Influences of intermittent preventive treatment and persistent multiclonal Plasmodium falciparum infections on clinical malaria risk

Abstract

Background: Intermittent preventive treatment (IPT) of malaria involves administration of curative doses of antimalarials at specified time points to vulnerable populations in endemic areas, regardless whether a subject is known to be infected. The effect of this new intervention on the development and maintenance of protective immunity needs further understanding. We have investigated how seasonal IPT affects the genetic diversity of Plasmodium falciparum infections and the risk of subsequent clinical malaria.

Material and methods: The study included 2227 Ghanaian children (3-59 months) who were given sulphadoxine-pyrimethamine (SP) bimonthly, artesunate plus amodiaquine (AS+AQ) monthly or bimonthly, or placebo monthly for six months spanning the malaria transmission season. Blood samples collected at three post-interventional surveys were analysed by genotyping of the polymorphic merozoite surface protein 2 gene. Malaria morbidity and anaemia was monitored during 12 months follow-up.

Results: Monthly IPT with AS+AQ resulted in a marked reduction in number of concurrent clones and only children parasite negative just after the intervention period developed clinical malaria during follow-up. In the placebo group, children without parasites as well as those infected with ≥2 clones had a reduced risk of subsequent malaria. The bimonthly SP or AS+AQ groups had similar number of clones as placebo after intervention; however, diversity and parasite negativity did not predict the risk of malaria. An interaction effect showed that multiclonal infections were only associated with protection in children without intermittent treatment.

Conclusion: Molecular typing revealed effects of the intervention not detected by ordinary microscopy. Effective seasonal IPT temporarily reduced the prevalence and genetic diversity of P. falciparum infections. The reduced risk of malaria in children with multiclonal infections only seen in untreated children suggests that persistence of antigenically diverse P. falciparum infections is important for the maintenance of protective malaria immunity in high transmission settings.

Figure 1. Study outline.

Intermittent preventive treatment or placebo was given over a six month-period spanning peak malaria transmission season, followed by a 12- month post intervention surveillance period. Cross-sectional surveys were performed 1 month (November 2005), 6 months (April 2006) and 12 months (November 2006) after the intervention was stopped. Blood films and filter paper samples were collected at these three time points.

Figure 2. a) Number (n) and b) proportion (%) of PCR positive asymptomatic children infected with different number of msp2 genotypes at the respective surveys; 1 month after the intervention, at the following dry season 6 months post-intervention, and at the end of the following rainy season 12 months post-intervention.

The number within brackets in Figure 2a represents the total number of children in the respective groups.

Figure 3. Kaplan Meier estimate (unadjusted) of time to subsequent clinical episode (fever and any P. falciparum) in 1856 asymptomatic children.

Figure 4. Kaplan Meier estimate (unadjusted) of time to subsequent clinical episode (fever and any P. falciparum) in 1856 asymptomatic children; a) placebo, b) SP bimonthly c) AS+AQ bimonthly and d) AS+AQ monthly.

In the AS+AQ monthly group no children with parasites at the survey after ended intervention developed clinical malaria.