Paul Milligan

Background The use of seasonal malaria chemoprevention (SMC) to prevent malaria in children has expanded rapidly since it was recommended by the World Health Organisation (WHO) in 2012. Deriving consistent and comparable estimates of SMC coverage and adherence is challenging due to varied deployment approaches, coverage indicators, and implementing partners. Understanding where and to what extent SMC has been implemented is crucial for optimising deployment strategies and incorporating SMC into models of malaria burden. Methods Comprehensive campaign data were used to map where and when SMC was implemented. Household surveys provided robust measures of coverage and adherence, but were not available for all locations and years. We developed and validated a framework to select the most accurate method for imputing missing coverage and adherence data. Full-course adherence was calculated as the proportion of eligible children receiving the full 3-day treatment per cycle. Findings We provide the first standardised sub-annual and sub-national estimates and maps of SMC coverage and full-course adherence. Monthly estimates capture shifts in the timing and frequency of SMC implementation. The scope and population coverage of SMC has increased considerably since 2012. In 2024, across the 19 countries, we estimate that there were 204 (187-219) million child-months of treatments with the first dose and 185 (167-202) million child-months of treatments with reported adherence to the full three-day course. Interpretation We found widespread increase in uptake of SMC, with more children are being reached and covered with SMC for longer deployment periods. Our results provide a resource to support future evaluation of SMC deployment strategies and impact on regional and national malaria burden.

In cluster trials of interventions which target a subset of the at-risk population, contemporaneous event counts in a non-target group can be used in estimating the population direct effect if indirect effects are unlikely, but the application of this approach has been limited. We describe the rationale for using the contemporaneous counts approach in the WHO’s Malaria Vaccine Programme Evaluation and how it was applied, and in a re-analysis of a human rotavirus vaccine trial, we demonstrate its application and compare results to conventional methods using event rates per person-time. Indirect effects were considered unlikely because the target group represents a very small proportion of the at-risk population. The population direct effect of intervention introduction in the target group is estimated by comparing between arms the ratio of event counts in the target group to the non-target group. Expanding surveillance into a non-target group may often be possible without significant additional costs. Confounding due to chance imbalance is reduced implicitly insofar that there is better balance in the relative difference between the target and non-target groups than in the variable itself within the target group alone. The approach can improve efficiency when target-group event counts are more strongly correlated with non-target-group counts than they are with target-group person-time, which is more likely as heterogeneity increases. The contemporaneous counts approach can increase the efficiency and internal validity of cluster trials and reduce their operational complexity since person-time denominators are not used.

The self‐controlled case series (SCCS) method is frequently employed to explore the relationship between transient exposures and subsequent health events, utilizing data from individuals who have experienced the event of interest. Conventional spline‐based SCCS models typically do not account for overlapping exposure periods and fail to accommodate complex interactive effects among multiple exposures. In this paper, we introduce a novel semiparametric SCCS method that employs a functional partial‐linear single index (PLSI) link function, allowing for the estimation of overlapping exposure risks. Our approach offers greater interpretability and flexibility compared with existing methods by consolidating multiple exposures into a single index and modeling complex interactions through a nonparametric link function. We validate our model through simulation studies comparing its performance with standard methods under various practical exposure settings. Furthermore, we apply our method to two real‐world datasets involving MMR vaccination and malaria chemoprevention, demonstrating its practical utility and enhanced capability to handle multiple, overlapping exposures effectively. Our findings suggest that the PLSI‐SCCS model is a robust tool for modern epidemiological and pharmaceutical research, providing a nuanced understanding of exposure effects, particularly in complex multi‐exposure scenarios.

Background: Severe Plasmodium falciparum malaria is a leading cause of death in sub-Saharan Africa, with most deaths occurring in children younger than five years of age. The RTS,S/AS01 _E (RTS,S) malaria vaccine delivered seasonally with Seasonal Malaria Chemoprevention (SMC) led to a two-third reduction in severe malaria and malaria deaths compared with either intervention given alone. The aim of this study was to assess the seasonal distribution and clinical presentation of children admitted in hospital with severe malaria who received RTS,S with or without SMC, and whether seasonal vaccination with RTS,S affected their distribution and clinical presentation. Methods: We conducted a secondary ad-hoc analysis of hospital admissions in children aged 5 to 17 months of age when enrolled in the RTS,S + SMC trial in April 2017 in Houndé, Burkina Faso, and Bougouni, Mali, and who were followed until they reached five years of age. Results: Three hundred and thirtythirty-seven serious adverse events were reported during the trial with 222 (65.9%) in Burkina Faso and 115 (34.1%) in Mali, and 48.1% (162/337) were due to severe malaria. The mean age of children with severe malaria was 2.9 years; 79.0% (128/162) of the cases occurred in children aged 3 years or less and 21.0% (34/162) in those aged 4 to 5 years. The most common presentation was severe anemia reported in 50% (81/162) of children, followed by repeated convulsions 25.3%, (41/162), prostration 11.1%, (18/162), hyperparasitaemia 8.0%, (13/162) and cerebral malaria 6.2%, (10/162). Severe malaria anemia was a more frequent form of severe malaria in children in the SMC alone arm 62.1%, (36/58) and lower in children in the SMC+ RTS,S arm 37.1%, (13/35), p=0.048. There was no significant difference in frequency of other clinical presentations between the study arms. Most severe malaria cases, 85.8% (139/162) occurred during the transmission season (July to December). Conclusions: Severe anaemia was the most common presentation of severe malaria and was most frequent in the SMC alone arm. Children aged 3 years or less were the most affected and almost all the cases occurred between July and December. Trial registration: ClinicalTrials.gov , NCT04319380

Numerous trials have evaluated the effectiveness of mass drug administration (MDA) to rapidly reduce malaria transmission, but it is unknown whether estimated effects generalize to other populations eligible for MDA. A recent cluster-randomized trial in Senegal found that MDA reduced malaria incidence by 55% in areas routinely deploying seasonal malaria chemoprevention (SMC). Here, we used transportability models with machine learning to generalize trial effects to 116 non-trial Communes where SMC is standard-of-care. Accounting for differences in weather, vegetation, and population density between trial and non-trial areas, we estimated significant reductions in incidence of 36%–65% in 74 non-trial Communes, with larger reductions in areas with higher precipitation, denser vegetation, and lower temperatures. We found that MDA was not effective in the post-intervention year in non-trial Communes, supporting the notion that MDA effects are short-lived. Our approach offers a scalable framework for generalizing trial findings to target environmentally-mediated infectious disease interventions.

In studies of infectious disease prevention, the level of protective efficacy of medicinal products such as vaccines and prophylactic drugs tends to vary over time. Many products require administration of multiple doses at scheduled times, as opposed to one‐off or continual intervention. Accurate information on the trajectory of the level of protective efficacy over time facilitates informed clinical recommendations and implementation strategies, for example, with respect to the timing of administration of the doses. Based on concepts from pharmacokinetic and pharmacodynamic modeling, we propose a non‐linear function for modeling the trajectory after each dose. The cumulative effect of multiple doses of the products is captured by an additive series of the function. The model has the advantages of parsimony and interpretability, while remaining flexible in capturing features of the trajectories. We incorporate this series into the Andersen‐Gill model for analysis of recurrent event time data and compare it with alternative parametric and non‐parametric functions. We use data on clinical malaria disease episodes from a trial of four doses of an anti‐malarial drug combination for chemoprevention to illustrate, and evaluate the performance of the methods using simulation. The proposed method out‐performed the alternatives in the analysis of real data in terms of Akaike and Bayesian Information Criterion. It also accurately captured the features of the protective efficacy trajectory such as the area under curve in simulations. The proposed method has strong potential to enhance the evaluation of disease prevention measures and improve their implementation strategies.

: Despite marked progress in Senegal, three regions in the southeast part continue to have a high burden of malaria, but there have been no recent studies assessing the prevalence of malaria associated with pregnancy. This study aimed to determine the prevalence of malaria infection in pregnant women attending antenatal clinics in Senegal. During the malaria transmission season of 2019, pregnant women attending 11 health care facilities for a scheduled visit and those presenting unwell with signs of malaria were invited to participate in a malaria screening study. A finger prick blood sample was taken for malaria diagnosis by rapid diagnosis test (RDT) and polymerase chain reaction (PCR). A total of 877 pregnant women were enrolled, 787 for a scheduled antenatal consultation and 90 for an unscheduled consultation with signs of malaria. The prevalence of Plasmodium falciparum among the first group was 48% by PCR and 20% by RDT, and that among the second group was 86% by PCR and 83% by RDT. RDT sensitivity in capturing asymptomatic, PCR-positive infections was 9.2% but ranged from 83% to 94% among febrile women. The prevalence of infection by PCR in women who reported having received at least three doses of sulfadoxine pyrimethamine (SP) was 41.9% compared with 58.9% in women who reported they had not received any SP doses (prevalence ratio adjusted for gravidity and gestational age, 0.54; 95% CI, 0.41–0.73). The burden of P. falciparum infections remains high among pregnant women, the majority of which are not captured by RDT. More effective measures to prevent malaria infection in pregnancy are needed.

Background The RTS,S/AS01 malaria vaccine was introduced in Ghana, Kenya, and Malawi in 2019. Evaluation includes case-control studies designed to monitor individual-level safety and effectiveness to complement population-level estimates derived from the MVPE. Here, we discuss design and practical considerations for conducting case-control studies to measure vaccine effectiveness against severe malaria, the need for a 4th dose, and for assessment of safety outcomes. Methods For the severe malaria study we aimed to estimate the effectiveness of the primary 3 doses, and of the 4th dose. We also aimed to estimate rebound, if any, in children who received only the primary 3 doses. Cases were patients with severe malaria admitted to a study hospital, residing in an RTS,S/AS01 implementation area, and eligible to have received the 3rd or 4th dose of the vaccine. The case patient’s home is visited to collect data on vaccination status and other details. Four controls are then recruited from the same community, matched closely on date of birth. Vaccination status is determined from home-based records, and from clinic registers. Similar approaches were used for studies of safety outcomes. Results We share preliminary results and discuss the challenges encountered and lessons learned about implementing a multi-centre case control study for a malaria vaccine, and approaches to data collection which have proved effective, including establishing surveillance, the use of specific case definitions standardized across centres, recruiting closely age-matched community controls, and obtaining reliable information from both cases and controls on potential confounding factors which may be associated with both risk of the outcome and with access to vaccination. Conclusion Case control studies are an efficient means of monitoring vaccine effectiveness and safety, but require care in design and implementation. The lessons learned from the malaria vaccine pilots will be useful for countries planning introduction of a malaria vaccine.