Malaria control priorities and constraints.

Each year, there are still between 300-500 million clinical cases of malaria and over one million deaths due to the disease, 90% of which occur in Africa south of the Sahara. In all continents, malaria risk is highest in remote rural areas where poverty abounds, population densities are low and the quality and coverage of the health services are poor or in existent. A sustained impact on the malaria burden can only be achieved through the cost-effective use of current tools, by including malaria in health sector development and inter-sectorial action, by mobilizing malaria control within communities and by investing in new and more effective tools. This paper highlights some of the constraints faced by countries in controlling malaria and outlines the priority activities that are being carried out to address these constraints within both communities and the health services. It aims to be set the scene for the papers of this Centenary book which address some of these issues in more detail.

Commentary: malaria control in the 1990s.

In May 1955 the Eighth World Health Assembly adopted a Global Malaria Eradication Campaign based on the widespread use of DDT against mosquitos and of antimalarial drugs to treat malaria and to eliminate the parasite in humans. As a result of the Campaign, malaria was eradicated by 1967 from all developed countries where the disease was endemic and large areas of tropical Asia and Latin America were freed from the risk of infection. The Malaria Eradication Campaign was only launched in three countries of tropical Africa since it was not considered feasible in the others. Despite these achievements, improvements in the malaria situation could not be maintained indefinitely by time-limited, highly prescriptive and centralized programmes. Also, vector resistance to DDT and of malaria parasites to chloroquine, a safe and affordable drug, began to affect programme activities. A global Malaria Control Strategy was endorsed by a Ministerial Conference on Malaria Control in 1992 and confirmed by the World Health Assembly in 1993. This strategy differs considerably from the approach used in the eradication era. It is rooted in the primary health care approach and calls for flexible, decentralized programmes, based on disease rather than parasite control, using the rational and selective use of tools to combat malaria. The implementation of the Global Strategy is beginning to have an impact in several countries, such as Brazil, China, Solomon Islands, Philippines, Vanuatu, Viet Nam and Thailand. The lesson from these areas is clear: malaria is being controlled using the tools that are currently available. The challenge is now to apply these tools among vulnerable individuals and groups experiencing high levels of morbidity and mortality, particularly in sub-Saharan Africa, for which long-term investments are required.

PIP: The global malaria eradication campaign adopted by the 8th World Health Assembly in 1955 was based upon the widespread use of DDT against mosquitos and of antimalarial drugs to treat malaria and eliminate the parasite in humans. While eradicating endemic malaria by 1967 in all developed countries and parts of tropical Asia and Latin America, the approach employed in the campaign was both unsustainable and not feasible for implementation globally. In 1992, a Global Malaria Control Strategy was endorsed by a ministerial conference on malaria control and confirmed by the World Health Assembly in 1993. This new strategy is based largely upon the primary health care approach and requires flexible, cost-effective, sustainable, and decentralized programs based upon disease rather than parasite control, adapted to local conditions and responding to local needs. The implementation of this strategy is beginning to have an impact in several countries, such as Brazil, China, Solomon Islands, Philippines, Vanuatu, Vietnam, and Thailand. Its success demonstrates that malaria can be controlled by locally and currently available tools. This new control approach now needs to be brought to populations experiencing high levels of malaria-related morbidity and mortality, especially in sub-Saharan Africa.

Global overview of malaria.

Malaria continues to be one of the main public health problems in the world, especially in the majority of African countries. It particularly affects young children, young adults engaged in economic development activities, pregnant women and international itinerant groups of population, moving into malaria endemic areas. Malaria epidemics became a regular feature in many parts of the world, including the highlands of Africa, being associated with the warming of the climate, disruption of health services and large scale uncontrolled population movement as a result of social disruption and civil wars. Further proliferation of drug resistance is closely related to massive population movements, inadequate health services, improper use of antimalarial drugs, limited resources and operational difficulties in implementing malaria control activities. The economic impact of malaria is felt by various social groups of the society particularly by the poorest countries of the world and among populations living under the most difficult conditions. To overcome the malaria challenge, there is a need for concerted efforts by the health services, the private sector, the communities themselves, including the international community. Much could be achieved through the research and development (the use of insecticide-impregnated materials) and disease management (the use of artemisinin and its derivatives in areas with multi-drug resistance) will facilitate the achievement of the global goal of malaria control-to eliminate mortality and to reduce morbidity due to malaria.

Status of antimalarial drugs under development.

Despite the urgent need of a new antimalarial drugs, particularly those against multiresistant falciparum malaria, only a limited number of drugs are now at an advanced stage of preclinical or clinical development. They include artemisinin derivatives, pyronaridine and benflumetol (all originally developed in China), as well as new antifolate combinations, the hydroxynaphoquinone atovaquone which has a novel mode of action, and a new 8-aminoquinoline which appears more active and less toxic than primaquine. Some of these drugs may become available in the next few years. It is therefore essential to find mechanisms to ensure that they are made available at an affordable price to the populations that really need them.

A phase II/III double-blind, dose-finding clinical trial of a combination of mefloquine, sulfadoxine, and pyrimethamine (Fansimef) in falciparum malaria.

Fansimef is a combination of 250 mg mefloquine (base), 500 mg sulfadoxine, and 25 mg pyrimethamine per tablet. One hundred and fifty adult male Brazilian patients at Belém (Pará), who had peripheral blood smears positive for Plasmodium falciparum, with or without clinical symptoms of falciparum malaria, were treated in a double-blind randomized fashion with either one, two or three tablets of Fansimef. Of those receiving one tablet (48 patients), 81% were cured and 19% exhibited RI recrudescences. All the patients receiving two or three tablets of Fansimef (49 patients in each group) were cured. The rates of initial clearance of parasitaemia and fever were similar in all treatment groups. Tolerance was good at all dose levels. The main side-effects included nausea, vomiting, dizziness, diarrhoea and abdominal pain, but these were mild and transient and required no specific treatment. The incidence of vomiting and nausea was highest in patients given the three-tablet dose. The results of various haematological, biochemical and urine analyses were not adversely altered by the administration of Fansimef.

Recent advances in malaria parasite cultivation and their application to studies on host-parasite relationships: a review.

The continuous cultivation of the erythrocytic stages of Plasmodium falciparum was achieved in 1976 and techniques have now also been developed for continuous cultivation of these stages from P. knowlesi, P. fragile, P. inui, P. cynomolgi and P. berghei. The requisite conditions for successful cultivation are described. Gametes of certain isolates of P. falciparum can also now be produced in vitro and these are infective to mosquitos, leading to normal development of the parasite.The successful cultivation in vitro of the exoerythrocytic stages of P. berghei and P. vivax was achieved in 1981 and 1983, respectively. These cultures give rise to infective merozoites.There have been no significant advances in the in vitro cultivation of the sporogonic stages of malaria parasites for the last 15 years, although studies indicate that the in vitro cultivation of these stages from gamete to sporozoite stage is theoretically possible.The application of cultivation techniques to the study of parasite epidemiology is discussed. To date the major epidemiological impact has related to their use for measuring the incidence and spread of drug resistance. Applications to the study of the genetics of drug resistance, antigen production, development of tests for protective immunity, and drug development and screening are reviewed.

Double diffusion analysis of antigens released from Plasmodium knowlesi in vitro.

Two parasite-derived antigens (designated band 1 and band 2) were identified upon double-diffusion analysis of culture medium from reinvading culture of P. knowlesi. Band 1 antigen showed characteristics with the R-antigens of P. falciparum while the other was similar to the P. falciparum L-antigens. Both antigens appeared to be largely particulate in character and did not display any obvious variant-specificity. Analysis of plasma from rhesus monkeys infected with the same antigenic variant showed the presence of band 1 antigen only.