Mass-Drug Administration With a Gametocytocidal Drug Combination, a Model for a Transmission Blocking Vaccine

1. INTRODUCTION

1.1 Mass drug administration as a public health tool In the 1950s, the WHO included mass drug administration (MDA) with antimalarial drugs as a tool for malaria control in 'exceptional conditions when conventional control strategies have failed'. Subsequently, MDA has received little attention until the introduction of artemisinin based combination therapy (ACT). The principle aim of MDA is to interrupt malaria transmission by clearing the population of sexual stage parasites, gametocytes, prior to the transmission season (figure 1). Gametocytes are essential for propagation of the disease and elimination of gametocytes will result in a reduction in malaria transmission. As a consequence, a successful MDA will reduce the burden of disease in a population and is expected to have little influence on the development of protective immunity in areas of low transmission intensity. In Africa, only one large scale MDA study was conducted in the last 10 years. That study, conducted in The Gambia using sulphadoxine-pyrimethamine (SP) plus a single dose of artesunate (AS), failed to show a significant impact of MDA on malaria transmission.1 Possible reasons for this failure are the limited impact of the drug regimen (a single dose of AS) on malaria transmission, the incomplete coverage, the relatively high transmission intensity in the area and the migration of individuals between villages. Here, we propose to conduct an MDA study in an area of very low malaria transmission intensity in Tanzania.

1.2 Drug-combinations for MDA Antimalarial drugs are only suitable for MDA if they are safe, effective in clearing asexual parasites and have a profound effect on gametocytes. Artemisinin based combination therapy fulfils all these criteria. The combination of sulphadoxine-pyrimethamine (SP) and a three dose regimen of artesunate (AS) has been extensively tested in Tanzania, Uganda and Kenya, is safe and efficacious in clearing asexual parasites and reduces gametocytaemia. In pregnant women, no negative effects of AS were reported.

SP + AS is, however, not capable of clearing all gametocytes and is therefore unable to fully prevent malaria transmission. Primaquine (PQ) is the only drug that has been shown to actively clear gametocytes.

PQ has previously been used for treating symptomatic patients in the lower Moshi area, the area where the current study will be carried out. The rationale was to reduce post-treatment malaria transmission. The strategy was abandoned to follow national guidelines but no side effects were reported. In addition, PQ was recently used in combination with SP and AS and found to be safe and highly efficacious in clearing all parasite stages. However, there is concern for negative haemolytic side effects that have been reported for the full dose regimen in individuals who are G6PD deficient. Haemolytic side effects are generally self-limiting and, more importantly, are observed in individuals receiving the full dose PQ treatment (0.5 mg/kg, 14 days). Despite these limitations of PQ as full-dose treatment, PQ can also be used to clear gametocytes, after clearing asexual parasites with a different drug or drug-combination. This gametocytocidal treatment requires a single dose of PQ only and is mentioned by the World Health Organization (WHO) as beneficial in areas of low malaria transmission. PQ has a short half-life of 5-6 hours and the single dose of 0.75mg/kg (adults 45mg) is too low to cause haemolytic effects. According to WHO standards, testing for G6PD deficiency is therefore not required.