Showing papers by "Paul Milligan published in 2021"

Seasonal Malaria Vaccination with or without Seasonal Malaria Chemoprevention.

Abstract: Background Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa. Methods We conducted an individually randomized, controlled trial to assess whether seasonal vaccination with RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria and whether the two interventions combined were superior to either one alone in preventing uncomplicated malaria and severe malaria-related outcomes. Results We randomly assigned 6861 children 5 to 17 months of age to receive sulfadoxine-pyrimethamine and amodiaquine (2287 children [chemoprevention-alone group]), RTS,S/AS01E (2288 children [vaccine-alone group]), or chemoprevention and RTS,S/AS01E (2286 children [combination group]). Of these, 1965, 1988, and 1967 children in the three groups, respectively, received the first dose of the assigned intervention and were followed for 3 years. Febrile seizure developed in 5 children the day after receipt of the vaccine, but the children recovered and had no sequelae. There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01E as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively. Conclusions Administration of RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria. The combination of these interventions resulted in a substantially lower incidence of uncomplicated malaria, severe malaria, and death from malaria than either intervention alone. (Funded by the Joint Global Health Trials and PATH; ClinicalTrials.gov number, NCT03143218.).

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.

The Duration of Protection from Azithromycin Against Malaria, Acute Respiratory, Gastrointestinal, and Skin Infections When Given Alongside Seasonal Malaria Chemoprevention: Secondary Analyses of Data from a Clinical Trial in Houndé, Burkina Faso, and Bougouni, Mali.

Abstract: Background Mass drug administration (MDA) with azithromycin (AZ) is being considered as a strategy to promote child survival in sub-Saharan Africa, but the mechanism by which AZ reduces mortality is unclear. To better understand the nature and extent of protection provided by AZ, we explored the profile of protection by time since administration, using data from a household-randomised, placebo-controlled trial in Burkina Faso and Mali. Methods Between 2014 and 2016, 30,977 children aged 3-59 months received seasonal malaria chemoprevention (SMC) with sulphadoxine-pyrimethamine plus amodiaquine and either AZ or placebo monthly, on four occasions each year. Poisson regression with gamma-distributed random effects, accounting for the household randomisation and within-individual clustering of illness episodes, was used to compare incidence of pre-specified outcomes between SMC+AZ versus SMC+placebo groups in fixed time strata post-treatment. The likelihood ratio test was used to assess evidence for a time-treatment group interaction. Results Relative to SMC+placebo, there was no evidence of protection from SMC+AZ against hospital admissions and deaths. Additional protection from SMC+AZ against malaria was confined to the first two weeks post-administration (protective efficacy (PE): 24.2% [95% CI: 17.8%, 30.1%]). Gastroenteritis and pneumonia were reduced by 29.9% [21.7; 37.3%], and 34.3% [14.9; 49.3%], respectively in the first two weeks post-administration. Protection against non-malaria fevers with a skin condition persisted up to 28 days: PE: 46.3% [35.1; 55.6%]). Conclusions The benefits of AZ-MDA are broad-ranging but short-lived. To maximise impact, timing of AZ-MDA must address the challenge of targeting asynchronous morbidity and mortality peaks from different causes.

Ratio estimators of intervention effects on event rates in cluster randomized trials.

Abstract: We consider five asymptotically unbiased estimators of intervention effects on event rates in non-matched and matched-pair cluster randomized trials, including ratio of mean counts r1 , ratio of mean cluster-level event rates r2 , ratio of event rates r3 , double ratio of counts r4 , and double ratio of event rates r5 . In the absence of an indirect effect, they all estimate the direct effect of the intervention. Otherwise, r1 , r2, and r3 estimate the total effect, which comprises the direct and indirect effects, whereas r4 and r5 estimate the direct effect only. We derive the conditions under which each estimator is more precise or powerful than its alternatives. To control bias in studies with a small number of clusters, we propose a set of approximately unbiased estimators. We evaluate their properties by simulation and apply the methods to a trial of seasonal malaria chemoprevention. The approximately unbiased estimators are practically unbiased and their confidence intervals usually have coverage probability close to the nominal level; the asymptotically unbiased estimators perform well when the number of clusters is approximately 32 or more per trial arm. Despite its simplicity, r1 performs comparably with r2 and r3 in trials with a large but realistic number of clusters. When the variability of baseline event rate is large and there is no indirect effect, r4 and r5 tend to offer higher power than r1 , r2, and r3 . We discuss the implications of these findings to the planning and analysis of cluster randomized trials.