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This trial assessed the efficacy of the vaccine RTS,S/AS01 E as compared with chemoprevention in preventing malaria. The protective efficacy of RTS,S/AS01 E was noninferior to that of chemoprevention, and the combination of RTS,S/AS01 E and chemoprevention was more effective than either intervention alone.

Malaria causes complications during pregnancy, and its prevention is more challenging in the setting of drug-resistant parasites. This trial from Uganda, where resistance to the standard therapy is common, compares three different drug regimens for prevention of malaria. In 2007, more than 30 million pregnancies were estimated to have occurred in areas of sub-Saharan Africa in which Plasmodium falciparum is endemic. 1 Malaria during pregnancy is associated with placental malaria, adverse birth outcomes, and complications and death in both the mother and the infant. 2 , 3 In sub-Saharan Africa, malaria during pregnancy is estimated to be the cause of low birth weight in up to 20% of deliveries, leading to more than 100,000 infant deaths annually. 2 , 3 Given the high burden of malaria in this vulnerable population, the World Health Organization (WHO) recommends the routine implementation of malaria-preventive measures among . . .

Primaquine and methylene blue are gametocytocidal compounds that could prevent Plasmodium falciparum transmission to mosquitoes. We aimed to assess the efficacy and safety of primaquine and methylene blue in preventing human to mosquito transmission of P falciparum among glucose-6-phosphate dehydrogenase (G6PD)-normal, gametocytaemic male participants. This was a phase 2, single-blind, randomised controlled trial done at the Clinical Research Centre of the Malaria Research and Training Centre (MRTC) of the University of Bamako (Bamako, Mali). We enrolled male participants aged 5–50 years with asymptomatic P falciparum malaria. G6PD-normal participants with gametocytes detected by blood smear were randomised 1:1:1:1 in block sizes of eight, using a sealed-envelope design, to receive either sulfadoxine-pyrimethamine and amodiaquine, sulfadoxine-pyrimethamine and amodiaquine plus a single dose of 0·25 mg/kg primaquine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus 15 mg/kg per day methylene blue for 3 days. Laboratory staff, investigators, and insectary technicians were masked to the treatment group and gametocyte density of study participants. The study pharmacist and treating physician were not masked. Participants could request unmasking. The primary efficacy endpoint, analysed in all infected patients with at least one infectivity measure before and after treatment, was median within-person percentage change in mosquito infectivity 2 and 7 days after treatment, assessed by membrane feeding. This study is registered with ClinicalTrials.gov, number NCT02831023. Between June 27, 2016, and Nov 1, 2016, 80 participants were enrolled and assigned to the sulfadoxine-pyrimethamine and amodiaquine (n=20), sulfadoxine-pyrimethamine and amodiaquine plus primaquine (n=20), dihydroartemisinin-piperaquine (n=20), or dihydroartemisinin-piperaquine plus methylene blue (n=20) groups. Among participants infectious at baseline (54 [68%] of 80), those in the sulfadoxine-pyrimethamine and amodiaquine plus primaquine group (n=19) had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with sulfadoxine-pyrimethamine and amodiaquine alone (n=12; −10·2%, IQR −143·9 to 56·6; p<0·0001). The dihydroartemisinin-piperaquine plus methylene blue (n=11) group had a median 100% (IQR 100 to 100) within-person reduction in mosquito infectivity on day 2, a larger reduction than was noted with dihydroartemisinin-piperaquine alone (n=12; −6·0%, IQR −126·1 to 86·9; p<0·0001). Haemoglobin changes were similar between gametocytocidal arms and their respective controls. After exclusion of blue urine, adverse events were similar across all groups (59 [74%] of 80 participants had 162 adverse events overall, 145 [90%] of which were mild). Adding a single dose of 0·25 mg/kg primaquine to sulfadoxine-pyrimethamine and amodiaquine or 3 days of 15 mg/kg per day methylene blue to dihydroartemisinin-piperaquine was highly efficacious for preventing P falciparum transmission. Both primaquine and methylene blue were well tolerated. Bill & Melinda Gates Foundation, European Research Council.

To mitigate adverse consequences of malaria in pregnancy, the World Health Organization recommends intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine. However, the effectiveness of IPTp with sulfadoxine-pyrimethamine has been threatened by widespread Plasmodium falciparum resistance, especially in East and Southern Africa. For IPTp, dihydroartemisinin-piperaquine has shown superior antimalarial effects compared to sulfadoxine-pyrimethamine, but sulfadoxine-pyrimethamine has been associated with improved birth outcomes compared to dihydroartemisinin-piperaquine. We hypothesized that a combination of both dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine would provide superior birth outcomes compared to either drug alone. We conducted a double-blinded, randomized, controlled trial of 2,757 pregnant women in Uganda, where resistance of malaria parasites to sulfadoxine-pyrimethamine is widespread. Women were randomly assigned (1:1:1) to monthly IPTp with sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine, or dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine. The primary outcome was the risk of a composite adverse birth outcome defined as any of the following: spontaneous abortion, stillbirth, low birthweight (LBW, < 2,500 g), preterm delivery (<37 weeks), small-for-gestational age, or neonatal death. Secondary outcomes included specific individual adverse birth outcomes, measures of malaria during pregnancy, and safety/tolerability. Combining dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine did not reduce the risk of a composite adverse birth outcome compared to dihydroartemisinin-piperaquine (30.0% versus 30.9%, relative risk (RR) 0.97 [95% CI 0.84-1.12]; p = 0.70) or sulfadoxine-pyrimethamine (30.0% versus 26.4%, RR 1.14 [95% CI 0.98-1.33]; p = 0.10). The risk of a composite adverse birth outcome was higher with dihydroartemisinin-piperaquine compared to sulfadoxine-pyrimethamine (30.9% versus 26.4%, RR 1.17 [95% CI 1.01-1.36]; p = 0.04). Considering individual adverse birth outcomes, combining dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine was associated with a higher risk of small-for-gestational age (23.4% versus 18.7%, RR 1.25 [95% CI 1.04-1.51]; p = 0.02) and low birthweight (8.6% versus 5.8%, RR 1.48 [95 CI 1.04-2.12]; p = 0.03) compared to sulfadoxine-pyrimethamine and a higher risk of preterm delivery (5.3% versus 3.1%, RR 1.73 [95% CI 1.07-2.79]; p = 0.03) compared to dihydroartemisinin-piperaquine. During pregnancy, compared to sulfadoxine-pyrimethamine, dihydroartemisinin-piperaquine was associated with a 94% reduction in the incidence of symptomatic malaria (0.46 versus 0.03 episodes per person-year, incidence rate ratio 0.06 [95% CI 0.03-0.12]; p < 0.001) and a 97% reduction in the risk of microscopic parasitemia (17.7% versus 0.6%, RR 0.03 [95% CI 0.02-0.05]; p < 0.001), but dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine was not associated with improved malaria outcomes over dihydroartemisinin-piperaquine alone. There were no significant differences in the incidence of any grade 3-4 adverse events between the treatment arms. As this study was conducted in an area of high transmission intensity with widespread resistance to sulfadoxine-pyrimethamine, findings may not be generalizable to other settings. Despite the superior antimalarial activity of dihydroartemisinin-piperaquine, sulfadoxine-pyrimethamine alone was associated with improved birth outcomes. Combining dihydroartemisinin-piperaquine plus sulfadoxine-pyrimethamine for IPTp did not improve birth outcomes compared to either sulfadoxine-pyrimethamine or dihydroartemisinin-piperaquine alone. ClinicalTrials.gov (NCT04336189; https://clinicaltrials.gov/study/NCT04336189).

Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ), given each month during the transmission season, is recommended for children living in areas of the Sahel where malaria transmission is highly seasonal. The recommendation for SMC is currently limited to children under five years of age, but, in many areas of seasonal transmission, the burden in older children may justify extending this age limit. This study was done to determine the effectiveness of SMC in Senegalese children up to ten years of age. SMC was introduced into three districts over three years in central Senegal using a stepped-wedge cluster-randomised design. A census of the population was undertaken and a surveillance system was established to record all deaths and to record all cases of malaria seen at health facilities. A pharmacovigilance system was put in place to detect adverse drug reactions. Fifty-four health posts were randomised. Nine started implementation of SMC in 2008, 18 in 2009, and a further 18 in 2010, with 9 remaining as controls. In the first year of implementation, SMC was delivered to children aged 3-59 months; the age range was then extended for the latter two years of the study to include children up to 10 years of age. Cluster sample surveys at the end of each transmission season were done to measure coverage of SMC and the prevalence of parasitaemia and anaemia, to monitor molecular markers of drug resistance, and to measure insecticide-treated net (ITN) use. Entomological monitoring and assessment of costs of delivery in each health post and of community attitudes to SMC were also undertaken. About 780,000 treatments were administered over three years. Coverage exceeded 80% each month. Mortality, the primary endpoint, was similar in SMC and control areas (4.6 and 4.5 per 1000 respectively in children under 5 years and 1.3 and 1.2 per 1000 in children 5-9 years of age; the overall mortality rate ratio [SMC: no SMC] was 0.90, 95% CI 0.68-1.2, p = 0.496). A reduction of 60% (95% CI 54%-64%, p < 0.001) in the incidence of malaria cases confirmed by a rapid diagnostic test (RDT) and a reduction of 69% (95% CI 65%-72%, p < 0.001) in the number of treatments for malaria (confirmed and unconfirmed) was observed in children. In areas where SMC was implemented, incidence of confirmed malaria in adults and in children too old to receive SMC was reduced by 26% (95% CI 18%-33%, p < 0.001) and the total number of treatments for malaria (confirmed and unconfirmed) in these older age groups was reduced by 29% (95% CI 21%-35%, p < 0.001). One hundred and twenty-three children were admitted to hospital with a diagnosis of severe malaria, with 64 in control areas and 59 in SMC areas, showing a reduction in the incidence rate of severe disease of 45% (95% CI 5%-68%, p = 0.031). Estimates of the reduction in the prevalence of parasitaemia at the end of the transmission season in SMC areas were 68% (95% CI 35%-85%) p = 0.002 in 2008, 84% (95% CI 58%-94%, p < 0.001) in 2009, and 30% (95% CI -130%-79%, p = 0.56) in 2010. SMC was well tolerated with no serious adverse reactions attributable to SMC drugs. Vomiting was the most commonly reported mild adverse event but was reported in less than 1% of treatments. The average cost of delivery was US$0.50 per child per month, but varied widely depending on the size of the health post. Limitations included the low rate of mortality, which limited our ability to detect an effect on this endpoint. SMC substantially reduced the incidence of outpatient cases of malaria and of severe malaria in children, but no difference in all-cause mortality was observed. Introduction of SMC was associated with an overall reduction in malaria incidence in untreated age groups. In many areas of Africa with seasonal malaria, there is a substantial burden in older children that could be prevented by SMC. SMC in older children is well tolerated and effective and can contribute to reducing malaria transmission. ClinicalTrials.gov NCT00712374.

In this randomized, placebo-controlled trial, azithromycin was assessed as an adjuvant agent for malaria prevention in children in Burkina Faso and Mali. No survival or antimalarial benefit associated with azithromycin was observed.

In many sub-Saharan African countries, it is recommended that children with sickle cell anaemia receive malaria chemoprevention with monthly sulfadoxine–pyrimethamine or daily proguanil as the standard of care. However, the efficacy of these interventions is compromised by high-grade antifolate resistance of Plasmodium falciparum and poor adherence. We aimed to compare the efficacy of weekly dihydroartemisinin–piperaquine and monthly sulfadoxine–pyrimethamine for the prevention of clinical malaria in children with sickle cell anaemia in areas with high-grade sulfadoxine–pyrimethamine resistance of P falciparum in Uganda and Malawi. We did an individually randomised, parallel group, double-blind, placebo-controlled trial at two hospitals in Uganda and two hospitals in Malawi. Children (aged 6 months to 15 years) with sickle cell anaemia with a bodyweight of at least 5kg were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and weight category, to receive either weekly dihydroartemisinin–piperaquine (approximately 2·5 mg per kg bodyweight dihydroartemisinin and 20 mg per kg bodyweight per day piperaquine) or monthly sulfadoxine–pyrimethamine (approximately 25 mg per kg bodyweight sulfadoxine and 1·25 mg per kg bodyweight). Placebos matching the alternative treatment were used in each treatment group to maintain masking of the different dosing schedules from the participants and caregivers, study staff, investigators, and data analysts. All children younger than 5 years received penicillin twice daily as standard of care. The primary endpoint was the incidence of clinical malaria, defined as a history of fever in the preceding 48 h or documented axillary temperature of 37·5°C or higher plus the detection of P falciparum parasites on microscopy (any parasite density). Secondary efficacy outcomes were any malaria parasitaemia (on either microscopy or malaria rapid diagnostic test), all-cause unscheduled clinic visits, all-cause and malaria-specific hospitalisation, sickle cell anaemia-related events (including vaso-occlusive crises, acute chest syndrome, stroke), need for blood transfusion, and death. All primary and secondary outcomes were assessed in the modified intention-to-treat population, which included all participants who were randomly assigned for whom endpoint data were available. Safety was assessed in in all children who received at least one dose of the study drug. Complete case analysis was conducted using negative-binomial regression. This study was registered with Clinicaltrials.gov, NCT04844099. Between April 17, 2021, and May 30, 2022, 725 participants were randomly assigned; of whom 724 were included in the primary analysis (367 participants in the dihydroartemisinin–piperaquine group and 357 participants in the sulfadoxine–pyrimethamine group). The median follow-up time was 14·7 months (IQR 11·2–18·2). The incidence of clinical malaria was 8·8 cases per 100 person-years in the dihydroartemisinin–piperaquine group and 43.7 events per 100 person-years in the sulfadoxine–pyrimethamine group (incidence rate ratio [IRR] 0·20 [95% CI 0·14–0·30], p<0·0001). The incidence of hospitalisation with any malaria was lower in the dihydroartemisinin–piperaquine group than the sulfadoxine–pyrimethamine group (10·4 vs 37·0 events per 100 person-years; IRR 0·29 [0·20–0·42], p<0·0001) and the number of blood transfusions was also lower in the dihydroartemisinin–piperaquine group than the sulfadoxine–pyrimethamine group (52·1 vs 72·5 events per 100 person-years; IRR 0·70 [0·54–0·90], p=0·006). The incidence of all-cause unscheduled clinic visits and all-cause hospitalisations were similar between the two groups, however, participants in the dihydroartemisinin–piperaquine group had more clinic visits unrelated to malaria (IRR 1·12 [1·00–1·24], p=0·042) and more hospitalisations with lower respiratory tract events (16·5 vs 8·5 events per 100 person-years; IRR 1·99 [1·25–3·16], p=0·0036) than participants in the sulfadoxine–pyrimethamine group. The number of serious adverse events in the dihydroartemisinin–piperaquine group was similar to that in the sulfadoxine–pyrimethamine group (vaso-occlusive crisis [154 of 367 participants dihydroartemisinin–piperaquine group vs 132 of 357 participants in the sulfadoxine–pyrimethamine group] and suspected sepsis [115 participants vs 92 participants]), with the exception of acute chest syndrome or pneumonia (51 participants vs 32 participants). The number of deaths were similar between groups (six [2%] of 367 participants in the dihydroartemisinin–piperaquine group and eight (2%) of 357 participants in the sulfadoxine–pyrimethamine group). Malaria chemoprophylaxis with weekly dihydroartemisinin–piperaquine in children with sickle cell anaemia is safe and considerably more efficacious than monthly sulfadoxine–pyrimethamine. However, monthly sulfadoxine–pyrimethamine was associated with fewer episodes of non-malaria-related illnesses, especially in children 5 years or older not receiving penicillin prophylaxis, which might reflect its antimicrobial effects. In areas with high P falciparum antifolate resistance, dihydroartemisinin–piperaquine should be considered as an alternative to sulfadoxine–pyrimethamine for malaria chemoprevention in children younger than 5 years with sickle cell anaemia receiving penicillin-V prophylaxis. However, there is need for further studies in children older than 5 years. Research Council of Norway and UK Medical Research Council. For the Chichewa, Acholi, Lusoga and Luganda translations of the abstract see Supplementary Materials section.

Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs. To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children. This study was conducted between June 28, 2010, and September 25, 2013. 400 infants were enrolled and 393 randomized at 6 mo of age to no chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP). Study drugs were administered at home without supervision. Piperaquine (PQ) levels were used as a measure of compliance in the DP arm. Participants were given insecticide-treated bednets, and caregivers were encouraged to bring their child to a study clinic whenever they were ill. Chemoprevention was stopped at 24 mo of age, and participants followed-up an additional year. Primary outcome was the incidence of malaria during the intervention period. During the intervention, the incidence of malaria in the no chemoprevention arm was 6.95 episodes per person-year at risk. Protective efficacy was 58% (95% CI, 45%-67%, p<0.001) for DP, 28% (95% CI, 7%-44%, p = 0.01) for TS, and 7% for SP (95% CI, -19% to 28%, p = 0.57). PQ levels were below the detection limit 52% of the time when malaria was diagnosed in the DP arm, suggesting non-adherence. There were no differences between the study arms in the incidence of serious adverse events during the intervention and the incidence of malaria during the 1-y period after the intervention was stopped. For preventing malaria in children living in an area of high transmission intensity, monthly DP was the most efficacious and safe, although adherence may pose a problem. Monthly SP and daily TS may not be appropriate in areas with high transmission intensity and frequent resistance to antifolates. www.ClinicalTrials.gov NCT00948896 Please see later in the article for the Editors' Summary.

Adding community-based scheduled malaria screening and treatment to existing intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) strategies did not reduce malaria in pregnancy. Increasing the number of IPTp-SP doses given during pregnancy continues to be a priority. Abstract Background We investigated whether adding community scheduled malaria screening and treatment (CSST) with artemether-lumefantrine by community health workers (CHWs) to standard intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) would improve maternal and infant health. Methods In this 2-arm cluster-randomized, controlled trial, villages in Burkina Faso, The Gambia, and Benin were randomized to receive CSST plus IPTp-SP or IPTp-SP alone. CHWs in the intervention arm performed monthly CSST during pregnancy. At each contact, filter paper and blood slides were collected, and at delivery, a placental biopsy was collected. Primary and secondary endpoints were the prevalence of placental malaria, maternal anemia, maternal peripheral infection, low birth weight, antenatal clinic (ANC) attendance, and IPTp-SP coverage. Results Malaria infection was detected at least once for 3.8% women in The Gambia, 16.9% in Benin, and 31.6% in Burkina Faso. There was no difference between study arms in terms of placenta malaria after adjusting for birth season, parity, and IPTp-SP doses (adjusted odds ratio, 1.06 [95% confidence interval, .78-1.44]; P = .72). No difference between the study arms was found for peripheral maternal infection, anemia, and adverse pregnancy outcomes. ANC attendance was significantly higher in the intervention arm in Burkina Faso but not in The Gambia and Benin. Increasing number of IPTp-SP doses was associated with a significantly lower risk of placenta malaria, anemia at delivery, and low birth weight. Conclusions Adding CSST to existing IPTp-SP strategies did not reduce malaria in pregnancy. Increasing the number of IPTp-SP doses given during pregnancy is a priority. Clinical Trials Registration NCT01941264; ISRCTN37259296.

Background The declining effectiveness of Intermittent Preventive Treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) due to the emergence of Plasmodium falciparum resistance highlights the need for alternative malaria prevention strategies in pregnant women. A novel approach was proposed: screening with an ultra-sensitive rapid diagnostic test and treating positive with pyronaridine-artesunate (ISTp-uRDT-PA). This trial compared the impact of both strategies on maternal malaria and anaemia, abortion, intrauterine death, birth weight, preterm delivery. Methods This non-inferiority trial, conducted in Kinshasa, enrolled pregnant women in their second and third trimesters. Participants in the IPTp-SP arm (n = 124) received SP at monthly antenatal visit as per guidelines, while those in the ISTp-uRDT-PA arm (n = 126) were screened monthly with an uRDT and treated with PA if positive. Primary outcomes included asymptomatic parasitaemia (uRDT positive without fever) or symptomatic parasitaemia (uRDT positive with fever or history of fever, and parasite density by microscopy during pregnancy. Results Asymptomatic parasitaemia by uRDT during pregnancy was similar in both arms (20.8% in IPTp-SP vs 21.0% in ISTp-uRDT-PA). At delivery, asymptomatic parasitaemia was 51% higher in ISTp-uRDT-PA arm compared to IPTp-SP (cRR = 1.51 [95% CI 0.76–3.00], p = 0.24). Symptomatic parasitaemia by uRDT at delivery showed no significant difference. Malaria by microscopy at enrolment was detected in 34.4% of women. Malaria by microscopy during pregnancy was 9.6% in IPTp-SP and 10.1%. ISTp-uRDT-PA (p = 0.19), decreasing to 3.2% and 0.9%, respectively, at delivery (p = 0.24). Mean haemoglobin concentration at enrolment was 10.1 g/dl in the IPTp-SP and 9.8 g/dl in the ISTp-uRDT-PA with no significant difference in maternal anaemia at delivery (7%; cRR = 1.07 [95% CI 0.87–1.31], p = 0.52). No significant differences were found for spontaneous abortions and in utero death in both arms. The risk of a premature newborn declined by 14% in ISTp-uRDT-PA compared to the IPTp-SP arm (cRR = 0.86 [95% CI 0.29–2.85], p = 0.79) while low-birth-weight was not significantly higher (cRR = 1.74 [95% CI 0.86–3.53], p = 0.12). Conclusion ISTp-uRDT-PA was non inferior to IPTp-SP and can be considered as a future alternative for IPTp-SP in case this intervention can no longer be used due to high SP resistance. Clinical trials registration: NCT04783051.