Experimental, therapeutic and natural transmission of Plasmodium vivax tertian malaria: scientific and anecdotal data on the history of Dutch malaria studies

When Plasmodium vivax tertian malaria was prevalent in The Netherlands, the use of therapeutic malaria for the treatment of neurosyphilis patients presented an opportunity for biological studies of the parasite’s behaviour, in healthy volunteers. One unexplained phenomenon was the long latency between natural exposure to a single infected mosquito and the appearance of clinical signs (average 8 months). Dutch studies with volunteers and syphilis patients, suggested that hundreds of sporozoites transmitted by several mosquito bites were enough to provoke an early attack, known from tropical vivax-malaria. Sporozoites appeared to be programmed either to delay their pre-erythrocytic development or to proceed to an early attack within three weeks. The number of infectious bites also determined the relapse rate and the number of relapses after a primary attack. Analyses of primary cases and relapses from the previous year were used to predict the incidence for the next year. These historic findings fit well with recent studies on genotyping of blood stages during primary attacks and relapses. External factors (i.e. the milieu inside the human host) may trigger hypnozoites to reactivate, but predetermined periods of latency should also be considered.