Feasibility, safety, and impact of the RTS,S/AS01E malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi.

BACKGROUND: The RTS,S/AS01E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. METHODS: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. FINDINGS: By April 30, 2021, 652 673 children had received at least one dose of RTS,S and 494 745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26 285 children aged 1-59 months were admitted to sentinel hospitals and 13 198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). INTERPRETATION: In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. FUNDING: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

Estimation of trajectory of protective efficacy in infectious disease prevention trials using recurrent event times.

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.

Mass drug administration to reduce malaria incidence in a low-to-moderate endemic setting: short-term impact results from a cluster randomised controlled trial in Senegal.

Background: In Africa, the scale-up of malaria control interventions, including seasonal malaria chemoprevention (SMC), has dramatically reduced malaria burden, but progress toward malaria elimination has stalled. We evaluated mass drug administration (MDA) as a strategy to accelerate reductions in malaria incidence in Senegal. Methods: We conducted an open-label, cluster-randomised controlled trial in a low-to-moderate transmission setting of Tambacounda, Senegal. Eligible villages had a population size between 200-800. All villages received pyrethroid-piperonyl butoxide bednets and proactive community case management of malaria at baseline. Sixty villages were randomised 1:1 to either three cycles of MDA with dihydroartemisinin-piperaquine+single-low dose primaquine administered to individuals aged ≥3 months, six-weeks apart starting the third week of June (intervention), or standard-of-care, which included three monthly cycles of SMC with sulfadoxine-pyrimethamine+amodiaquine administered to children aged 3-120 months starting end of July (control). MDA and SMC were delivered door-to-door. The primary outcome was clinical malaria incidence in all ages assessed during the peak transmission season (July-December), the year after intervention. Here, we report safety, coverage, and impact outcomes during the intervention year. The trial is registered at ClinicalTrials.Gov (NCT04864444). Findings: Between June 21, 2021 and October 3, 2021, 6505, 7125, and 7250 participants were administered MDA and 3202, 3174, and 3146 participants were administered SMC across cycles. Coverage of ≥1 dose of MDA drugs was 79%, 82%, and 83% across cycles. During the transmission season of the intervention year, MDA was associated with a 55% [95% CI: 28%-72%] lower incidence of malaria compared to control (MDA: 93 cases/1000 population; control: 173 cases/1000 population). No serious adverse events were reported in either arm. Interpretation: In low-to-moderate malaria transmission settings with scaled-up malaria control interventions, MDA with dihydroartemisinin-piperaquine+single-low dose primaquine is effective and well-tolerated for reducing malaria incidence. Further analyses will focus on the sustainability of this reduction. Funding: United States President's Malaria Initiative.