g)

research & discovery

Preclinical

clinicalPhase I

clinicalPhase II

clinicalPhase III

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Diagnostics
Sequella (transdermal tB Patch) Biotec Labs/FIND (FastPlaque & FPResponse tB) Becton, Dickinson & Co./FIND (MGIt tB) Sequella (the Bronx Box) eiken Chemical/FIND (LaMP technology) Proteome Systems/FIND (Rapid antigen-based) Cepheid/FIND (Genexpert System tB)

research & discovery

Preclinical

clinicalPhase I

clinicalPhase II

clinicalPhase III

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According to the Global Alliance for TB Drug Development (TB Alliance), the current TB drug market is estimated at $450 million and is projected to reach $700 million by 2010 . n With nine million new cases each year, and many fold greater new latent infections, there is a very large target patient population . n BVGH estimates the peak annual market for a TB vaccine is over $750 million for a booster vaccine and over $400 million for a BCG replacement vaccine, with most of these revenues coming from developed and emerging economies . n Despite potentially profitable developed and emerging country markets, donor support will still be needed for delivery to the neediest patients .
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Drugs
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Vaccines
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Diagnostics
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Latent tB is difficult to reach with standard antibiotics Persistent bacteria often minimally affected by therapy

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Lack of immune correlates of protection or surrogate markers that predict clinical efficacy of a vaccine Development and maintenance of clinical trial site capacity

New diagnostics will require the discovery of tB-specific serum biomarkers

BVGH Global Health Primer 

tuBeRCuLOSIS (tB)

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General Disease Links
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World Health Organization (WHO) ~ www .who .int/tb/en Centers for Disease Control & Prevention (CDC) ~ www .cdc .gov/nchstp/tb/default .htm

Key Organizations
Global Alliance for TB Drug Development ~ www .tballiance .org Aeras Global TB Vaccine Foundation ~ www .aeras .org n Stop TB Partnership ~ www .stoptb .org n Global Fund to Fight AIDS, Tuberculosis & Malaria ~ www .theglobalfund .org/en
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Important Papers
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Andries, K, et al . A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307:223-227 (2005) Ghandi, NR, et al . Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa . Lancet 368:1575-80 (2006) Reichman, LB, and Tanne, JH . Timebomb: the global epidemic of multi-drug resistant tuberculosis. New York: McGraw-Hill (2002) Skeiky, YAW, and Sadoff, JC . Advances in tuberculosis vaccine strategies . Nature Rev: Microbiol 4:469-76 (2006) The Stop TB Strategy ~ www .who .int/tb/publications/2006/who_htm_tb_2006_368 .pdf Tuberculosis Vaccines: The Case for Investment ~ www .bvgh .org/documents/ BVGHTBVaccineReport10-6FINAL .pdf 

BVGH Global Health Primer

aBOut BVGH

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Expand the pipeline of products targeting neglected diseases. Build incentives to attract the most capable biopharmaceutical innovators. Generate demand among donors for investment in innovative R&D.

BIO Ventures for Global Health, a nonprofit organization, is accelerating the development of innovative vaccines, drugs and diagnostics to treat the most devastating diseases of the developing world. Our mission is to harness the biopharmaceutical skills and resources that have transformed medicine in the industrialized world to help save the lives of millions in the developing world.

Bringing Innovation to Neglected Diseases Despite many recent initiatives to improve health care for patients in the developing world, we are still far from launching groundbreaking new medicines that could conquer infectious diseases such as malaria, tuberculosis, and African sleeping sickness. Tools and technologies exist today that can make major inroads on developing world diseases – and offer hope for cures in our lifetimes.
To access these tools, we must address the barriers that have hindered the most innovative players in modern medicine from engaging in global health research and development. The perceptions of insufficient markets, inadequate funding, and unfamiliarity with these diseases have so far deterred industry involvement. By focusing more of today’s global health investment on innovation and bringing to bear the full capabilities of advanced biopharmaceutical R&D, we can succeed in our quest for better health for patients throughout the world.

BVGH Goals At BVGH we are devoting our efforts to building marketbased solutions to encourage greater industry investment and ensure a sustainable pipeline of new products to save lives and relieve suffering from developing-world diseases. Specifically, we aim to–

BVGH Accomplishments BVGH works at the interface of industry, donors, disease-focused foundations, and academia. We identify compelling targets for biopharmaceutical impact, define viable markets for new global health products, and catalyze private sector R&D through new strategies, partnerships, and funding. Recently we– n Published a comprehensive business case for investment in TB vaccines, revealing a viable global market sufficient to attract industry investment, and presented our findings to leading biopharmaceutical vaccine firms. Spurred by our conclusion that the TB vaccine market could generate as much as $1 billion per year, several companies boosted their TB vaccine R&D efforts and have sought to license technologies key to creating a new vaccine. n Launched our Innovation Map project designed to link proven technology platforms in biotech’s top drug discovery companies with scientific needs for key neglected diseases. Our published report, to be released in November 2007, will outline our findings and lay the groundwork for new models of collaboration and partnership for the fight against neglected diseases. n Announced plans with the Biotechnology Industry Organization (BIO) and the Bill & Melinda Gates Foundation to co-host an international conference in March 2008—Partnering for Global Health Forum. The Forum will promote new collaborations and ideas to tackle global health challenges by bringing together leaders from the biopharmaceutical industry, academia, international NGOs, governments, investors and donors. www.pghforum.org Learn more about BIO Ventures for Global Health at our website www.bvgh.org 

BVGH Global Health Primer

Building Biotech Solutions for Diseases of the Developing World
BIO Ventures for Global Health 1225 eye Street, NW, Suite 1010 Washington, DC 20005 uSa Phone: +1 202-312-9260 Fax: +1 443-320-4430 www.bvgh.org