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ConneII, N.D. et d. (1993) Pm. Natl Acud. Sci. USA 90,11473-11477 McGhee, J.R. et al. (1993) Semin. Hematol. 30 (Suppl. 4), 3-15 Alonso, L.C.C. et al. (1994) Science 263,235-237 Kuntz, I.D. (1992) Science 257,1078-1082

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Anon. (1994) Trans. R. Sot. Trup. Med. HI/~. 88 (Suppl. 1) __ Maizels, R.Ik et al. (1993) N&e 365,7<<805. Krause, R.M. (19921 Science 257,1073-1078 Parham, P. (1493) dwr. Biol. 3, !!23-225

Drugs A. Cerami and KS. Warren Before dutifully discussing the essential role of drugs in the prevention and treatment of parasitic infections, it must be emphasized that the authors, one a pharmacologist and the other an immunologist, unequivocally agree that the proper conjunction for the title of this unit should be ‘and’, not ‘or. We ascribe to Geoffrey Edsall’s classical statement’ of 30 years ago, ‘Never in the history of human progress has a better and cheaper method of preventing illness been developed than immunization at its best’. It is also noteworthy that, while excellent vaccines exist against bacterial and viral infections, there are none available for human protozoan and helminth infections. Years ago, with the advent of genetic engineering, peptide vaccines and vectors a paper was published2 with the subtitle, ‘The inevitable new age of vaccines.’ With groups in the USA, Colombia, UK, Sweden, Australia and elsewhere doing brilliant work, it looked as if malaria would be the first and most important parasitic disease to succumb to the advance of modem science. Almost a decade later, there is the possibility that a malaria vaccine does indeed exist, but it may be only about 30-40% effectives, a far cry from Edsall’s ‘immunization at its best’. The situation with respect to drugs has not been much better. The great success has been the treatment and prophylaxis of malaria, but a major problem is the development of resistance to drugs by Plasmodium. With respect to the other major protozoan infections, we are still reliant on highly toxic or potentially carcinogenic and mutagenic drugs which would be totally unacceptable to drug-monitoring agencies today. Until quite recently, anthelmintic drugs (most of which have been developed for veterinary use) have also been plagued by high toxicity, and by a general failure to appreciate that the great majority of infected individuals do not require treatment. As with the vaccines, molecular biomedical research is now providing powerful new tools by which the mechanisms of drug action are being determined. Specific targets, such as enzymes and receptors, are being identified, and their three-dimensional structures determined for the optimal design of new drugs.

Protozoa Most people think of vaccines as prophylaxis and drugs as therapeutic, but quinine, the first major prophylactic drug, has been in use for malaria for centuries. It is, perhaps, ironic that quinine is still needed today because of the development of resistance to newer Anthony Cerami and Kenneth Warren are at the Picower Institute of Medical Research, 350 Community Drive, Manhasset, NY I 1030, USA

drugs. Of the two major groups of antimalarials now in general use, the antifolates (eg. pyrimethamine) and the quinolines (eg. chloroquine), the mechanism of resistance has been elucidated for the former, ie. mutations in the dihydrofolate reductase gene which decreases its affinity for pyrimethamine*, while that of the latter remains controversial. It has been emphasized that understanding the mode of action of drugs is invaluable for the development of new and better pharmacological agents. With respect to pyrimethamine, both the target enzyme (dihydrofolate reductase) and its structure are now known. As to the mode of action of chloroquine, the ‘most likely explanation came with the identification of a haem polymerase activity in the lysosome (of I? falciparum parasites)5 and the demonstration that this activity can be inhibited by pharmacological concentrations of chloroquine’6. While antimalarial drugs have been a necessity, brought on largely by the impetus of 20th century global warfare, the status of drugs for other major protozoan infections remains abysmal. Since these infections are not major problems in the developed world, investment by industry has been inadequate, as has been support by bilateral and multilateral international agencies, and the on again/off again activities of the major philanthropic organizations. Most antiprotozoan drugs now available are either toxic or lethal, and many require intravenous administration and prolonged courses of treatment. None of them would possibly be approved today by drug-monitoring agencies. Examples are metronidazole (carcinogenic in rodents and mutagenic in bacteria) administered in ten-day courses for amebiasis; the antimony-containing pentostam administered intramuscularly or intravenously in two or three 20-day courses for visceral or mucocutaneous leishmaniasis; the questionably effective, toxic nifurtimox, given for 30-120 days for American trypanosomiasis; and the arsenic-containing melarsoprol or the highly toxic suramin administered intravenously for five weeks for African trypanosomiasis7. With respect to the latter, hope is offered by the discovery in trypanosomatids, only a decade ago, of the unique anti-oxidant compound, trypanothione and related enzymes and their structuresa. Again, these findings bring us into the modern world of rational drug development. Helminths Worms have been observed and recorded in their human hosts in both ancient civilizations and primitive societies, since they are all visible to the naked eye9. A large variety of herbal and home remedies have traditionally been used to treat them, but most have been useless and many harmful. Helminth infections, as those caused by protozoa, have been cursed by the 0

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development of effective but extremely toxic therapeutic agents. In the 192Os, oral carbon tetrachloride was the drug of choice for the treatment of hookworm infection. Dithiazinine, a drug widely used for the treatment of trichuriasi:s had to be recalled in the USA when it was associated with nine deaths. In 1918, Christopherson discovered that the antimony compound known as tartar emetic, used in multiple intravenous doses for treating leishmaniasis, was effective in schistosomiasisl0. It became the drug of choice over the next 60 years and is still in use today. Tartar emetic therapy is associated with severe vomiting, coughing and major abnormalities in the electrocardiogram. It has been estimated that fatalities may be as high as one per 1000 patients treated. Mass treatment has been tried in Egypt, and was a major tool in the attempt to eradicate schistosomiasis in China during the 1950s and 1960s. This is of particular concern because the great majority of those infected with helminth infections did not require treatment. In an editorial11 entitled ‘The guerrilla worm’ in the New England Journal of Medicine in 1970, it was observed that helminths ‘are unique among infectious agents - they do not, as a rule, multiply in the hmnan body. Instead, they appear to follow the precepts of guerrilla warfare as outlined by Chairman Mao, repeatedly infiltrating host defenses as individuals or in small groups and gradually building up into large forces; warfare is usually by attrition and tends to be prolonged’. The clinical consequences

were described

as follows,

‘Infection is not synonymous with disease. Many patients invaded by schistosomes, trichinellae, ascarides, filariae and hookworms never had and never will have overt signs 01: symptoms of disease. The respective manifestations caused by these worms -liver fibrosis, myositis, intestinal obstruction, elephantiasis, and anemia - occur only when there is an unusually

heavy attacking force or when large numbers of parasites have accumulated”. Shortly after these observations, Crofton in a seminal paper entitled ‘A quantitative approach to parasitism’ described the negative binomial distribution of helminths, in which the majority of hosts harbor few parasites. It is the minority with heavy infections in which morbidity and mortality occurs. Given the above circumstances, it was re(alizedi3 that: ‘it is not necessary to eradicate the invaders since the

few organisms remaining after therapy are static unless reinforced by further infiltration. In non-endemic localities one course of treatment should permanently reduce the worm population below disease-producing levels; in endemic areas further infiltration is almost inevitable. Thus, attempts to cure worm infections by high doses of toxic drugs or excessively prolonged courses of treatment are unnecessary and may be distinctly harmful and even lethal to the host’. In 1988, at a meeting to commemorate the 75th anniversary of the Rocklefeller Foundation’s global attempt to eradicate hookworm, the question was raised about what should be done now. It was suddenly realized that an oral, single-dose, non-toxic drug such as albendazole would treat ascaris and trichuris as well

as hookworm. It was then noted that another such drug praziquantel, would treat schistosomiasis and virtually all the other trematodes and cestode infections of human@. Ivermectin for the filariases, onchocerciasis and strongyloides was soon added. Prophylaxis was necessary only at intervals of one year or longer. A strategic plan was then suggested for the control of helminth infections in school-age children throughout the world*5. Although the question of drug resistance was raised, particularly in intensive treatment of domestic animals and under extreme conditions in the laboratory, helminths do not multiply at the rates of other infectious agents and are less likely to develop resistance or would do so more slowlyis. In order to minimize expenses, diagnostic tests would not be administered to individual children, and treatment would be given by the educational rather than the medical establishment. Under these conditions, the bill would be approximately one dollar a year per childis. Thus, the costs of anthelmintic treatment of school-age children for ten years are actually somewhat lower than full immunizationl6. On the basis of the above data, the United Nations Development Programme and the Rockefeller Foundation founded the Partnership for Child Development led by Donald A.P. Bundy of the Scientific Coordinating Centre at Oxford University to pursue anthelmintic and micronutrient treatment of school-age children throughout the developing world. They were quickly joined in this endeavor by the Edna McConnell Clark and James S. McDonnell Foundations. Major pilot programs are now under development in several countries in Africa, Asia and Latin America. Thus, the status of therapy for the 18 major human helminth infections is now excellent. To achieve a similar or better effect would require the development of 18 specific vaccines, ‘at their best’. Do we believe that such an effort should not be made? Of course not!

Conclusion The possibility of new and better drugs and vaccines for parasitic infections has been remarkably enhanced by the concepts and tools provided by the burgeoning of molecular biology, chemistry and computer imaging. In establishing priorities for the development of better means of dealing with parasitic diseases, the comparative value of all means of treating and preventing them must be taken into consideration. The final arbiter of the availability of new modalities of treatment and prophylaxis, however, is the pharmaceutical industry, which is based essentially on the profit motive. In order to stimulate new means of therapy for rare diseases in the relatively rich USA, its government provides subsidies for research and development of drugs for the so-called ‘orphan’ diseases. In a paperI sub-titled ‘all the worlds an orphanage’, it was suggested that this concept should be expanded to encompass many of the common diseases in the relatively poor, developing world. References Playfair, J.H.L. (1984) in Immune Intervention: New Trends in Vaccines (Vol. 1) (Roitt, I.M., ed.), p. 1, Academic Press Warren, KS. (1986) in Protecting the World’s Children, p. 151, The Rockefeller Foundation Valero, M.V. et al. (1993) Lancet 341,706-710 Siriwarapom, W. et al. (1990) Biochemisby 29,10779-10785 Slater, A.F. and Cerami, A. (1992) Nature 355,167-169 Foote, S.J. and Cowman, A.F. (1994) Acta Tropica 56,157-171 Warren, K.S. and Mahmoud, A.A.F. (1990) Tropical and Geographiud

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Medicine (2nd edn), McGraw-Hill 8 Fairlamb, A.H. and Cerami, A. (1992) Annu. Rev. MicrobioI. 46, 695-729 9 Hoeppli, R. (1959) Parasites and Parasitic Infections in Early Medicine and Science, Universitv of Malava Press 10 Christopherson, J.BI (1918) La&et ii, 325L3-327 11 Warren, KS. (1970) New Engl. J. Med. 282,810-811 12 Crofton, H.D. (1971) Parasitology 62,179-193 13 Warren, K.S. (1981) Annu. Rev. Public Health 2,101-115

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14 Warren, K.S. (1988) Lancet ii, 897-898 15 Warren, K.S. et al. (1993) in Disease ControI Priorities in Developing Countries (Jam&n, D.T. et al., eds), pp 131-160, Oxford University Press 16 The World Bank (1993) World Development Report: Investing in Health, Oxford University Press 17 Warren, KS. (1986) in Orphan Diseases and Orphan Drugs (Scheinberg, I.H. and WaIshe, J.M., eds), pp 169-176, Manchester University Press

or Drugs:

Complementarity M. Tanner Virtually all parasitic diseases are diseases of poverty, and the long-term solution to their control is to eliminate poverty rather than to develop biomedical tools or intervention packages. That being said, tools such as vaccines and drugs can complement efforts to reduce poverty, or can at least reduce some suffering in the absence of poverty reduction. We argue, and also agree, with the position of Cerami and Warren (this issue) that, in such cases, it is not necessarily a question of deciding whether to develop and deploy a vaccine or a drug. It may make sense to develop both tools, either for targeting different populations, or for use in combination. The latter possibility may be particularly promising for helminth (especially schistosomiasis) control. Moreover, asking the question in terms of one or the other tool creates an unhealthy competition at the level of priority setting and of funding research and development, with possible serious consequences. Using the example of the development of antimalarials, Schuster and Milhousl illustrate how the premature hope that a malaria vaccine would be available within five years has led to a decline in funds for drug development, despite the rapid increase of multidrug-resistant strains of PZusmodium faZciparum, which calls for new, effective drugs.

Levels of decision-making There are at least three levels at which decisions about the development of new biomedical tools should be assessed: (1) the laboratory, where technical opportunities are considered; (2) the field, where the overall effectiveness of the new tool2 is determined by the epidemiological situation, acceptability to and use by health care providers, and the need-demand pattern and priorities of the affected population; and (3) the economic level, where the affordability, efficiency and sustainability of the intervention are paramount. Too often, decisions about drug or vaccine development and subsequent funding commitments are determined by technical possibilities in the laboratory, the interests of researchers, the narrow interests of a small group of Marcel Tanner is at the Swiss Tropical Institute, Department of Public Health and Epidemiology, CH-4002 Basel, Switzerland. David Evans is at the UNDP/WORLD BANK/WHO Special Programme for Research and Training in Tropical Diseases (TDR), CH-I 2 I I Geneva 27, Switzerland.

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and D. Evans potential users and /or of the private sector for potential markets, rather than by the needs in the field.

Malaria vaccines The attempts to develop malaria vaccines are a case in poinP. Notwithstanding the tremendous achievements that have been realized in the North, with new approaches in molecular biology and the insights that have been gained into immune mechanisms in the past decades, the development of SPf66 as a potential vaccine suggests that the difficulties it experienced in being finally accepted as a candidate were not related to its potential value to people in endemic areas, but more to the fact that it was not developed in the North, and would be of little use to either Northern travellers or the militarya. The initial scepticism about SPf66 could even be supported on scientific grounds, as the first promising results5 could not be reproduced in two independent monkey t&&+7, and the design of the early field trials was deficienta. However, the latter problem was rectified, and new trials provided evidence that SPf66 can reduce clinical malaria under conditions of natural exposure 8. In addition, independent randomized, placebo-controlled phase III trials are now in progress in Tanzania, Thailand and The Gambia9JJ and will clarify the efficacy of SPf66 in areas of different endemicity. Nevertheless, the case of SPf66 illustrates that the potential value for reducing community morbidity in developing countries is not necessarily the driving force behind vaccine research and developmental decisions. Malaria vaccine development also suggests that new technologies do not necessarily require a choice between one or the other vaccine. Different types of tools can be applied at the same time for different populations or in different circumstances. Vaccines against blood-stage antigens will not prevent infection, but (in the best case, by mimicking natural immunity and being boosted by natural exposure) might reduce morbidity and mortality. Once available, they would be most useful components of integrated malaria control programmes in highly endemic areas of the world. Vaccines that act against any pre-erythrocytic stage of the parasite would be of most value for short-term visitors to endemic areas, such as tourists, business travellers and military personnel. Transmission-blocking vaccines might be of importance as complements to other vaccines and in 0

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