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Initial WHO program (1955–1969)

In 1955 the WHO launched the Global Malaria Eradication Program (GMEP). The program relied largely on DDT for mosquito control and rapid diagnosis and treatment to break the transmission cycle. The program eliminated the disease in "North America, Europe, the former Soviet Union ", and in " Taiwan, much of the Caribbean, the Balkans, parts of northern Africa, the northern region of Australia, and a large swath of the South Pacific" and dramatically reduced mortality in Sri Lanka and India.

However, failure to sustain the program, increasing mosquito tolerance to DDT, and increasing parasite tolerance led to a resurgence. In many areas early successes partially or completely reversed, and in some cases rates of transmission increased. Experts tie malarial resurgence to multiple factors, including poor leadership, management and funding of malaria control programs; poverty; civil unrest; and increased irrigation. The evolution of resistance to first-generation drugs (e.g. chloroquine) and to insecticides exacerbated the situation. The program succeeded in eliminating malaria only in areas with "high socio-economic status, well-organized healthcare systems, and relatively less intensive or seasonal malaria transmission".

For example, in Sri Lanka, the program reduced cases from about one million per year before spraying to just 18 in 1963 and 29 in 1964. Thereafter the program was halted to save money and malaria rebounded to 600,000 cases in 1968 and the first quarter of 1969. The country resumed DDT vector control but the mosquitoes had evolved resistance in the interim, presumably because of continued agricultural use. The program switched to malathion, but despite initial successes, malaria continued its resurgence into the 1980s.

Due to vector and parasite resistance and other factors, the feasibility of eradicating malaria with the strategy used at the time and resources available led to waning support for the program. WHO suspended the program in 1969 and attention instead focused on controlling and treating the disease. Spraying programs (especially using DDT) were curtailed due to concerns over safety and environmental effects, as well as problems in administrative, managerial and financial implementation. Efforts shifted from spraying to the use of bednets impregnated with insecticides and other interventions.