As malaria control interventions are scaled-up, rational approaches are needed for monitoring impact over time. One proposed approach includes monitoring the prevalence of malaria infection among pregnant women and children at the time of routine preventive health facility (HF) visits. This pilot explored the feasibility and utility of tracking the prevalence of malaria infection in pregnant women attending their first antenatal care (ANC) visit and infants presenting at 9-12 months of age for measles vaccination.

Children hospitalised with severe anaemia in malaria endemic areas in Africa are at high risk of readmission or death within 6 months post-discharge. Currently, no strategy specifically addresses this period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment courses of artemether-lumefantrine given at discharge and at 1 and 2 months prevented 30% of all-cause readmissions by 6 months post-discharge. Another efficacy trial is needed before a policy of malaria chemoprevention can be considered for the post-discharge management of severe anaemia in children under 5 years of age living in malaria endemic areas.

Rapid diagnostic tests (RDTs) detecting histidine-rich protein 2 (HRP2) and HRP3 are widely used throughout sub-Saharan Africa (SSA) to diagnose Plasmodium falciparum malaria. However, multiple SSA countries have reported pfhrp2 and pfhrp3 (pfhrp2/3) gene deletions. Blood samples (n = 1109) collected from patients with P. falciparum infection from six health facilities throughout the Democratic Republic of the Congo (DRC) from March 2017 to January 2018 were evaluated for pfhrp2/3 deletions. Samples were assayed for HRP2, pan-Plasmodium LDH (pLDH) and aldolase (pAldolase) antigens by bead-based multiplex antigen assay. Samples with low HRP2 concentration compared to pLDH and pAldolase antigens were selected for further pfhrp2/3 genotyping PCRs. The majority of blood samples (93.3%, 1035/1109) had high concentrations of the HRP2 antigen. Single deletions of pfhrp2 were identified in 0.27% (3/1109) of screened samples, with one sample from each of the Kapolowe, Mikalayi, and Rutshuru study sites. A pfhrp3 single deletion (0.09%, 1/1109) was found in the Kapolowe site. Dual pfhrp2 and pfhrp3 deletions were not observed. Due to, the low numbers of pfhrp2 deletions and the sporadic locations of these deletions, the use of HRP2-based RDTs appears to still be appropriate for these locations in DRC.

Histidine-rich protein 2 (HRP2)-based rapid diagnostic tests detect Plasmodium falciparum malaria and are used throughout sub-Saharan Africa. However, deletions in the pfhrp2 and related pfhrp3 (pfhrp2/3) genes threaten use of these tests. Therapeutic efficacy studies (TESs) enroll persons with symptomatic P. falciparum infection. We screened TES samples collected during 2016-2018 in Ethiopia, Kenya, Rwanda, and Madagascar for HRP2/3, pan-Plasmodium lactate dehydrogenase, and pan-Plasmodium aldolase antigen levels and selected samples with low levels of HRP2/3 for pfhrp2/3 genotyping. We observed deletion of pfhrp3 in samples from all countries except Kenya. Single-gene deletions in pfhrp2 were observed in 1.4% (95% CI 0.2%-4.8%) of Ethiopia samples and in 0.6% (95% CI 0.2%-1.6%) of Madagascar samples, and dual pfhrp2/3 deletions were noted in 2.0% (95% CI 0.4%-5.9%) of Ethiopia samples. Although this study was not powered for precise prevalence estimates, evaluating TES samples revealed a low prevalence of pfhrp2/3 deletions in most sites.

Controlled infection studies in malaria-naive adults suggest increased vaccine efficacy for fractional-dose versus full-dose regimens of RTS,S/AS01. We report first results of an ongoing trial assessing different fractional-dose regimens in children, in natural exposure settings.

Attractive targeted sugar baits (ATSBs) are a potential vector control tool that exploits the sugar-feeding behaviour of mosquitoes. We evaluated the sugar-feeding behaviour of Anopheles mosquitoes as part of baseline studies for cluster randomised controlled trials of ATSBs. Mosquitoes were collected indoors and outdoors from two villages in western Kenya using prokopack aspirations, malaise tent traps and ultraviolet (UV) light traps. Individual mosquitoes were subjected to the cold anthrone test to assess the presence of sugar. Overall, 15.7% of collected mosquitoes had fed on natural sugar sources. By species and sex, the proportion sugar-fed was 41.3% and 27.7% in male and female Anopheles funestus, 27.2% and 12.8% in male and female An. arabiensis, and 9.7% and 8.3% in male and female An. coustani, respectively. Sugar-feeding was higher in unfed than blood-fed mosquitoes and higher in male than gravid mosquitoes. Anopheles mosquitoes obtained sugar meals from natural sources during all physiological stages, whether they rest indoors or outdoors. These findings offer a potential avenue to exploit for the control of mosquitoes, particularly with the advent of ATSBs, which have been shown to reduce mosquito densities in other regions.

The spread of drug resistance to antimalarial treatments poses a serious public health risk globally. To combat this risk, molecular surveillance of drug resistance is imperative. We report the prevalence of mutations in the Plasmodium falciparum kelch 13 propeller domain associated with partial artemisinin resistance, which we determined by using Sanger sequencing samples from patients enrolled in therapeutic efficacy studies from 9 sub-Saharan countries during 2014-2018. Of the 2,865 samples successfully sequenced before treatment (day of enrollment) and on the day of treatment failure, 29 (1.0%) samples contained 11 unique nonsynonymous mutations and 83 (2.9%) samples contained 27 unique synonymous mutations. Two samples from Kenya contained the S522C mutation, which has been associated with delayed parasite clearance; however, no samples contained validated or candidate artemisinin-resistance mutations.

Prevention of malaria infection during pregnancy in HIV-negative women currently relies on the use of long-lasting insecticidal nets together with intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP). Increasing sulfadoxine-pyrimethamine resistance in Africa threatens current prevention of malaria during pregnancy. Thus, a replacement for IPTp-SP is urgently needed, especially for locations with high sulfadoxine-pyrimethamine resistance. Dihydroartemisinin-piperaquine is a promising candidate. We aimed to estimate the cost-effectiveness of intermittent preventive treatment in pregnancy with dihydroartemisinin-piperaquine (IPTp-DP) versus IPTp-SP to prevent clinical malaria infection (and its sequelae) during pregnancy.

Limited evidence suggests that children in sub-Saharan Africa hospitalized with all-cause severe anemia or severe acute malnutrition (SAM) are at high risk of dying in the first few months after discharge. We aimed to compare the risks of post-discharge mortality by health condition among hospitalized children in an area with high malaria transmission in western Kenya. We conducted a retrospective cohort study among recently discharged children aged < 5 years using mortality data from a health and demographic surveillance system that included household and pediatric in-hospital surveillance. Cox regression was used to compare post-discharge mortality. Between 2008 and 2013, overall in-hospital mortality was 2.8% (101/3,639). The mortality by 6 months after discharge (primary outcome) was 6.2% (159/2,556) and was highest in children with SAM (21.6%), followed by severe anemia (15.5%), severe pneumonia (5.6%), "other conditions" (5.6%), and severe malaria (0.7%). Overall, the 6-month post-discharge mortality in children hospitalized with SAM (hazard ratio [HR] = 3.95, 2.60-6.00, P < 0.001) or severe anemia (HR = 2.55, 1.74-3.71, P < 0.001) was significantly higher than that in children without these conditions. Severe malaria was associated with lower 6-month post-discharge mortality than children without severe malaria (HR = 0.33, 0.21-0.53, P < 0.001). The odds of dying by 6 months after discharge tended to be higher than during the in-hospital period for all children, except for those admitted with severe malaria. The first 6 months after discharge is a high-risk period for mortality among children admitted with severe anemia and SAM in western Kenya. Strategies to address this risk period are urgently needed.

Ivermectin is being considered for mass drug administration for malaria, due to its ability to kill mosquitoes feeding on recently treated individuals. In a recent trial, 3-day courses of 300 and 600 mcg/kg/day were shown to kill Anopheles mosquitoes for at least 28 days post-treatment when fed patients' venous blood using membrane feeding assays. Direct skin feeding on humans may lead to higher mosquito mortality, as ivermectin capillary concentrations are higher. We compared mosquito mortality following direct skin and membrane feeding.

The Democratic Republic of the Congo (DRC) harbors 11% of global malaria cases, yet little is known about the spatial and genetic structure of the parasite population in that country. We sequence 2537 Plasmodium falciparum infections, including a nationally representative population sample from DRC and samples from surrounding countries, using molecular inversion probes - a high-throughput genotyping tool. We identify an east-west divide in haplotypes known to confer resistance to chloroquine and sulfadoxine-pyrimethamine. Furthermore, we identify highly related parasites over large geographic distances, indicative of gene flow and migration. Our results are consistent with a background of isolation by distance combined with the effects of selection for antimalarial drug resistance. This study provides a high-resolution view of parasite genetic structure across a large country in Africa and provides a baseline to study how implementation programs may impact parasite populations.

Integrated community case management of malaria, pneumonia, and diarrhoea can reduce mortality in children under five years (CU5) in resource-poor countries. There is growing interest in expanding malaria community case management (mCCM) to older individuals, but limited empirical evidence exists to guide this expansion. As part of a two-year cluster-randomized trial of mCCM expansion to all ages in southeastern Madagascar, a cross-sectional survey was conducted to assess baseline malaria prevalence and healthcare-seeking behaviours.

High-dose ivermectin, co-administered for 3 days with dihydroartemisinin-piperaquine (DP), killed mosquitoes feeding on individuals for at least 28 days posttreatment in a recent trial (IVERMAL), whereas 7 days was predicted pretrial. The current study assessed the relationship between ivermectin blood concentrations and the observed mosquitocidal effects against Anopheles gambiae s.s. Three days of ivermectin 0, 300, or 600 mcg/kg/day plus DP was randomly assigned to 141 adults with uncomplicated malaria in Kenya. During 28 days of follow-up, 1,393 venous and 335 paired capillary plasma samples, 850 mosquito-cluster mortality rates, and 524 QTcF-intervals were collected. Using pharmacokinetic/pharmacodynamic (PK/PD) modeling, we show a consistent correlation between predicted ivermectin concentrations and observed mosquitocidal-effects throughout the 28-day study duration, without invoking an unidentified mosquitocidal metabolite or drug-drug interaction. Ivermectin had no effect on piperaquine's PKs or QTcF-prolongation. The PK/PD model can be used to design new treatment regimens with predicted mosquitocidal effect. This methodology could be used to evaluate effectiveness of other endectocides.

The effectiveness of sulphadoxine-pyrimethamine (SP) intermittent preventive treatment of malaria in pregnancy (IPTp) might be compromised by high prevalence of resistance-associated Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutations. As a proxy for IPTp-SP effectiveness, the in vivo efficacy of SP to clear parasitaemia and prevent reinfection in asymptomatic parasitaemic pregnant women in an area with high SP resistance prevalence was assessed.

Over the last two decades, the scale-up of vector control and changes in the first-line anti-malarial, from chloroquine (CQ) to sulfadoxine-pyrimethamine (SP) and then to artemether-lumefantrine (AL), have resulted in significant decreases in malaria burden in western Kenya. This study evaluated the long-term effects of control interventions on molecular markers of Plasmodium falciparum drug resistance using parasites obtained from humans and mosquitoes at discrete time points.

Identifying design features and implementation strategies to optimise community health worker (CHW) programmes is important in the context of mixed results at scale. We systematically reviewed evidence of the effects of proactive case detection by CHWs in low-income and middle-income countries (LMICs) on mortality, morbidity and access to care for common childhood illnesses.

Indoor residual spraying (IRS) of insecticides is a major vector control strategy for malaria prevention. We evaluated the impact of a single round of IRS with the organophosphate, pirimiphos-methyl (Actellic 300CS), on entomological and parasitological parameters of malaria in Migori County, western Kenya in 2017, in an area where primary vectors are resistant to pyrethroids but susceptible to the IRS compound. Entomological monitoring was conducted by indoor CDC light trap, pyrethrum spray catches (PSC) and human landing collection (HLC) before and after IRS. The residual effect of the insecticide was assessed monthly by exposing susceptible An. gambiae s.s. Kisumu strain to sprayed surfaces in cone assays and measuring mortality at 24 hours. Malaria case burden data were extracted from laboratory records of four health facilities within the sprayed area and two adjacent unsprayed areas. IRS was associated with reductions in An. funestus numbers in the intervention areas compared to non-intervention areas by 88% with light traps (risk ratio [RR] 0.12, 95% CI 0.07-0.21, p < 0.001) and 93% with PSC collections (RR = 0.07, 0.03-0.17, p < 0.001). The corresponding reductions in the numbers of An. arabiensis collected by PSC were 69% in the intervention compared to the non-intervention areas (RR = 0.31, 0.14-0.68, p = 0.006), but there was no significant difference with light traps (RR = 0.45, 0.21-0.96, p = 0.05). Before IRS, An. funestus accounted for over 80% of Anopheles mosquitoes collected by light trap and PSC in all sites. After IRS, An. arabiensis accounted for 86% of Anopheles collected by PSC and 66% by CDC light trap in the sprayed sites while the proportion in non-intervention sites remained unchanged. No sporozoite infections were detected in intervention areas after IRS and biting rates by An. funestus were reduced to near zero. Anopheles funestus and An. arabiensis were fully susceptible to pirimiphos-methyl and resistant to pyrethroids. The residual effect of Actellic 300CS lasted ten months on mud and concrete walls. Malaria case counts among febrile patients within IRS areas was lower post- compared to pre-IRS by 44%, 65% and 47% in Rongo, Uriri and Nyatike health facilities respectively. A single application of IRS with Actellic 300CS in Migori County provided ten months protection and resulted in the near elimination of the primary malaria vector An. funestus and a corresponding reduction of malaria case count among out-patients. The impact was less on An. arabiensis, most likely due to their exophilic nature.

Trials of intermittent preventive treatment (IPTp) of malaria in pregnant women that compared dihydroartemisinin-piperaquine with the standard of care, sulfadoxine-pyrimethamine, showed dihydroartemisinin-piperaquine was superior at preventing malaria infection, but not at improving birthweight. We aimed to assess whether sulfadoxine-pyrimethamine shows greater non-malarial benefits for birth outcomes than does dihydroartemisinin-piperaquine, and whether dihydroartemisinin-piperaquine shows greater antimalarial benefits for birth outcomes than does sulfadoxine-pyrimethamine.