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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.

Ivermectin is a potential new vector control tool to reduce malaria transmission. Mosquitoes feeding on a bloodmeal containing ivermectin have a reduced lifespan, meaning they are less likely to live long enough to complete sporogony and become infectious. We aimed to estimate the effect of ivermectin on malaria transmission in various scenarios of use. We validated an existing population-level mathematical model of the effect of ivermectin mass drug administration (MDA) on the mosquito population and malaria transmission against two datasets: clinical data from a cluster- randomised trial done in Burkina Faso in 2015 wherein ivermectin was given to individuals taller than 90 cm and entomological data from a study of mosquito outcomes after ivermectin MDA for onchocerciasis or lymphatic filariasis in Burkina Faso, Senegal, and Liberia between 2008 and 2013. We extended the existing model to include a range of complementary malaria interventions (seasonal malaria chemoprevention and MDA with dihydroartemisinin–piperaquine) and to incorporate new data on higher doses of ivermectin with a longer mosquitocidal effect. We consider two ivermectin regimens: a single dose of 400 μg/kg (1 × 400 μg/kg) and three consecutive daily doses of 300 μg/kg per day (3 × 300 μg/kg). We simulated the effect of these two doses in a range of usage scenarios in different transmission settings (highly seasonal, seasonal, and perennial). We report percentage reductions in clinical incidence and slide prevalence. We estimate that MDA with ivermectin will reduce prevalence and incidence and is most effective in areas with highly seasonal transmission. In a highly seasonal moderate transmission setting, three rounds of ivermectin only MDA at 3 × 300 μg/kg (rounds spaced 1 month apart) and 70% coverage is predicted to reduce clinical incidence by 71% and prevalence by 34%. We predict that adding ivermectin MDA to seasonal malaria chemoprevention in this setting would reduce clinical incidence by an additional 77% in children younger than 5 years compared with seasonal malaria chemoprevention alone; adding ivermectin MDA to MDA with dihydroartemisinin–piperaquine in this setting would reduce incidence by an additional 75% and prevalence by an additional 64% (all ages) compared with MDA with dihydroartemisinin–piperaquine alone. Our modelling predictions suggest that ivermectin could be a valuable addition to the malaria control toolbox, both in areas with persistently high transmission where existing interventions are insufficient and in areas approaching elimination to prevent resurgence. Imperial College Junior Research Fellowship.

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.

Optimal nutrition is crucial during the critical period of the first 1,000 days from conception to 2 years after birth. Prenatal and postnatal supplementation of mothers with multimicronutrient-fortified balanced energy-protein (BEP) supplements is a potential nutritional intervention. However, evidence on the long-term effects of BEP supplementation on child growth is inconsistent. We evaluated the efficacy of daily fortified BEP supplementation during pregnancy and lactation on infant growth in rural Burkina Faso. A 2 × 2 factorial individually randomized controlled trial (MISAME-III) was implemented in 6 health center catchment areas in Houndé district under the Hauts-Bassins region. From October 2019 to December 2020, 1,897 pregnant women aged 15 to 40 years with gestational age <21 completed weeks were enrolled. Women were randomly assigned to the prenatal intervention arms receiving either fortified BEP supplements and iron-folic acid (IFA) tablets (i.e., intervention) or IFA alone (i.e., control), which is the standard of care during pregnancy. The same women were concurrently randomized to receive either of the postnatal intervention, which comprised fortified BEP supplementation during the first 6 months postpartum in combination with IFA for the first 6 weeks (i.e., intervention), or the postnatal control, which comprised IFA alone for 6 weeks postpartum (i.e., control). Supplements were provided by trained village-based project workers under direct observation during daily home visits. We previously reported the effect of prenatal BEP supplementation on birth outcomes. The primary postnatal study outcome was length-for-age z-score (LAZ) at 6 months of age. Secondary outcomes were anthropometric indices of growth (weight-for length and weight-for-age z-scores, and arm and head circumferences) and nutritional status (prevalence rates of stunting, wasting, underweight, anemia, and hemoglobin concentration) at 6 months. Additionally, the longitudinal prevalence of common childhood morbidities, incidence of wasting, number of months of exclusive breastfeeding, and trajectories of anthropometric indices from birth to 12 months were evaluated. Prenatal BEP supplementation resulted in a significantly higher LAZ (0.11 standard deviation (SD), 95% confidence interval (CI) [0.01 to 0.21], p = 0.032) and lower stunting prevalence (-3.18 percentage points (pp), 95% CI [-5.86 to -0.51], p = 0.020) at 6 months of age, whereas the postnatal BEP supplementation did not have statistically significant effects on LAZ or stunting at 6 months. On the other hand, postnatal BEP supplementation did modestly improve the rate of monthly LAZ increment during the first 12 months postpartum (0.01 z-score/month, 95% CI [0.00 to 0.02], p = 0.030), whereas no differences in growth trajectories were detected between the prenatal study arms. Furthermore, except for the trend towards a lower prevalence of underweight found for the prenatal BEP intervention at 6 months (-2.74 pp, 95% CI [-5.65 to 1.17], p = 0.065), no other secondary outcome was significantly affected by the pre- or postnatal BEP supplementation. This study provides evidence that the benefits obtained from prenatal BEP supplementation on size at birth are sustained during infancy in terms of linear growth. Maternal BEP supplementation during lactation may lead to a slightly better linear growth towards the second half of infancy. These findings suggest that BEP supplementation during pregnancy can contribute to the efforts to reduce the high burden of child growth faltering in low- and middle-income countries. ClinicalTrials.gov: NCT03533712.

Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved for Plasmodium falciparum malaria. However, neither induces blood-stage immunity against parasites that break through from the liver. RH5.1/Matrix-M, a blood-stage P falciparum malaria vaccine candidate, was highly immunogenic in Tanzanian adults and children. We therefore assessed the safety and efficacy of RH5.1/Matrix-M in Burkinabe children. In this double-blind, randomised, controlled, phase 2b trial, RH5.1/Matrix-M was given to children aged 5–17 months in Nanoro, Burkina Faso, a seasonal malaria transmission setting. Children received either three intramuscular vaccinations with 10 μg RH5.1 protein with 50 μg Matrix-M adjuvant or three doses of rabies control vaccine, Rabivax-S, given either in a delayed third-dose (0, 1, and 5 month) regimen (first cohort) or a 0, 1, and 2 month regimen (second cohort). Vaccinations were completed part way through the malaria season. Children were randomly assigned 2:1 within each cohort to receive RH5.1/Matrix-M or Rabivax-S. Participants were assigned according to a random allocation list generated by an independent statistician using block randomisation with variable block sizes. Participants, their families, and the study teams were masked to group allocation; only pharmacists who prepared the vaccines were unmasked. Vaccine safety, immunogenicity, and efficacy were evaluated. The coprimary outcomes assessed were: first, the safety and reactogenicity of RH5.1/Matrix-M; and second, the protective efficacy of RH5.1/Matrix-M against clinical malaria (measured as time to first episode of clinical malaria, using a Cox regression model) from 14 days to 6 months after the third vaccination in the per-protocol sample. This ongoing trial is registered with ClinicalTrials.gov (NCT05790889). From April 6 to 13 and July 3 to 7, 2023, 412 children aged 5–17 months were screened, and 51 were excluded. A total of 361 children were enrolled in this study. In the first cohort, 119 were assigned to the RH5.1/Matrix-M delayed third-dose group, and 62 to the equivalent rabies control group. The second cohort included 120 children in the monthly RH5.1/Matrix-M group and 60 in the equivalent rabies control group. The final vaccination was administered to all groups from Sept 4 to 21, 2023. RH5.1/Matrix-M in both cohorts had a favourable safety profile and was well tolerated. Most adverse events were mild, with the most common being local swelling and fever. No serious adverse events were reported. Comparing the RH5.1/Matrix-M delayed third-dose regimen with the pooled control groups resulted in a vaccine efficacy of 55% (95% CI 20 to 75%; p=0·0071). The same analysis showed a vaccine efficacy of 40% (–3 to 65%; p=0·066) when comparing the monthly regimen with the pooled control groups. Participants vaccinated with RH5.1/Matrix-M in both cohorts showed high concentrations of anti-RH5.1 serum IgG antibodies 14 days after the third vaccination, and the purified IgG showed high levels of in vitro growth inhibition activity against P falciparum; these responses were higher in patients who received the RH5.1/Matrix-M vaccine delayed third-dose regimen, as opposed to monthly regimen (growth inhibition activity 79·0% [SD 14·3] vs 74·2% [SD 15·9]; p=0·016). RH5.1/Matrix-M appears safe and highly immunogenic in African children and shows promising efficacy against clinical malaria when given in a delayed third-dose regimen. This trial is ongoing to further monitor efficacy over time. The European and Developing Countries Clinical Trials Partnership, the UK Medical Research Council, the National Institute for Health and Care Research Oxford Biomedical Research Centre, the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, the US Agency for International Development, and the Wellcome Trust.

The success of crucial vector control efforts in Africa (eg, long-lasting insecticide-treated nets [ITNs] and indoor residual spraying) are threatened by widespread insecticide resistance and insufficient effect on outdoor mosquito biting. Studies have shown that ivermectin, used for the treatment of parasitic diseases, can kill malaria vectors that feed on the blood of treated people and thus might be an effective complementary vector control tool if administered widely to communities in malaria endemic regions. We aimed to test the safety of repeated, high-dose ivermectin mass drug administration (MDA) and its efficacy for reducing malaria incidence among children when integrated with seasonal malaria chemoprevention (SMC) delivery. We conducted a phase 3, double-blind, placebo-controlled, cluster-randomised, parallel-group trial in southwest Burkina Faso over two consecutive rainy seasons (2019–20). 14 villages or village sectors (clusters) were randomly assigned (1:1) to ivermectin or placebo MDA by random draw, and study-eligible participants (those who regularly lived in the cluster and provided written informed consent) from all households were enrolled in July, 2019 and July, 2020. Participants were eligible for MDA if they were 90 cm in height or taller and not excluded for other safety reasons (eg, pregnancy or taking SMC drugs). There were no age restrictions for participants. Each rainy season (July to October), eligible participants from the intervention group clusters received monthly high-dose oral ivermectin MDA (three daily doses, approximately 300 μg/kg dosed by height bands) and those from the control group received monthly oral placebo MDA for up to eight treatment rounds. MDA was performed by study staff alongside community health worker administration of monthly SMC to children aged 3–59 months in both groups. All participants and study personnel, apart from the pharmacist, were masked to group assignment. The primary outcome was weekly malaria incidence in children aged 10 years and younger, as assessed by weekly active case detection until week 16 of year 2, by intention to treat. Adverse events were monitored in all MDA participants through active and passive surveillance. Blood was sampled for secondary parasitological outcomes, including analysis of parasite species distribution among malaria cases. Mosquitoes were sampled from pre-selected households in three clusters per group for secondary entomological outcomes, including analysis of blood-fed mosquito survivorship, mosquito biting rates, and entomological inoculation rates. Changes in haemoglobin pre-intervention and post-intervention in children aged 10 years and younger were assessed in 2020. The trial is registered with ClinicalTrials.gov (NCT03967054) and the Pan African Clinical Trials Registry (PACT201907479787308) and is completed. The study took place from July 13, 2019, to Nov 8, 2020, with seven villages assigned to the control group and seven to the intervention group. Participants were enrolled from households in both groups in July, 2019, and July, 2020. In the intervention group, 1928 participants in 2019 and 2163 participants in 2020 were followed up, and 703 children in 2019 and 686 children in 2020 were analysed. In the control group, 1604 participants in 2019 and 1921 participants in 2020 were followed up, and 605 children in 2019 and 641 children in 2020 were analysed. MDA coverage (receiving ≥1 dose) in the enrolled population (including those who were ineligible) varied over the intervention period (68–74%), with 86–95% of participants who were eligible receiving ivermectin or placebo over the study period. 288 (47·2%) of 610 children in the control group and 312 (44·2%) of 706 children in the ivermectin group received SMC, and all clusters received new dual-chemistry Interceptor G2 ITNs containing chlorfenapyr and α-cypermethrin by government authorities in October, 2019. The average estimated weekly malaria incidence rate per 100 person-weeks among children in the intervention group was 1·78 (95% CI 1·24–2·53) and 1·84 (1·29–2·64) in the control group, and the incidence rate ratio was 0·96 (95% CI 0·58–1·59; p=0·8723). The risk of adverse events among eligible participants in the intervention group was lower than in the control group (risk ratio 0·63, 95% CI 0·46–0·87; p=0·0049). The distribution of Plasmodium spp detected in children with clinical malaria was unexpectedly diverse with non-Plasmodium falciparum species detected in 56 (11%) of 505 symptomatic children; however, species distribution did not differ between groups (p=0·15). Blood-fed Anopheles gambiae species complex mosquitoes captured in intervention group clusters the week after MDA in 2019 had decreased survival relative to those captured from control group clusters (p<0·0001), but this effect was not seen in mosquitoes captured 3 weeks after MDA. Overall entomological inoculation rates (EIRs; infectious bites per person per night) did not differ between groups (intervention EIR 0·010; control EIR 0·011; between-group ratio 0·91, 95% CI 0·56–1·30; p=0·45). In 2020, children aged 10 years and younger in the intervention group had a significantly higher increase in haemoglobin pre-intervention versus post-intervention than children in the control group (p=0·007). Repeated high-dose ivermectin MDA integrated with SMC distributions at the study site did not reduce malaria incidence among children relative to placebo MDA, despite evidence that, compared with the control group, mosquito survivorship in the first year was reduced in the intervention group the week following MDA and overall improvements in haemoglobin were greater in children in the intervention group. Confounding factors, including unexpectedly low malaria incidence over the trial period, possibly due to government distribution of dual-chemistry ITNs to all trial clusters in the middle of the intervention period, overdispersion of the primary incidence outcome between clusters, and high parasite and mosquito species diversity, might have influenced the primary outcome. National Institute of Allergy and Infectious Diseases.

In 2023, the World Health Organization (WHO) revised its guidelines for management of severe acute malnutrition (SAM). The revised guidelines include a focus on infants at risk of poor growth and development. The guideline identifies evaluation of routine antibiotics for these infants as a priority research area. We pooled data from two large randomized controlled trials evaluating azithromycin for prevention of infant mortality in Burkina Faso to assess whether azithromycin reduces mortality or wasting in this subgroup. Infants in the two trials were 1-12 weeks of age at enrollment. Infants were considered at risk of poor risk of growth and development per WHO: underweight (weight-for-age Z-score, WAZ < -2), wasted (weight-for-length Z-score, WLZ < -2), or MUAC < 11.0 cm among infants ≥6 weeks of age. Infants were randomized to a single oral (20 mg/kg) dose of azithromycin or matching placebo and were followed until 6 months of age. We evaluated vital status, underweight (WAZ < -2), wasting (WLZ < -2), and stunting (length-for-age Z-score, LAZ) at 6 months among infants at risk of poor growth and development based on WHO single measurement criteria. A total of 54,709 infants were enrolled in the two trials. Of these, 9,728 were at risk of poor growth and development based on baseline WAZ (N = 5,385), WLZ (N = 6,022), or MUAC (N = 1,541). We found no evidence of a difference in mortality (1.3% vs 1.1%, odds ratio, OR, 1.19, 95% confidence interval, CI, 0.82 to 1.72) or wasting (20.6% vs 20.2%, OR 1.03, 95% CI 0.92 to 1.14) at 6 months among infants receiving azithromycin versus placebo. In infants aged 1-12 weeks at risk of poor growth and development, we do not have evidence that single dose azithromycin reduces mortality or improves growth outcomes. ClinicalTrials.gov NCT03682654 and NCT03676764.

Antibiotic use during early infancy has been linked to childhood obesity in high-income countries. We evaluated whether a single oral dose of azithromycin administered during infant-well visits led to changes in infant growth outcomes at 6 months of age in a setting with a high prevalence of undernutrition in rural Burkina Faso. Infants were enrolled from September 25, 2019, until October 22, 2022, in a randomized controlled trial designed to evaluate the efficacy of a single oral dose of azithromycin (20 mg/kg) compared to placebo when administered during well-child visits for prevention of infant mortality. The trial found no evidence of a difference in the primary endpoint. This paper presents prespecified secondary anthropometric endpoints including weight gain (g/day), height change (mm/day), weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ), and mid-upper arm circumference (MUAC). Infants were eligible for the trial if they were between 5 and 12 weeks of age, able to orally feed, and their families were planning to remain in the study area for the duration of the study. Anthropometric measurements were collected at enrollment (5 to 12 weeks of age) and 6 months of age. Among 32,877 infants enrolled in the trial, 27,298 (83%) were followed and had valid anthropometric measurements at 6 months of age. We found no evidence of a difference in weight gain (mean difference 0.03 g/day, 95% confidence interval (CI) -0.12 to 0.18), height change (mean difference 0.004 mm/day, 95% CI -0.05 to 0.06), WAZ (mean difference -0.004 SD, 95% CI -0.03 to 0.02), WLZ (mean difference 0.001 SD, 95% CI -0.03 to 0.03), LAZ (mean difference -0.005 SD, 95% CI -0.03 to 0.02), or MUAC (mean difference 0.01 cm, 95% CI -0.01 to 0.04). The primary limitation of the trial was that measurements were only collected at enrollment and 6 months of age, precluding assessment of shorter-term or long-term changes in growth. Single-dose azithromycin does not appear to affect weight and height outcomes when administered during early infancy. ClinicalTrials.gov NCT03676764.

Most evidence supporting screening for undernutrition is for children aged 6-59 months. However, the highest risk of mortality and highest incidence of wasting occurs in the first 6 months of life. We evaluated relationships between neonatal anthropometric indicators, including birth weight, weight-for-age -score (WAZ), weight-for-length Z-score (WLZ), length-for-age -score (LAZ) and mid-upper arm circumference (MUAC) and mortality and growth at 6 months of age among infants in Burkina Faso. Data arose from a randomised controlled trial evaluating neonatal azithromycin administration for the prevention of child mortality. We evaluated relationships between baseline anthropometric measures and mortality, wasting (WLZ < -2), stunting (LAZ < -2) and underweight (WAZ < -2) at 6 months of age were estimated using logistic regression models adjusted for the child's age and sex. Five regions of Burkina Faso. Infants aged 8-27 d followed until 6 months of age. Of 21 832 infants enrolled in the trial, 7·9 % were low birth weight (<2500 g), 13·3 % were wasted, 7·7 % were stunted and 7·4 % were underweight at enrolment. All anthropometric deficits were associated with mortality by 6 months of age, with WAZ the strongest predictor (WAZ < -2 to ≥ -3 at enrolment . WAZ ≥ -2: adjusted OR, 3·91, 95 % CI, 2·21, 6·56). Low WAZ was also associated with wasting, stunting, and underweight at 6 months. Interventions for identifying infants at highest risk of mortality and growth failure should consider WAZ as part of their screening protocol.

Community management of acute malnutrition (CMAM) is a highly efficacious approach for treating acute malnutrition (AM) in children who would otherwise be at significantly increased risk of mortality. In program settings, however, CMAM's effectiveness is limited because of low screening coverage of AM, in part because of the lack of perceived benefits for caregivers. In Burkina Faso, monthly screening for AM of children <2 years of age is conducted during well-baby consultations (consultation du nourrisson sain [CNS]) at health centers. We hypothesized that the integration of a preventive package including age-appropriate behavior change communication (BCC) on nutrition, health, and hygiene practices and a monthly supply of small-quantity lipid-based nutrient supplements (SQ-LNSs) to the monthly screening would increase AM screening and treatment coverage and decrease the incidence and prevalence of AM. We used a cluster-randomized controlled trial and allocated 16 health centers to the intervention group and 16 to a comparison group. Both groups had access to standard CMAM and CNS services; caregivers in the intervention group also received age-appropriate monthly BCC and SQ-LNS for children >6 months of age. We used two study designs: (1) a repeated cross-sectional study of children 0-17 months old (n = 2,318 and 2,317 at baseline and endline 2 years later) to assess impacts on AM screening coverage, treatment coverage, and prevalence; (2) a longitudinal study of 2,113 children enrolled soon after birth and followed up monthly for 18 months to assess impacts on AM screening coverage, treatment coverage, and incidence. Data were analyzed as intent to treat. Level of significance for primary outcomes was α = 0.016 after adjustment for multiple testing. Children's average age was 8.8 ± 4.9 months in the intervention group and 8.9 ± 5.0 months in the comparison group at baseline and, respectively, 0.66 ± 0.32 and 0.67 ± 0.33 months at enrollment in the longitudinal study. Relative to the comparison group, the intervention group had significantly higher monthly AM screening coverage (cross-sectional study: +18 percentage points [pp], 95% CI 10-26, P < 0.001; longitudinal study: +23 pp, 95% CI 17-29, P < 0.001). There were no impacts on either AM treatment coverage (cross-sectional study: +8.0 pp, 95% CI 0.09-16, P = 0.047; longitudinal study: +7.7 pp, 95% CI -1.2 to 17, P = 0.090), AM incidence (longitudinal study: incidence rate ratio = 0.98, 95% CI 0.75-1.3, P = 0.88), or AM prevalence (cross-sectional study: -0.46 pp, 95% CI -4.4 to 3.5, P = 0.82). A study limitation is the referral of AM cases (for ethical reasons) by study enumerators as part of the monthly measurement in the longitudinal study that may have attenuated the detectable impact on AM treatment coverage. Adding a preventive package to CMAM delivered at health facilities in Burkina Faso increased participation in monthly AM screening, thus overcoming a major impediment to CMAM effectiveness. The lack of impact on AM treatment coverage and on AM prevalence and incidence calls for research to address the remaining barriers to uptake of preventive and treatment services at the health center and to identify and test complementary approaches to bring integrated preventive and CMAM services closer to the community while ensuring high-quality implementation and service delivery. ClinicalTrials.gov NCT02245152.