Relapse in experimental and naturally acquired vivax malaria
In the experimental malaria studies, non-immune volunteers were infected either by blood taken from a malaria patient or by infected mosquito bites. The volunteers were then observed daily, usually for at least one year (many were prison volunteers). Building on the extensive experiences of malariatherapy of neurosyphilis during the early to mid-20th century, which had refined and standardized the methods of infection and clinical management, at least five and usually ten infected (i.e. sporozoite positive) laboratory reared anopheline mosquitoes were used to initiate the infection. This ensured a substantial sporozoite inoculum was delivered to the recipient. With the Chesson strain of P. vivax the consequent early relapse rate was 100% (7).
This high relapse rate in experimental malaria should be contrasted with natural infections in which a single mosquito, with an infection of variable age (and thus transmission potential), infects an individual who may already have significant natural immunity dampening illness (8). This distinction is important because it has a substantial bearing on the binary outcome therapeutic response to 8-aminoquinolines i.e. relapse or no relapse. Very high relapse rates usually result from multiple inoculations (e.g. in soldiers fighting in the Pacific theatre of World War 2) (9). Overall, the relapse prevention (i.e. radical curative) efficacy of 8-aminoquinolines was substantially better in clinical practice compared with the stern test applied in the volunteer infections. For example, the combination of quinine and plasmoquine at doses > 30mg base/day was considered highly effective in preventing relapse in clinical studies in endemic areas, but doses below 90mg base/day were relatively ineffective in the experimental challenge model (2, 3, 10, 11). Thus, to compare radical curative efficacies it is necessary to consider both drug dosage, and thus exposure, and also the likely hypnozoite burden (12).