Effectiveness of seasonal malaria chemoprevention (SMC) treatments when SMC is implemented at scale: Case-control studies in 5 countries

Abstract

Background: Seasonal malaria chemoprevention (SMC) has shown high protective efficacy against clinical malaria and severe malaria in a series of clinical trials. We evaluated the effectiveness of SMC treatments against clinical malaria when delivered at scale through national malaria control programmes in 2015 and 2016.

Methods and findings: Case-control studies were carried out in Mali and The Gambia in 2015, and in Burkina Faso, Chad, Mali, Nigeria, and The Gambia in 2016. Children aged 3-59 months presenting at selected health facilities with microscopically confirmed clinical malaria were recruited as cases. Two controls per case were recruited concurrently (on or shortly after the day the case was detected) from the neighbourhood in which the case lived. The primary exposure was the time since the most recent course of SMC treatment, determined from SMC recipient cards, caregiver recall, and administrative records. Conditional logistic regression was used to estimate the odds ratio (OR) associated with receipt of SMC within the previous 28 days, and SMC 29 to 42 days ago, compared with no SMC in the past 42 days. These ORs, which are equivalent to incidence rate ratios, were used to calculate the percentage reduction in clinical malaria incidence in the corresponding time periods. Results from individual countries were pooled in a random-effects meta-analysis. In total, 2,126 cases and 4,252 controls were included in the analysis. Across the 7 studies, the mean age ranged from 1.7 to 2.4 years and from 2.1 to 2.8 years among controls and cases, respectively; 42.2%-50.9% and 38.9%-46.9% of controls and cases, respectively, were male. In all 7 individual case-control studies, a high degree of personal protection from SMC against clinical malaria was observed, ranging from 73% in Mali in 2016 to 98% in Mali in 2015. The overall OR for SMC within 28 days was 0.12 (95% CI: 0.06, 0.21; p < 0.001), indicating a protective effectiveness of 88% (95% CI: 79%, 94%). Effectiveness against clinical malaria for SMC 29-42 days ago was 61% (95% CI: 47%, 72%). Similar results were obtained when the analysis was restricted to cases with parasite density in excess of 5,000 parasites per microlitre: Protective effectiveness 90% (95% CI: 79%, 96%; P<0.001), and 59% (95% CI: 34%, 74%; P<0.001) for SMC 0-28 days and 29-42 days ago, respectively. Potential limitations include the possibility of residual confounding due to an association between exposure to malaria and access to SMC, or differences in access to SMC between patients attending a clinic and community controls; however, neighbourhood matching of cases and controls, and covariate adjustment, attempted to control for these aspects, and the observed decline in protection over time, consistent with expected trends, argues against a major bias from these sources.

Conclusions: SMC administered as part of routine national malaria control activities provided a very high level of personal protection against clinical malaria over 28 days post-treatment, similar to the efficacy observed in clinical trials. The case-control design used in this study can be used at intervals to ensure SMC treatments remain effective.

Fig 1. Schematic of recruitment of cases and controls in 2015 and 2016.

(a) 2015; (b) 2016. This schematic of recruitment shows the timing of seasonal malaria chemoprevention (SMC) cycles (red arrows) and the recruitment period of the case–control study (black dots) in relation to the typical seasonal peak in malaria cases (hypothetical seasonality pattern shown by the blue line). In 2015, cases and corresponding controls were recruited in the late rainy season and early dry season in Mali and The Gambia. In 2016, cases and controls were recruited uniformly across the entire malaria transmission season in Burkina Faso, Chad, Mali, Nigeria, and The Gambia, from the time of the first SMC cycle until 8 weeks after the final cycle.

Fig 2. Calculation of exposure in controls with respect to the date that the case was diagnosed.

For cases, the primary exposure (time since the most recent seasonal malaria chemoprevention [SMC] course) was defined on the basis of the most recent SMC cycle received at the time of diagnosis. For controls, the primary exposure was defined on the basis of the most recent SMC received at the time the case was diagnosed. On most occasions, this was straightforward, as for both case and control, the most recent SMC cycle was some time ago, and defining the exposure relied only on accurate recording of dates. However, in a few instances, the case was recruited just before a new SMC cycle was delivered, and the control was not recruited until just afterwards. The figure shows the example of a case being recruited just before SMC 3, and a control being recruited just after SMC 3. Because the exposure for the control is defined based on the most recent SMC received at the time the case is diagnosed, in this example the control’s exposure is based on SMC 2, rather than SMC 3. This avoids the possible bias of some controls appearing to have received SMC much more recently than cases (which would inflate the apparent benefit of SMC) as an artefact of the slight delay in the recruitment of controls.

Fig 3. Meta-analysis of the odds ratio for seasonal malaria chemoprevention (SMC) within the previous 28 days and 29–42 days ago.

(a) SMC within the previous 28 days; (b) SMC 29–42 days ago. Results from random-effects meta-analysis.