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MALARIA—YESTERDAY, TODAY, AND TOMORROW G. V. BROWN and G. J. V. NOSSAL* Introduction The 2.5 billion people living in malaria-endemic countries are a constant reminder of the failure of our current efforts to control this disease . Three hundred sixty-five million people live in areas where there are no specific antimalarial measures being applied, and it is estimated that 1,000,000 children less than 5 years old die of the disease each year in Africa alone [I]. In the 100 years since Laveran's discovery and description of malaria parasites in human blood, short periods of optimism stimulated by spectacular scientific progress have punctuated generally pessimistic predictions about our ability to control or conquer this parasite , table 1 [2]. With guarded optimism we are about to enter a new phase of antimalarial attack using genetically engineered vaccines. There are four major species of malaria responsible for the disease in man, each with a similar life cycle involving anopheline mosquitoes and the human host [2]. Plasmodiumfalciparum (malignant tertian fever) is the major killer, being responsible for the potentially lethal complications of cerebral malaria, algid malaria, and blackwater fever. Plasmodium vivax, (benign tertian fever) though less virulent, has the troublesome characteristic of relapsing months or years after a primary attack. Plasmodium ovale and P. malariae are less common, although the latter has been associated with chronic renal disease (nephrotic syndrome) and may persist in the blood for more than 20 years. Mosquito Control—Successes and Failures The classic studies of Ronald Ross at the end of the last century confirmed the "mosquito theory" of malaria transmission and at the The authors are supported by the National Health and Medical Research Council of Australia, the Rockefeller Foundation Great Neglected Diseases Network, and the John D. and Catherine T. MacArthur Foundation. *The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.© 1986 by The University of Chicago. AU rights reserved. 003 1-5982/87/300 1 -0508$0 1 .00 Perspectives in Biology and Medicine, 30, 1 ¦ Autumn 1986 \ 65 TABLE 1 Landmarks in the Understanding of Malaria 1880 ....... Discovery and description of malaria parasites in human blood 1897 ....... Discovery of pigmented cysts (oocysts) on the stomach wall of an Anopheles mosquito 1899 ....... Antilarval measures in Sierra Leone 1900 ....... Use of human volunteers to confirm the mosquito-transmission theory of malaria 1927 ....... First instance of eradication of an invading vector species (A. albimanus in Barbados) 1930 ....... Development of mepacrine (Atabrine) 1934 ....... Development of chloroquine 1935-1939 . . First large-scale control of rural malaria by pyrethrin spraying in southern Africa, The Netherlands, and India 1936-1939 . . Discovery of insecticidal action of DDT 1944 ....... Discovery of Proguanil 1942-1946 . . Development of synthetic insecticides (HCH, dieldrin) with residual action 1948 ....... Preerythrocyte forms oi'Plasmodium cynomolgii described in liver of rhesus monkeys 1946-1951 . . Successful antimalaria campaigns in Cyprus, Sardinia, Venezuela, and Greece 1952 ....... Development of pyrimethamine, primaquine 1955 ....... Adoption of principle of malaria eradication by Fourteenth World Health Assembly 1961 ....... Passive transfer to humans of protective antibody to P. falciparum 1961-1965 . . Reports from South America and Southeast Asia of P. falciparum resistant to chloroquine 1960-1966 . . Rediscovery of use of sulphonamides and sulphones as antimalarials 1969 ....... Revision of global strategy of malaria eradication 1970 ....... Demonstration of S-antigens as markers of antigenic diversity in P. falciparum 1973 ....... Immunization of humans with irradiated sporozoites 1973-1978 . . Resurgence of malaria in tropical endemic countries, especially in southern and Southeast Asia 1975 ....... Establishment of UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases 1976 ....... Continuous cultivation of P. falciparum in vitro 1978 ....... Microtest for detection of chloroquine resistance in vitro 1979-1982 . . Confirmation of chloroquine resistance in East Africa 1980 ....... Discovery of hypnozoites in P. cynomolgii 1983 ....... Cloning of parasite antigens in E. coli (sporozoite coat and several proteins of asexual stages) 1985 ....... Plans well advanced for human Phase I trials (safety and immunogenicity ) of antisporozoite vaccines using synthetic peptides and products of recombinant DNA technology 1986 ....... Demonstration that immunization with cloned protein of blood stage of P. falciparum can induce protection in Aotus monkeys Note.—Data largely from [2], same time suggested a method for disease control...


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