- Email: [email protected]
Reaching Maturity — 25 Years of the TDR
Reviews
Reaching Maturity – 25 Years of the TDR C.M. Morel In its first 25 years of existence, TDR has become a key player in the development of new tools for the control of tropical diseases and the training of researchers from disease-endemic countries. In order to maintain its leading position, cope with new health challenges and profit from new avenues opened by science and technology breakthroughs, a new strategic vision is now being implemented. It aims at a closer interaction with health systems and disease control programmes, capacity strengthening based on selected research initiatives and full exploitation of scientific and technological advances in the biomedical, social and information sciences, as discussed here by Carlos Morel. Twenty-five years ago, a handful of visionaries gained the approval of the 27th World Health Assembly for the creation of an international special programme for research and training in tropical diseases, co-sponsored by three United Nations organizations and hosted at the WHO1. This was in response to pleas from disease-endemic countries, where neglected diseases exact a huge toll on lives and productivity2. A clear and simple mandate guided its mission: (1) to conduct research on a defined group of tropical diseases aimed at developing new tools to help control them; and (2) to train scientists and strengthen institutions from the endemic countries, so that they could play a major role in this endeavour. This was the beginning of ‘TDR’ (the acronym for its official name of ‘UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases’), an organization funded entirely by contributions from a variety of donors. The creation of TDR represented a significant first shift of focus of a highly distorted global health research agenda, where 90% of the resources invested in health research are directed against diseases that affect only 10% of the global population – a disparity now known as the ‘10/90 disequilibrium’3,4. TDR’s mandate represents an immense challenge. The TDR ‘disease portfolio’ encompasses diseases (Table 1) for which there are no licensed vaccines, front-line drugs are losing their effectiveness, and solutions (when they exist) do not reach those who need them. Partly as a result of market forces, the private sector has failed repeatedly in developing efficient interventions. Today, previously neglected diseases of the poor are under coordinated attack. Some have almost been conquered, others have survived, and new ones have emerged. The battle is far from won. The need for assistance to help disease-endemic countries to realize their full human and economic potential remains as essential now as it was 25 years ago.
Carlos Morel is at TDR – World Health Organization, 20 Avenue Appia, CH-1211 Geneva 27, Switzerland.. Fax: +41 22 791 4854, e-mail: [email protected], http://www.who.int/tdr 522
TDR achievements TDR works with a diverse range of partners, occupying a unique position as trusted broker linking academia, governments, donors, industry, non-governmental organizations (NGOs), health professionals and affected communities. It is a formula that is well proven: external reviews have shown that TDR has made many significant contributions to disease control in its 25 years5 (Fig. 1), as documented in relation to TDR’s role in the development of multidrug therapy6, ivermectin7 and fumigant canisters8 for leprosy, onchocerciasis and Chagas disease, respectively (Table 2). In fact, these three diseases9–11 and lymphatic filariasis12 are in the process of being eliminated as public health problems. TDR has made significant and often pathfinding contributions in four main areas: • Basic and strategic research. TDR pioneered the organization of networks of researchers and institutions dedicated to the study of parasite genomes13, because it is envisaged that genome sequencing and mapping, gene discovery and functional genomics research will provide new ways for drug, vaccine and diagnostics development14. TDR was instrumental in fostering the use of biotechnological advances in the area of vector genetics and Plasmodium–mosquito relationships as an innovative approach for malaria control in the future by genetic manipulation of the vector15–17. • Product research and development. TDR has worked with a variety of partners – public and private sectors, NGOs, civil society – to develop various tools for the control of tropical diseases18,19. The latest developments include the successful Phase II clinical trials of miltefosine as an oral drug against visceral leishmaniasis20, and the initiation within TDR of the Medicines for Malaria Venture (MMV) – now a non-profit Swiss Foundation (Box 1). TDR is also recognized as a major global contributor to the field of vaccine research and development for malaria, leishmaniasis and schistosomiasis, especially in the development of guidelines and protocols and in the monitoring of field trials21,22. • Field research. TDR’s comparative advantage in organizing and implementing large-scale, multi-centric field studies at the global level has yielded exceptional results. TDR was a key player in demonstrating the usefulness of insecticide-impregnated bednets in the prevention of malaria mortality23, and the potential of combination therapy in the prevention of drug resistance24. The principal strategy of both the African Programme for Onchocerciasis Control (APOC) and the Onchocerciasis Elimination Programme of the Americas (OEPA) derives directly from research conducted by TDR in collaboration with Merck & Co. Inc., which showed that the drug ivermectin is effective and suitable for mass administration in the control of onchocerciasis. TDR research also led to the development of appropriate tools and procedures that have become standard practice in the execution of control programmes (Table 2). Notable among these are the means of rapid epidemiological mapping of onchocerciasis
0169-4758/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0169-4758(00)01815-9
Parasitology Today, vol. 16, no. 12, 2000
Reviews (REMO)25 and lymphatic filariasis (RAGFIL)26, as well as the community-directed treatment (ComDT)27 approach that ensures drug administration coverage reaches, and is sustained at, levels that are needed to achieve disease control. • Training of human resources and research capability strengthening. TDR is recognized as a global leader in this area, particularly regarding Africa, and invests 25% of its budget in these activities28,29. During its existence, TDR has awarded 1115 Research Training Grants to 1048 trainees from 416 institutions/research groups from 76 developing countries, and 275 Institutional Strengthening Grants to 230 principal investigators from 175 institutes/research groups from 60 developing countries. These grants have helped establish a core group of skilled scientists and strong institutions in developing countries. Taking stock TDR’s 25th anniversary represented an opportunity for critically evaluating its overall performance and for shaping a new strategy targeted specifically at today’s changing priorities – as well as those of tomorrow. As a first step in this process, in July 1999, TDR’s governing body, the Joint Coordinating Board (composed of representatives of governments, donors and of cosponsors), approved the inclusion of TB and dengue in TDR’s disease portfolio and, in 2000, endorsed the new ‘TDR Strategy 2000–2005’ (the full version of the Strategy is available on the TDR website – see Box 1). TDR’s new strategy is in synergy with the new vision of health research and the new corporate strategy of the WHO30,31, and proposes a natural evolution of the Special Programme as it reaches maturity (Box 2). In order to implement its new strategy, TDR will need to interact much more actively with ministries of health, health systems and disease control programmes at country and regional levels. Although such interactions did occur occasionally in the past, the new strategy calls for a much more proactive role of TDR in this direction. This will require stronger partnerships with the donor community, international organizations and foundations, as well as the continuing participation of the global scientific community in all areas – from basic to applied research, from biomedical to human sciences, and from laboratory-based to field research. It will not be an easy task. Although much has been accomplished in the first 25 years of TDR, the challenges today (Box 3) are even more formidable than when TDR was created. Meeting these challenges will require renewed commitment. TDR will remain one of the leaders in setting the public-sector agenda for research and development in tropical infectious diseases – eg. TDR plays a lead role in the Multilateral Initiative for Malaria (MIM) (Box 1). But TDR must also strengthen other present collaborations (Box 1), such as with the Roll Back Malaria global partnership and the Stop TB initiative, and build new ones, engaging in global public–private partnerships47,48. TDR itself was one of the first such partnerships to emerge in the 1980s19,47 and is now actively involved in partnerships such as the Global Alliance for Vaccines and Immunization (GAVI) (Box 1) and the Global Alliance for TB Drug Development49. In addition, work initiated50 and carried out in TDR has given rise to the Parasitology Today, vol. 16, no. 12, 2000
Table 1. Tropical disease dataa Disease burden DALYs (thousands)
Deaths (thousands)
Malaria
Male Female Totalb Male Female Totalb 22 758 22 240 44 998 553 532 1086
Tuberculosis
19 030 14 257
33 287 1003 666
1669
Lymphatic filariasis
3777
1141
4918
0
0
0
African trypanosomiasis
1111
937
2048
37
30
66
Leishmaniasis
1200
782
1983
32
25
57
Schistosomiasis
1174
758
1932
8
6
14
Onchocerciasis
623
461
1085
0
0
0
Chagas disease
400
277
676
11
10
21
Leprosy
253
223
476
2
1
3
Dengue
220
245
465
6
7
13
a
b
Global burden of disease in disability-adjusted life years (DALYs) and deaths for the ‘TDR diseases’ (1999 estimates), from The World Health Report 2000 (WHO, Geneva; WHO website, Box 1). Discrepancies in totals are due to rounding up and down of figures.
Global Forum for Health Research and the MMV, both independent, non-profit organizations (Box 1). As well as its partnership activities, TDR will continue to focus and develop its key operational strengths, which are found in knowledge management, global overview of tropical disease research issues, and the ability to foster North–South and South–South collaborations, thus strengthening research capacity. The new strategy emphasizes the need for TDR to act as a bridge between research potential and the realities of country-level control operations and their implementation – and the need to engage the world’s scientific community, interdisciplinary experts and affected communities at every step in the process. TDR will have to both gather and distribute knowledge and wisdom, new and old, from and to all sources. To help accomplish this, TDR will continue to expand and diversify its information gathering and dissemination systems and make extensive use of electronic communications, including a website (TDR website, Box 1). With the new strategy, TDR reaches maturity as a knowledge-management network organization, harnessing the full potential of science and technology in the fight against tropical diseases. Acknowledgements I thank Andy Crump and Lisa Schwarb for Fig. 1, Nina Mattock for final revision, and all TDR staff for valuable contributions, comments and suggestions. References 1 Lucas, A.O. (1985) TDR: a very ‘Special Programme’. World Health May, 19–20 2 Gwatkin, D.R. and Guillot, M. (2000) The Burden of Disease Among the Global Poor (Health, Nutrition and Population Series), The World Bank 3 Commission on Health Research for Development (1990) Health Research: Essential Link to Equity in Development, Oxford University Press 4 Global Forum for Health Research (2000) The 10/90 Report on Health Research 2000, Global Forum for Health Research
523
Reviews Table 2. Products from TDR and its partnersa,b Years 1982 1982 1983 1983 1981–1984
Disease Leprosy Leprosy African trypanosomiasis Schistosomiasis Onchocerciasis
1984 1984 1984
Malaria Malaria Chagas disease
1985 1985
African trypanosomiasis Malaria
1987 1980–1989
Onchocerciasis Chagas disease
Ivermectin Fumigant canisters
1990
Eflornithine Artemether DNA probes for Onchocerca volvulus Single-dose DEC
Rhône-Poulenc Rorer OCP WHO/CTD
1993 1993 1994 1994
African trypanosomiasis Malaria Onchocerciasis Lymphatic filariasis Onchocerciasis Malaria Leishmaniasis Leishmaniasis
Ministry of Public Health, Philippines; WHO/MAP OCP; Merck & Co. Inc. Ministry of Health of Argentina, National Research Council of Argentina and CHEMOTECNICA, S.A., Buenos Aires Hoechst Marion Roussel
REMO Integrated management of childhood illness Lipid-associated amphotericin B Direct agglutination test
1994
Schistosomiasis
Praziquantel combinations
1994
Lymphatic filariasis
Detection and monitoring of adult Wuchereria bancrofti in humans by ultrasonography
1995 1996
Onchocerciasis Malaria
ComDT Insecticide-treated bednets
1997
Malaria
1997 1997 1999
Schistosomiasis Leprosy Lymphatic filariasis Lymphatic filariasis Malaria Leprosy Visceral leishmaniasis Malaria Malaria Schistosomiasis
Iron supplementation for prevention of death from severe anaemia Schistosoma haematobium morbidity by ultrasonography Ofloxacin plus rifampicin plus minocycline Rapid mapping of filariasis
The World Bank UNICEF; WHO/CHD; IDRC; WHO/CTD NexStar Institut de Médecine Tropicale Prince Leopold, Antwerp, Belgium; University of Amsterdam; WHO/CTD SmithKline Beecham; E. Merck Pharma; WHO/CTD FIOCRUZ, FACEPE, Fundação Nacional de Saude, Clinica Radiologica de Pernambuco (Brazil) OCP/APOC; The World Bank; Merck & Co Inc. UNICEF; USAID; IDRC; CDC; CIDA; Wellcome Trust; Save the Children Fund; London School of Hygiene and Tropical Medicine, Italian cooperation; Ministries of Health in Ghana, Tanzania, Gambia, Kenya, and Burkina Faso UNICEF; Swiss Development Cooperation; Spanish Agency for International Cooperation CERMES/OCCGE; Ministry of Health, Niger National leprosy programmes; various NGOs WHO/CEE; Liverpool School of Tropical Medicine WHO/CPE; SmithKline Beecham; Merck & Co. Inc. Dutch cooperation; Artecef and WRAIR National leprosy programmes; various NGOs Asta Medica
1991 1991 1993
1999 2000 In the pipeline In the pipeline In the pipeline In the pipeline In the pipeline a
b
Product Combination drug regimens for pauci-bacillary leprosy Combination drug regimens for multi-bacillary leprosy CATT Diagnostic urine filtration test Bacillus thuringiensis H-14 for black fly control Mefloquine Mefloquine plus sulphadoxine–pyrimethamine Rapid test for blood bank screening with defined antigens Tsetse traps for control of epidemics Microtest test kit for drug sensitivity
Albendazole combinations Artemotil Ofloxacin plus rifampicin combination Miltefosine oral LAPDAP oral Artesunate rectal Artemether oral as a prophylatic
Partner(s) National leprosy programmes; various NGOs National leprosy programmes; various NGOs Institute of Tropical Medicine ‘Prince Leopold’, Anvers, Belgium WHO/PDP Institute Pierre Richet, Bouake; OCP; TEKNAR/Sandoz & Thermotrilogy; VECTOBAC/Abbott WRAIR; Hoffmann La Roche WRAIR; Hoffmann La Roche Fundación Campomar and Laboratorios Gador, Buenos Aires, Argentina WHO/PDP; ORSTOM, France
SmithKline Beecham Knoll; R.P. Scherer; Scanpharm Chinese Academy of Preventive Medicine; Swiss Tropical Institute
For most, if not all, of the products listed, TDR had as partners individual scientists funded from various sources, as well as trainees and institutions that were recipients of TDR grants or research capacity strengthening projects (see also Fig. 1). Abbreviations: APOC, African Programme for Onchocerciasis Control; CATT, Card agglutination test; CERMES, Center for Research on Meningitis and Schistosomiasis; ComDT, Community-directed therapy for onchocerciasis; DEC, diethylcarbamazine; CDC, Centers for Disease Control and Prevention; CIDA, Canadian International Development Agency; FACEPE, Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco; IDRC, International Development Research Centre; NGO, non-governmental organization; OCCGE, Organisation de Coordination de la Cooperation pour la lutte contre les Grandes Endemies; OCP, Onchocerciasis Control Programme; ORSTOM, Institut Français de Recherche Scientifique pour le Dévelopment en Coopération; REMO, Rapid epidemiological mapping of onchocerciasis; USAID, US Agency for International Development; WHO/CEE, WHO department for Strategy Development and Monitoring for Eradication and Elimination; WHO/CHD, WHO division of Child Health and Development; WHO/CPE, WHO department for Communicable Diseases Control, Prevention and Eradication; WHO/CTD, WHO Control of Tropical Diseases unit; WHO/MAP, WHO Malaria Action Programme; WHO/PDP, WHO Parasitic Diseases Programme; WRAIR, Walter Reed Army Institute for Research.
524
Parasitology Today, vol. 16, no. 12, 2000
Reviews Box 1. Websites relevant to TDR Activities Name (and acronym) Medicines for Malaria Venture (MMV) TDR Strategy 2000–2005 Multilateral Initiative for Malaria (MIM) Roll Back Malaria (RBM) Stop TB Initiative (STB) Global Alliance for Vaccines and Immunization (GAVI) Global Forum for Health Research (GFHR) TDR Website WHO Website
Box 2. The New Strategy of the TDR • A reinforced focus on ‘implementation research’, or the research needed during the introduction of a new tool into disease control by the health systems of diseaseendemic countries. As the successful examples of the onchocerciasis and Chagas disease control programmes have demonstrated, research should be present during all phases of operations, from planning to implementation and evaluation11,32–35. • Full exploration of the new opportunities provided by science and technology – such as genomics, bioinformatics and high-throughput screening – which open new ways for accelerated discovery of new drugs, vaccines and diagnostics14, as well as new perspectives for vector control36. • Exploration of new opportunities of collaboration through public–private partnerships19,37. • A renewed emphasis on social, economic and behavioural research to achieve a better understanding of the limitations and opportunities posed by contextual factors to control and prevent tropical diseases. • Greater involvement of researchers and institutions from disease-endemic countries in all areas of TDR activity, with a high emphasis on capacity strengthening based on selected research activities. • Intensive use of new information and communications technology38.
5 Wigzell, H. et al. (1998) Third External Review – Final Report [TDR/JCB(21)98.5: Third External Review of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)], WHO 6 Milleron, R. et al. (1998) TDR’s Contribution to the Development of Multidrug Therapy for Leprosy (Reference Document 4, Third External Review/TDR) [TDR/ER/RD/98.4: Third External Review of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)], WHO 7 Fujisaki, T. and Reich, M. (1998) TDR’s Contribution to the Development of Ivermectin for Onchocerciasis (Reference Document 3, Third External Review/TDR) [TDR/ER/RD/98.3: Third External Review of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)], WHO 8 Fujisaki, T. and Reich, M. (1998) TDR’s Contribution to the Development of the Fumigant Canister for Controlling Chagas Disease (Reference Document 5, Third External Review/TDR) [TDR/ ER/RD/98.5: Third External Review of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)], WHO 9 Anon. (2000) Leprosy – global situation. Weekly Epidemiol. Rec. 75, 226–226 10 Onchocerciasis Control Programme (1994) 20 Years of Onchocerciasis Control in West Africa, WHO 11 Moncayo, A. (1999) Progress towards interruption of transmission of Chagas disease. Mem. Inst. Oswaldo Cruz 94, 401–404 12 World Health Assembly (1997) Elimination of Lymphatic Filariasis as a Public Health Problem (Resolution 29 of the 50th World Health Assembly), WHO
Parasitology Today, vol. 16, no. 12, 2000
Website http://www.malariamedicines.org http://www.who.int/tdr/about/strategy http://mim.nih.gov http://www.rbm.who.int http://www.stoptb.org http://www.vaccinealliance.org http://www.globalforumhealth.org http://www.who.int/tdr http://www.who.int
Box 3. Challenges for TDR in the Year 2000 and Beyond • TB39,40, dengue41,42, malaria43,44 and African trypanosomiasis45, which continue to impose a heavy toll among the poorest populations2. • Microbial drug resistance, which is closing some of the few windows of opportunity in disease control46. • HIV/AIDS, unknown when TDR was created, which is undermining global health and exacerbating the clinical aspects of diseases such as TB and leishmaniasis. • New patterns of disease transmission and distribution, which are being introduced by environmental, economic and political changes related to globalization.
13 Johnston, D.A. et al. (1999) Genomics and the biology of parasites. BioEssays 21, 131–147 14 Anon. (1998) Report of WHO/TDR Scientific Working Group on the utilization of genomic information for tropical disease drug and vaccine discovery (TDR/Genomics/98.1: http://www. who.int/tdr/ publications/publications/genomic.htm) WHO/ TDR 15 Crampton, J.M. et al. (1990) Transgenic mosquitoes: a future vector control strategy. Parasitol. Today 6, 31 16 Anon. (1991) Report of the Meeting ‘Prospects for Malaria Control by Genetic Manipulation of its Vectors’ (TDR/BCV/MAL-ENT/91.3), WHO and TDR 17 Catteruccia, F. et al. (2000) Stable germ line transformation of Anopheles stephensi, a mosquito vector of human malaria. Nature 405, 959–962 18 Reich, M.R. (2000) The global drug gap. Science 287, 1979–1981 19 Lucas, A. (2000) Public-Private Partnerships: Illustrative Examples (Workshop on Public-Private Partnerships in Public Health, Endicott House, Dedham, MA, 7–8 April), Harvard School of Public Health 20 Jha, T.K. et al. (1999) Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. New Engl. J. Med. 341, 1795–1800 21 World Health Organization (1997) Guidelines for the Evaluation of Plasmodium falciparum Vaccines in Populations exposed to Natural Infections (TDR/MAL/VAC/97), WHO 22 Modabber, F. (2000) First generation leishmaniasis vaccines in clinical development: moving, but what next? Curr. Opin. AntiInfective Invest. Drugs 2, 35–39 23 Lengeler, C. et al. (1996) Net Gain: A New Method for Preventing Malaria Deaths, IDRC, TDR 24 Von Seidlein, L. et al. (2000) Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial. Lancet 355, 352–357 25 Ngoumou, P. et al. (1994) A rapid mapping technique for the prevalence and distribution of onchocerciasis: a Cameroon case study. Ann. Trop. Med. Parasitol. 88, 463–474 26 World Health Organization (1998) Research on Rapid Geographical Assessment of Bancroftian Filariasis (TDR/TDF/COMDT/98.2), WHO 27 World Health Organization (1996) Community-Directed Treatment with Ivermectin: Report of a Multi-Country Study (TDR/AFR/ RP/96.1), WHO
525
TDR progress indicators Main industry partners (1975–2000)
1999 Lymphatic filariasis
Rapid Epidemiological Mapping • ACF Beheer (Netherlands) • Air Liquide (France) • Asta Medica (Germany) • Aquila Biopharmaceuticals (USA) • Bayer A.G. (Germany) 1997 Leprosy • Biobras-Bioquimica do Brasil (Brazil) Ofloxacin plus • Biotech Australia (Australia) rifampicin combination • Burroughs Wellcome Company (USA) • Chemotecnica S.A. (Argentina) Ofloxacin plus rifampicin • Ciba Geigy, Ltd (Switzerland) plus minocycline • Daiichi Pharmaceutical Co. Ltd (Japan) • Eli Lilly and Company (USA) • E. Merck Pharma (Germany) • F. Hoffman La-Roche (Switzerland) • Genetic Institutes (USA) • Glaxo Group Research Ltd (UK) • Hoechst Marion Roussel (France) • IHARABRAS S.A. (Brazil) 1994 Leishmaniasis • International Federation of Pharmaceutical Direct Agglutination Test Manufacturers Associations (Switzerland) • Janssen Research Foundation (Belgium) • Kunming Pharmaceuticals (China) • Laboratorios Gador (Argentina) • Merck and Co. Inc. (USA) 1992 Chagas disease • NexStar (USA) Dipstick test for blood bank screening • Novartis (Switzerland) • Novo Nordisk A/S (Denmark) • Pasteur-Mérieux-Connaught (USA) • Pharmacia Farmitalia Carlo Elba (Italy) • Rhône-Poulenc Rorer Doma (France) 1990 African • SmithKline Beecham (UK/Belgium) Trypanosomiasis • Tibotec (Belgium) • Vaccine Solutions (Australia) Eflornithine 1991 Onchocerciasis • Vestar Inc. (USA) DNA probes for Onchocerca volvulus • Zeneca Pharmaceuticals (UK)
1983 African Trypanosomiasis Card Agglutination Test
1982 Leprosy Drug combinations for paucibacillary leprosy Drug combinations for multibacillary leprosy
1987 Onchocerciasis Ivermectin
2000 Malaria Artemotil
2000 Malaria Parasitology Today
Germline transformation of Anopheles
1999 Lymphatic filariasis Albendazole combinations
1996 Malaria 1996 Multidisease
Insecticide-treated bednets
Healthy Women Counselling Guide
1995 Onchocerciasis 1994 Schistosomiasis
Community-directed treatment with ivermectin
Praziquantel combinations
Research Capacity Strengthening Institutional Grants (2000) 112 projects* in 41 countries (27 Least Developed Countries)
Fumigant canister
* Including Re-Entry Grants and Career Development Awards
Fig. 1. Examples of products, industry partnerships and capacity building.
Number of Grants
1–4 5–9 > 10
www.who.int/tdr
1989 Chagas disease
Reviews 28 Beattie, P. et al. (1999) Strengthening Health Research in the Developing World: Malaria Research Capacity in Africa, The Trustees of the Wellcome Trust 29 Davies, C. et al. (2000) Out of Africa: training collaboration and malaria research. Parasitol. Today 16, 219–220 30 Brundtland, G.H. (1998) Reaching out for world health. Science 280, 2027–2027 31 Brundtland, G.H. (1999) A Corporate Strategy for the WHO Secretariat. Report by the Director-General (EB105/3, Executive Board 105th Session), WHO 32 Morel, C.M. (1999) Chagas disease, from discovery to control – and beyond: history, myths and lessons to take home. Mem. Inst. Oswaldo Cruz 94, 3–16 33 Molyneux, D.H. and Morel, C. (1998) Onchocerciasis and Chagas disease control: the evolution of control via applied research through changing development scenarios. Br. Med. Bull. 54, 327–339 34 Remme, J.H.F. (1995) The African Programme for Onchocerciasis Control: preparing for launch. Parasitol. Today 11, 403–406 35 Plaisier, A.P. et al. (1995) Irreversible effects of ivermectin on adult parasites in onchocerciasis patients in the Onchocerciasis Control Programme in West Africa. J. Infect. Dis. 172, 204–210 36 Balter, M. (1999) Gene sequencers target malaria mosquito. Science 285, 508–509 37 Reich, M.R. (2000) Public-private partnerships for public health. Nat. Med. 6, 617–620 38 Lucky, R. (2000) The quickening of science communication. Science 289, 259–264
39 Dye, C. et al. (1999) Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. J. Am Med. Assoc. 282, 677–686 40 World Health Organization (2000) Global Tuberculosis Control. WHO Report 2000 (WHO/CDS/TB/2000.275), WHO 41 Rigau-Pérez, J.G. et al. (1998) Dengue and dengue haemorrhagic fever. Lancet 352, 971–977 42 Gubler, D.J. and Meltzer, M. (1999) Impact of dengue/dengue hemorrhagic fever on the developing world. Adv. Virus Res. 53, 35–70 43 Snow, R.W. et al. (1999) Estimating mortality, morbidity and disability due to malaria among Africa’s non-pregnant population. Bull. WHO 77, 624–640 44 Snow, R.W. et al. (1999) A preliminary continental risk map for malaria mortality among African children. Parasitol. Today 15, 99–104 45 Smith, D.H. et al. (1998) Human African trypanosomiasis: an emerging public health crisis. Br. Med. Bull. 54, 341–355 46 World Health Organization (2000) Overcoming Antimicrobial Resistance – World Health Organization Report on Infectious Diseases 2000, WHO/CDS/2000.2 WHO 47 Buse, K. and Walt, G. (2000) Global public-private partnerships: part I – a new development in health? Bull. WHO 78, 549–561 48 Buse, K. and Walt, G. (2000) Global public-private partnerships: part II – what are the health issues for global governance? Bull. WHO 78, 699–709 49 Butler, D. (2000) Consortium aims to kick-start TB research. Nature 403, 692–692 50 Godal, T. et al. (1996) Investing in Health Research and Development. Report of the Ad Hoc Committee on Health Research Relating to Future Intervention Options (TDR/Gen/96.1), WHO
The Interface Between Epidemiology and Population Genetics S. Paterson and M.E. Viney Modern biology increasingly integrates disparate disciplines. Here, Steve Paterson and Mark Viney examine the interface between epidemiology and population genetics. They argue that infection and inheritance can be considered as analogous processes, and that epidemiology and population genetics share many common features. They consider the potential for existing population genetic theory to dissect epidemiological patterns in field studies and they consider other relationships between genetics and epidemiology that provide a research challenge for the future. Epidemiology is the study of disease dynamics within a population. Current models of infection dynamics attempt to describe the process of infection from one host to another and the consequence of this process on host and parasite populations1. Population genetics is concerned with the inheritance of genes at the population level2. There is, therefore, a clear analogy between inheritance – the transmission of genes from one generation to the next – and infection – the transmission of parasites from one host to another – and the population-level consequences of each of these processes. Inheritance and infection both occur within populations and, in this respect, both population genetics and epidemiology are concerned with problems of scale; specifically, to extend a basic biological process (inherSteve Paterson and Mark Viney are at the School of Biological Sciences, University of Bristol, Woodland Road, Bristol, UK BS8 1UG. Tel: +44 117 928 7470, Fax: +44 117 925 7374, e-mail: [email protected] 528
itance or infection) that occurs at the individual level to the population-level consequence of that process3. The interface of inheritance and infection Modeling drug resistance in parasite populations is one area where population genetics and epidemiology come together4,5. The task is to construct a model that combines both the spread of drug-resistance genes through a parasite population and the spread of drugresistant parasites through a host population (Box 1). Recent work by Smith et al.6 provides a good example of how this can be achieved. Here, the basic unit of the model is the parasite itself, rather than the infected host. Parasites of different anthelmintic genotypes (eg. RR, Rr or rr, where R is the anthelmintic-resistance allele) were modeled deterministically within a host population that was subjected to various anthelmintic dosing regimens. In each parasite generation, adult parasites mate and produce progeny whose genotype frequencies are determined by Hardy–Weinberg processes from the allele frequencies of the parents. This mating function allowed the frequency of the anthelmintic-resistant and -sensitive alleles to be followed within the parasite population. One important prediction from this model was that there was little difference in the rate of spread of anthelminticresistant parasites under chemoprophylatic or chemotheraputic dosing regimens. Therefore, this model directly uses population genetic and epidemiological modeling to understand the movement of anthelmintic parasites through a host population subject to different dosing regimens and, thus, is powerfully predictive.
0169-4758/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0169-4758(00)01776-2
Parasitology Today, vol. 16, no. 12, 2000
Reaching Maturity – 25 Years of the TDR C.M. Morel In its first 25 years of existence, TDR has become a key player in the development of new tools for the control of tropical diseases and the training of researchers from disease-endemic countries. In order to maintain its leading position, cope with new health challenges and profit from new avenues opened by science and technology breakthroughs, a new strategic vision is now being implemented. It aims at a closer interaction with health systems and disease control programmes, capacity strengthening based on selected research initiatives and full exploitation of scientific and technological advances in the biomedical, social and information sciences, as discussed here by Carlos Morel. Twenty-five years ago, a handful of visionaries gained the approval of the 27th World Health Assembly for the creation of an international special programme for research and training in tropical diseases, co-sponsored by three United Nations organizations and hosted at the WHO1. This was in response to pleas from disease-endemic countries, where neglected diseases exact a huge toll on lives and productivity2. A clear and simple mandate guided its mission: (1) to conduct research on a defined group of tropical diseases aimed at developing new tools to help control them; and (2) to train scientists and strengthen institutions from the endemic countries, so that they could play a major role in this endeavour. This was the beginning of ‘TDR’ (the acronym for its official name of ‘UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases’), an organization funded entirely by contributions from a variety of donors. The creation of TDR represented a significant first shift of focus of a highly distorted global health research agenda, where 90% of the resources invested in health research are directed against diseases that affect only 10% of the global population – a disparity now known as the ‘10/90 disequilibrium’3,4. TDR’s mandate represents an immense challenge. The TDR ‘disease portfolio’ encompasses diseases (Table 1) for which there are no licensed vaccines, front-line drugs are losing their effectiveness, and solutions (when they exist) do not reach those who need them. Partly as a result of market forces, the private sector has failed repeatedly in developing efficient interventions. Today, previously neglected diseases of the poor are under coordinated attack. Some have almost been conquered, others have survived, and new ones have emerged. The battle is far from won. The need for assistance to help disease-endemic countries to realize their full human and economic potential remains as essential now as it was 25 years ago.
Carlos Morel is at TDR – World Health Organization, 20 Avenue Appia, CH-1211 Geneva 27, Switzerland.. Fax: +41 22 791 4854, e-mail: [email protected], http://www.who.int/tdr 522
TDR achievements TDR works with a diverse range of partners, occupying a unique position as trusted broker linking academia, governments, donors, industry, non-governmental organizations (NGOs), health professionals and affected communities. It is a formula that is well proven: external reviews have shown that TDR has made many significant contributions to disease control in its 25 years5 (Fig. 1), as documented in relation to TDR’s role in the development of multidrug therapy6, ivermectin7 and fumigant canisters8 for leprosy, onchocerciasis and Chagas disease, respectively (Table 2). In fact, these three diseases9–11 and lymphatic filariasis12 are in the process of being eliminated as public health problems. TDR has made significant and often pathfinding contributions in four main areas: • Basic and strategic research. TDR pioneered the organization of networks of researchers and institutions dedicated to the study of parasite genomes13, because it is envisaged that genome sequencing and mapping, gene discovery and functional genomics research will provide new ways for drug, vaccine and diagnostics development14. TDR was instrumental in fostering the use of biotechnological advances in the area of vector genetics and Plasmodium–mosquito relationships as an innovative approach for malaria control in the future by genetic manipulation of the vector15–17. • Product research and development. TDR has worked with a variety of partners – public and private sectors, NGOs, civil society – to develop various tools for the control of tropical diseases18,19. The latest developments include the successful Phase II clinical trials of miltefosine as an oral drug against visceral leishmaniasis20, and the initiation within TDR of the Medicines for Malaria Venture (MMV) – now a non-profit Swiss Foundation (Box 1). TDR is also recognized as a major global contributor to the field of vaccine research and development for malaria, leishmaniasis and schistosomiasis, especially in the development of guidelines and protocols and in the monitoring of field trials21,22. • Field research. TDR’s comparative advantage in organizing and implementing large-scale, multi-centric field studies at the global level has yielded exceptional results. TDR was a key player in demonstrating the usefulness of insecticide-impregnated bednets in the prevention of malaria mortality23, and the potential of combination therapy in the prevention of drug resistance24. The principal strategy of both the African Programme for Onchocerciasis Control (APOC) and the Onchocerciasis Elimination Programme of the Americas (OEPA) derives directly from research conducted by TDR in collaboration with Merck & Co. Inc., which showed that the drug ivermectin is effective and suitable for mass administration in the control of onchocerciasis. TDR research also led to the development of appropriate tools and procedures that have become standard practice in the execution of control programmes (Table 2). Notable among these are the means of rapid epidemiological mapping of onchocerciasis
0169-4758/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0169-4758(00)01815-9
Parasitology Today, vol. 16, no. 12, 2000
Reviews (REMO)25 and lymphatic filariasis (RAGFIL)26, as well as the community-directed treatment (ComDT)27 approach that ensures drug administration coverage reaches, and is sustained at, levels that are needed to achieve disease control. • Training of human resources and research capability strengthening. TDR is recognized as a global leader in this area, particularly regarding Africa, and invests 25% of its budget in these activities28,29. During its existence, TDR has awarded 1115 Research Training Grants to 1048 trainees from 416 institutions/research groups from 76 developing countries, and 275 Institutional Strengthening Grants to 230 principal investigators from 175 institutes/research groups from 60 developing countries. These grants have helped establish a core group of skilled scientists and strong institutions in developing countries. Taking stock TDR’s 25th anniversary represented an opportunity for critically evaluating its overall performance and for shaping a new strategy targeted specifically at today’s changing priorities – as well as those of tomorrow. As a first step in this process, in July 1999, TDR’s governing body, the Joint Coordinating Board (composed of representatives of governments, donors and of cosponsors), approved the inclusion of TB and dengue in TDR’s disease portfolio and, in 2000, endorsed the new ‘TDR Strategy 2000–2005’ (the full version of the Strategy is available on the TDR website – see Box 1). TDR’s new strategy is in synergy with the new vision of health research and the new corporate strategy of the WHO30,31, and proposes a natural evolution of the Special Programme as it reaches maturity (Box 2). In order to implement its new strategy, TDR will need to interact much more actively with ministries of health, health systems and disease control programmes at country and regional levels. Although such interactions did occur occasionally in the past, the new strategy calls for a much more proactive role of TDR in this direction. This will require stronger partnerships with the donor community, international organizations and foundations, as well as the continuing participation of the global scientific community in all areas – from basic to applied research, from biomedical to human sciences, and from laboratory-based to field research. It will not be an easy task. Although much has been accomplished in the first 25 years of TDR, the challenges today (Box 3) are even more formidable than when TDR was created. Meeting these challenges will require renewed commitment. TDR will remain one of the leaders in setting the public-sector agenda for research and development in tropical infectious diseases – eg. TDR plays a lead role in the Multilateral Initiative for Malaria (MIM) (Box 1). But TDR must also strengthen other present collaborations (Box 1), such as with the Roll Back Malaria global partnership and the Stop TB initiative, and build new ones, engaging in global public–private partnerships47,48. TDR itself was one of the first such partnerships to emerge in the 1980s19,47 and is now actively involved in partnerships such as the Global Alliance for Vaccines and Immunization (GAVI) (Box 1) and the Global Alliance for TB Drug Development49. In addition, work initiated50 and carried out in TDR has given rise to the Parasitology Today, vol. 16, no. 12, 2000
Table 1. Tropical disease dataa Disease burden DALYs (thousands)
Deaths (thousands)
Malaria
Male Female Totalb Male Female Totalb 22 758 22 240 44 998 553 532 1086
Tuberculosis
19 030 14 257
33 287 1003 666
1669
Lymphatic filariasis
3777
1141
4918
0
0
0
African trypanosomiasis
1111
937
2048
37
30
66
Leishmaniasis
1200
782
1983
32
25
57
Schistosomiasis
1174
758
1932
8
6
14
Onchocerciasis
623
461
1085
0
0
0
Chagas disease
400
277
676
11
10
21
Leprosy
253
223
476
2
1
3
Dengue
220
245
465
6
7
13
a
b
Global burden of disease in disability-adjusted life years (DALYs) and deaths for the ‘TDR diseases’ (1999 estimates), from The World Health Report 2000 (WHO, Geneva; WHO website, Box 1). Discrepancies in totals are due to rounding up and down of figures.
Global Forum for Health Research and the MMV, both independent, non-profit organizations (Box 1). As well as its partnership activities, TDR will continue to focus and develop its key operational strengths, which are found in knowledge management, global overview of tropical disease research issues, and the ability to foster North–South and South–South collaborations, thus strengthening research capacity. The new strategy emphasizes the need for TDR to act as a bridge between research potential and the realities of country-level control operations and their implementation – and the need to engage the world’s scientific community, interdisciplinary experts and affected communities at every step in the process. TDR will have to both gather and distribute knowledge and wisdom, new and old, from and to all sources. To help accomplish this, TDR will continue to expand and diversify its information gathering and dissemination systems and make extensive use of electronic communications, including a website (TDR website, Box 1). With the new strategy, TDR reaches maturity as a knowledge-management network organization, harnessing the full potential of science and technology in the fight against tropical diseases. Acknowledgements I thank Andy Crump and Lisa Schwarb for Fig. 1, Nina Mattock for final revision, and all TDR staff for valuable contributions, comments and suggestions. References 1 Lucas, A.O. (1985) TDR: a very ‘Special Programme’. World Health May, 19–20 2 Gwatkin, D.R. and Guillot, M. (2000) The Burden of Disease Among the Global Poor (Health, Nutrition and Population Series), The World Bank 3 Commission on Health Research for Development (1990) Health Research: Essential Link to Equity in Development, Oxford University Press 4 Global Forum for Health Research (2000) The 10/90 Report on Health Research 2000, Global Forum for Health Research
523
Reviews Table 2. Products from TDR and its partnersa,b Years 1982 1982 1983 1983 1981–1984
Disease Leprosy Leprosy African trypanosomiasis Schistosomiasis Onchocerciasis
1984 1984 1984
Malaria Malaria Chagas disease
1985 1985
African trypanosomiasis Malaria
1987 1980–1989
Onchocerciasis Chagas disease
Ivermectin Fumigant canisters
1990
Eflornithine Artemether DNA probes for Onchocerca volvulus Single-dose DEC
Rhône-Poulenc Rorer OCP WHO/CTD
1993 1993 1994 1994
African trypanosomiasis Malaria Onchocerciasis Lymphatic filariasis Onchocerciasis Malaria Leishmaniasis Leishmaniasis
Ministry of Public Health, Philippines; WHO/MAP OCP; Merck & Co. Inc. Ministry of Health of Argentina, National Research Council of Argentina and CHEMOTECNICA, S.A., Buenos Aires Hoechst Marion Roussel
REMO Integrated management of childhood illness Lipid-associated amphotericin B Direct agglutination test
1994
Schistosomiasis
Praziquantel combinations
1994
Lymphatic filariasis
Detection and monitoring of adult Wuchereria bancrofti in humans by ultrasonography
1995 1996
Onchocerciasis Malaria
ComDT Insecticide-treated bednets
1997
Malaria
1997 1997 1999
Schistosomiasis Leprosy Lymphatic filariasis Lymphatic filariasis Malaria Leprosy Visceral leishmaniasis Malaria Malaria Schistosomiasis
Iron supplementation for prevention of death from severe anaemia Schistosoma haematobium morbidity by ultrasonography Ofloxacin plus rifampicin plus minocycline Rapid mapping of filariasis
The World Bank UNICEF; WHO/CHD; IDRC; WHO/CTD NexStar Institut de Médecine Tropicale Prince Leopold, Antwerp, Belgium; University of Amsterdam; WHO/CTD SmithKline Beecham; E. Merck Pharma; WHO/CTD FIOCRUZ, FACEPE, Fundação Nacional de Saude, Clinica Radiologica de Pernambuco (Brazil) OCP/APOC; The World Bank; Merck & Co Inc. UNICEF; USAID; IDRC; CDC; CIDA; Wellcome Trust; Save the Children Fund; London School of Hygiene and Tropical Medicine, Italian cooperation; Ministries of Health in Ghana, Tanzania, Gambia, Kenya, and Burkina Faso UNICEF; Swiss Development Cooperation; Spanish Agency for International Cooperation CERMES/OCCGE; Ministry of Health, Niger National leprosy programmes; various NGOs WHO/CEE; Liverpool School of Tropical Medicine WHO/CPE; SmithKline Beecham; Merck & Co. Inc. Dutch cooperation; Artecef and WRAIR National leprosy programmes; various NGOs Asta Medica
1991 1991 1993
1999 2000 In the pipeline In the pipeline In the pipeline In the pipeline In the pipeline a
b
Product Combination drug regimens for pauci-bacillary leprosy Combination drug regimens for multi-bacillary leprosy CATT Diagnostic urine filtration test Bacillus thuringiensis H-14 for black fly control Mefloquine Mefloquine plus sulphadoxine–pyrimethamine Rapid test for blood bank screening with defined antigens Tsetse traps for control of epidemics Microtest test kit for drug sensitivity
Albendazole combinations Artemotil Ofloxacin plus rifampicin combination Miltefosine oral LAPDAP oral Artesunate rectal Artemether oral as a prophylatic
Partner(s) National leprosy programmes; various NGOs National leprosy programmes; various NGOs Institute of Tropical Medicine ‘Prince Leopold’, Anvers, Belgium WHO/PDP Institute Pierre Richet, Bouake; OCP; TEKNAR/Sandoz & Thermotrilogy; VECTOBAC/Abbott WRAIR; Hoffmann La Roche WRAIR; Hoffmann La Roche Fundación Campomar and Laboratorios Gador, Buenos Aires, Argentina WHO/PDP; ORSTOM, France
SmithKline Beecham Knoll; R.P. Scherer; Scanpharm Chinese Academy of Preventive Medicine; Swiss Tropical Institute
For most, if not all, of the products listed, TDR had as partners individual scientists funded from various sources, as well as trainees and institutions that were recipients of TDR grants or research capacity strengthening projects (see also Fig. 1). Abbreviations: APOC, African Programme for Onchocerciasis Control; CATT, Card agglutination test; CERMES, Center for Research on Meningitis and Schistosomiasis; ComDT, Community-directed therapy for onchocerciasis; DEC, diethylcarbamazine; CDC, Centers for Disease Control and Prevention; CIDA, Canadian International Development Agency; FACEPE, Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco; IDRC, International Development Research Centre; NGO, non-governmental organization; OCCGE, Organisation de Coordination de la Cooperation pour la lutte contre les Grandes Endemies; OCP, Onchocerciasis Control Programme; ORSTOM, Institut Français de Recherche Scientifique pour le Dévelopment en Coopération; REMO, Rapid epidemiological mapping of onchocerciasis; USAID, US Agency for International Development; WHO/CEE, WHO department for Strategy Development and Monitoring for Eradication and Elimination; WHO/CHD, WHO division of Child Health and Development; WHO/CPE, WHO department for Communicable Diseases Control, Prevention and Eradication; WHO/CTD, WHO Control of Tropical Diseases unit; WHO/MAP, WHO Malaria Action Programme; WHO/PDP, WHO Parasitic Diseases Programme; WRAIR, Walter Reed Army Institute for Research.
524
Parasitology Today, vol. 16, no. 12, 2000
Reviews Box 1. Websites relevant to TDR Activities Name (and acronym) Medicines for Malaria Venture (MMV) TDR Strategy 2000–2005 Multilateral Initiative for Malaria (MIM) Roll Back Malaria (RBM) Stop TB Initiative (STB) Global Alliance for Vaccines and Immunization (GAVI) Global Forum for Health Research (GFHR) TDR Website WHO Website
Box 2. The New Strategy of the TDR • A reinforced focus on ‘implementation research’, or the research needed during the introduction of a new tool into disease control by the health systems of diseaseendemic countries. As the successful examples of the onchocerciasis and Chagas disease control programmes have demonstrated, research should be present during all phases of operations, from planning to implementation and evaluation11,32–35. • Full exploration of the new opportunities provided by science and technology – such as genomics, bioinformatics and high-throughput screening – which open new ways for accelerated discovery of new drugs, vaccines and diagnostics14, as well as new perspectives for vector control36. • Exploration of new opportunities of collaboration through public–private partnerships19,37. • A renewed emphasis on social, economic and behavioural research to achieve a better understanding of the limitations and opportunities posed by contextual factors to control and prevent tropical diseases. • Greater involvement of researchers and institutions from disease-endemic countries in all areas of TDR activity, with a high emphasis on capacity strengthening based on selected research activities. • Intensive use of new information and communications technology38.
5 Wigzell, H. et al. (1998) Third External Review – Final Report [TDR/JCB(21)98.5: Third External Review of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)], WHO 6 Milleron, R. et al. (1998) TDR’s Contribution to the Development of Multidrug Therapy for Leprosy (Reference Document 4, Third External Review/TDR) [TDR/ER/RD/98.4: Third External Review of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)], WHO 7 Fujisaki, T. and Reich, M. (1998) TDR’s Contribution to the Development of Ivermectin for Onchocerciasis (Reference Document 3, Third External Review/TDR) [TDR/ER/RD/98.3: Third External Review of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)], WHO 8 Fujisaki, T. and Reich, M. (1998) TDR’s Contribution to the Development of the Fumigant Canister for Controlling Chagas Disease (Reference Document 5, Third External Review/TDR) [TDR/ ER/RD/98.5: Third External Review of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)], WHO 9 Anon. (2000) Leprosy – global situation. Weekly Epidemiol. Rec. 75, 226–226 10 Onchocerciasis Control Programme (1994) 20 Years of Onchocerciasis Control in West Africa, WHO 11 Moncayo, A. (1999) Progress towards interruption of transmission of Chagas disease. Mem. Inst. Oswaldo Cruz 94, 401–404 12 World Health Assembly (1997) Elimination of Lymphatic Filariasis as a Public Health Problem (Resolution 29 of the 50th World Health Assembly), WHO
Parasitology Today, vol. 16, no. 12, 2000
Website http://www.malariamedicines.org http://www.who.int/tdr/about/strategy http://mim.nih.gov http://www.rbm.who.int http://www.stoptb.org http://www.vaccinealliance.org http://www.globalforumhealth.org http://www.who.int/tdr http://www.who.int
Box 3. Challenges for TDR in the Year 2000 and Beyond • TB39,40, dengue41,42, malaria43,44 and African trypanosomiasis45, which continue to impose a heavy toll among the poorest populations2. • Microbial drug resistance, which is closing some of the few windows of opportunity in disease control46. • HIV/AIDS, unknown when TDR was created, which is undermining global health and exacerbating the clinical aspects of diseases such as TB and leishmaniasis. • New patterns of disease transmission and distribution, which are being introduced by environmental, economic and political changes related to globalization.
13 Johnston, D.A. et al. (1999) Genomics and the biology of parasites. BioEssays 21, 131–147 14 Anon. (1998) Report of WHO/TDR Scientific Working Group on the utilization of genomic information for tropical disease drug and vaccine discovery (TDR/Genomics/98.1: http://www. who.int/tdr/ publications/publications/genomic.htm) WHO/ TDR 15 Crampton, J.M. et al. (1990) Transgenic mosquitoes: a future vector control strategy. Parasitol. Today 6, 31 16 Anon. (1991) Report of the Meeting ‘Prospects for Malaria Control by Genetic Manipulation of its Vectors’ (TDR/BCV/MAL-ENT/91.3), WHO and TDR 17 Catteruccia, F. et al. (2000) Stable germ line transformation of Anopheles stephensi, a mosquito vector of human malaria. Nature 405, 959–962 18 Reich, M.R. (2000) The global drug gap. Science 287, 1979–1981 19 Lucas, A. (2000) Public-Private Partnerships: Illustrative Examples (Workshop on Public-Private Partnerships in Public Health, Endicott House, Dedham, MA, 7–8 April), Harvard School of Public Health 20 Jha, T.K. et al. (1999) Miltefosine, an oral agent, for the treatment of Indian visceral leishmaniasis. New Engl. J. Med. 341, 1795–1800 21 World Health Organization (1997) Guidelines for the Evaluation of Plasmodium falciparum Vaccines in Populations exposed to Natural Infections (TDR/MAL/VAC/97), WHO 22 Modabber, F. (2000) First generation leishmaniasis vaccines in clinical development: moving, but what next? Curr. Opin. AntiInfective Invest. Drugs 2, 35–39 23 Lengeler, C. et al. (1996) Net Gain: A New Method for Preventing Malaria Deaths, IDRC, TDR 24 Von Seidlein, L. et al. (2000) Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial. Lancet 355, 352–357 25 Ngoumou, P. et al. (1994) A rapid mapping technique for the prevalence and distribution of onchocerciasis: a Cameroon case study. Ann. Trop. Med. Parasitol. 88, 463–474 26 World Health Organization (1998) Research on Rapid Geographical Assessment of Bancroftian Filariasis (TDR/TDF/COMDT/98.2), WHO 27 World Health Organization (1996) Community-Directed Treatment with Ivermectin: Report of a Multi-Country Study (TDR/AFR/ RP/96.1), WHO
525
TDR progress indicators Main industry partners (1975–2000)
1999 Lymphatic filariasis
Rapid Epidemiological Mapping • ACF Beheer (Netherlands) • Air Liquide (France) • Asta Medica (Germany) • Aquila Biopharmaceuticals (USA) • Bayer A.G. (Germany) 1997 Leprosy • Biobras-Bioquimica do Brasil (Brazil) Ofloxacin plus • Biotech Australia (Australia) rifampicin combination • Burroughs Wellcome Company (USA) • Chemotecnica S.A. (Argentina) Ofloxacin plus rifampicin • Ciba Geigy, Ltd (Switzerland) plus minocycline • Daiichi Pharmaceutical Co. Ltd (Japan) • Eli Lilly and Company (USA) • E. Merck Pharma (Germany) • F. Hoffman La-Roche (Switzerland) • Genetic Institutes (USA) • Glaxo Group Research Ltd (UK) • Hoechst Marion Roussel (France) • IHARABRAS S.A. (Brazil) 1994 Leishmaniasis • International Federation of Pharmaceutical Direct Agglutination Test Manufacturers Associations (Switzerland) • Janssen Research Foundation (Belgium) • Kunming Pharmaceuticals (China) • Laboratorios Gador (Argentina) • Merck and Co. Inc. (USA) 1992 Chagas disease • NexStar (USA) Dipstick test for blood bank screening • Novartis (Switzerland) • Novo Nordisk A/S (Denmark) • Pasteur-Mérieux-Connaught (USA) • Pharmacia Farmitalia Carlo Elba (Italy) • Rhône-Poulenc Rorer Doma (France) 1990 African • SmithKline Beecham (UK/Belgium) Trypanosomiasis • Tibotec (Belgium) • Vaccine Solutions (Australia) Eflornithine 1991 Onchocerciasis • Vestar Inc. (USA) DNA probes for Onchocerca volvulus • Zeneca Pharmaceuticals (UK)
1983 African Trypanosomiasis Card Agglutination Test
1982 Leprosy Drug combinations for paucibacillary leprosy Drug combinations for multibacillary leprosy
1987 Onchocerciasis Ivermectin
2000 Malaria Artemotil
2000 Malaria Parasitology Today
Germline transformation of Anopheles
1999 Lymphatic filariasis Albendazole combinations
1996 Malaria 1996 Multidisease
Insecticide-treated bednets
Healthy Women Counselling Guide
1995 Onchocerciasis 1994 Schistosomiasis
Community-directed treatment with ivermectin
Praziquantel combinations
Research Capacity Strengthening Institutional Grants (2000) 112 projects* in 41 countries (27 Least Developed Countries)
Fumigant canister
* Including Re-Entry Grants and Career Development Awards
Fig. 1. Examples of products, industry partnerships and capacity building.
Number of Grants
1–4 5–9 > 10
www.who.int/tdr
1989 Chagas disease
Reviews 28 Beattie, P. et al. (1999) Strengthening Health Research in the Developing World: Malaria Research Capacity in Africa, The Trustees of the Wellcome Trust 29 Davies, C. et al. (2000) Out of Africa: training collaboration and malaria research. Parasitol. Today 16, 219–220 30 Brundtland, G.H. (1998) Reaching out for world health. Science 280, 2027–2027 31 Brundtland, G.H. (1999) A Corporate Strategy for the WHO Secretariat. Report by the Director-General (EB105/3, Executive Board 105th Session), WHO 32 Morel, C.M. (1999) Chagas disease, from discovery to control – and beyond: history, myths and lessons to take home. Mem. Inst. Oswaldo Cruz 94, 3–16 33 Molyneux, D.H. and Morel, C. (1998) Onchocerciasis and Chagas disease control: the evolution of control via applied research through changing development scenarios. Br. Med. Bull. 54, 327–339 34 Remme, J.H.F. (1995) The African Programme for Onchocerciasis Control: preparing for launch. Parasitol. Today 11, 403–406 35 Plaisier, A.P. et al. (1995) Irreversible effects of ivermectin on adult parasites in onchocerciasis patients in the Onchocerciasis Control Programme in West Africa. J. Infect. Dis. 172, 204–210 36 Balter, M. (1999) Gene sequencers target malaria mosquito. Science 285, 508–509 37 Reich, M.R. (2000) Public-private partnerships for public health. Nat. Med. 6, 617–620 38 Lucky, R. (2000) The quickening of science communication. Science 289, 259–264
39 Dye, C. et al. (1999) Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. J. Am Med. Assoc. 282, 677–686 40 World Health Organization (2000) Global Tuberculosis Control. WHO Report 2000 (WHO/CDS/TB/2000.275), WHO 41 Rigau-Pérez, J.G. et al. (1998) Dengue and dengue haemorrhagic fever. Lancet 352, 971–977 42 Gubler, D.J. and Meltzer, M. (1999) Impact of dengue/dengue hemorrhagic fever on the developing world. Adv. Virus Res. 53, 35–70 43 Snow, R.W. et al. (1999) Estimating mortality, morbidity and disability due to malaria among Africa’s non-pregnant population. Bull. WHO 77, 624–640 44 Snow, R.W. et al. (1999) A preliminary continental risk map for malaria mortality among African children. Parasitol. Today 15, 99–104 45 Smith, D.H. et al. (1998) Human African trypanosomiasis: an emerging public health crisis. Br. Med. Bull. 54, 341–355 46 World Health Organization (2000) Overcoming Antimicrobial Resistance – World Health Organization Report on Infectious Diseases 2000, WHO/CDS/2000.2 WHO 47 Buse, K. and Walt, G. (2000) Global public-private partnerships: part I – a new development in health? Bull. WHO 78, 549–561 48 Buse, K. and Walt, G. (2000) Global public-private partnerships: part II – what are the health issues for global governance? Bull. WHO 78, 699–709 49 Butler, D. (2000) Consortium aims to kick-start TB research. Nature 403, 692–692 50 Godal, T. et al. (1996) Investing in Health Research and Development. Report of the Ad Hoc Committee on Health Research Relating to Future Intervention Options (TDR/Gen/96.1), WHO
The Interface Between Epidemiology and Population Genetics S. Paterson and M.E. Viney Modern biology increasingly integrates disparate disciplines. Here, Steve Paterson and Mark Viney examine the interface between epidemiology and population genetics. They argue that infection and inheritance can be considered as analogous processes, and that epidemiology and population genetics share many common features. They consider the potential for existing population genetic theory to dissect epidemiological patterns in field studies and they consider other relationships between genetics and epidemiology that provide a research challenge for the future. Epidemiology is the study of disease dynamics within a population. Current models of infection dynamics attempt to describe the process of infection from one host to another and the consequence of this process on host and parasite populations1. Population genetics is concerned with the inheritance of genes at the population level2. There is, therefore, a clear analogy between inheritance – the transmission of genes from one generation to the next – and infection – the transmission of parasites from one host to another – and the population-level consequences of each of these processes. Inheritance and infection both occur within populations and, in this respect, both population genetics and epidemiology are concerned with problems of scale; specifically, to extend a basic biological process (inherSteve Paterson and Mark Viney are at the School of Biological Sciences, University of Bristol, Woodland Road, Bristol, UK BS8 1UG. Tel: +44 117 928 7470, Fax: +44 117 925 7374, e-mail: [email protected] 528
itance or infection) that occurs at the individual level to the population-level consequence of that process3. The interface of inheritance and infection Modeling drug resistance in parasite populations is one area where population genetics and epidemiology come together4,5. The task is to construct a model that combines both the spread of drug-resistance genes through a parasite population and the spread of drugresistant parasites through a host population (Box 1). Recent work by Smith et al.6 provides a good example of how this can be achieved. Here, the basic unit of the model is the parasite itself, rather than the infected host. Parasites of different anthelmintic genotypes (eg. RR, Rr or rr, where R is the anthelmintic-resistance allele) were modeled deterministically within a host population that was subjected to various anthelmintic dosing regimens. In each parasite generation, adult parasites mate and produce progeny whose genotype frequencies are determined by Hardy–Weinberg processes from the allele frequencies of the parents. This mating function allowed the frequency of the anthelmintic-resistant and -sensitive alleles to be followed within the parasite population. One important prediction from this model was that there was little difference in the rate of spread of anthelminticresistant parasites under chemoprophylatic or chemotheraputic dosing regimens. Therefore, this model directly uses population genetic and epidemiological modeling to understand the movement of anthelmintic parasites through a host population subject to different dosing regimens and, thus, is powerfully predictive.
0169-4758/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0169-4758(00)01776-2
Parasitology Today, vol. 16, no. 12, 2000