Abstract Background Our objective was to assess the role of delayed healthcare seeking and clinical care among deceased children aged < 5 years enrolled in Child Health and Mortality Prevention Surveillance (CHAMPS) in Western Kenya. Methods We conducted a retrospective descriptive analysis of verbal autopsies, health records, and postmortem-determined causes of death determined by an expert panel for decedent children aged < 5 years enrolled in CHAMPS-Kenya (2017–2022). We used the Three Delays framework to describe delays in (1) deciding to seek care, (2) reaching healthcare facilities, and (3) receiving adequate clinical care. Proportions were compared with Chi-square testing. Results There were 814 enrolled cases in CHAMPS-Kenya and 611 had complete data and were included in our analysis. Nearly all cases (97.9%, n = 598/611) experienced at least one delay. Delayed caregivers’ decisions to seek clinical care increased by child’s age from 52.0% of < 1-day old deaths ( n = 53/102) to 70.9% of child deaths among those aged 12–59 months ( n = 83/117, p < 0.001), and were more common in malaria (52/63,82.5%) and malnutrition (51/64,79.7%) deaths than in deaths from other causes. Delays in receiving adequate clinical care were more common (84.9%, n = 519/560) than parental delays in deciding to seek care (58.9%, n = 366). All HIV deaths (31/31, 100.0%) and most malaria deaths ( n = 57/63, 90.5%) experienced suboptimal or delayed clinical care. Conclusions Nearly all young children who died experienced delays in seeking and receiving adequate clinical care prior to their death. Reducing childhood mortality requires a multi-pronged approach including caregiver education on the detection and response to danger signs, availing a functional referral system, and providing adequate clinical care.

Background:It is unknown whether the choice of malaria treatment for uncomplicated malaria affects coronavirus disease 2019 (COVID-19) severity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load, or duration of viral shedding. Several antimalarials exhibit antiviral activity against SARS-CoV-2 in vitro and have been suggested as potential therapeutic candidates for COVID-19, particularly pyronaridine-artesunate (PA), despite disappointing clinical results with chloroquine and hydroxychloroquine. Methods:We conducted an open-label randomised trial comparing standard 3-day treatment with PA and artemether-lumefantrine (AL) in newly diagnosed SARS-CoV-2 infected patients aged ≥6 months with rapid diagnostic test or microscopy-confirmed non-severe malaria in Kenya and Burkina Faso. SARS-CoV-2 was assessed by RT-PCR on days 3, 7, 14, and 28, and symptom resolution was assessed daily for 14 days using FLU-PRO Plus. The primary endpoint was the proportion of participants with SARS-CoV-2 clearance by day 7. Secondary endpoints included SARS-CoV-2 clearance by days 14, 21, and 28, time to SARS-CoV-2 clearance over 28 days, median viral load on day 7, and time to symptom resolution. Complete case analysis was conducted using log-binomial regression for binary outcomes, Cox-regression for time-to-event outcomes, and negative binomial regression for count outcomes, all adjusted for disease severity and viral load at enrolment. The trial is registered with ClinicalTrials.gov NCT04695197. Findings:From January 2021 to January 2022, 143 participants were randomised (PA = 69, AL = 74, intention-to-treat [ITT] population), including 117 with reverse transcription polymerase chain reaction (RT-PCR) confirmed (PA = 58, AL = 59, modified intention-to-treat [mITT] population) and 26 with rapid-antigen test confirmed SARS-CoV-2 infection. The median age was 19 years (interquartile range [IQR] 13-38), 66% were aged ≥15 years. Baseline characteristics were comparable. SARS-CoV-2 clearance by day 7 (primary endpoint) was 41% (22/54) with PA versus 58% (33/57) with AL (adjusted risk ratio [aRR] = 0.78, 95% confidence interval [CI] 0.45-1.35, p = 0.37); by day-14: PA = 80% (44/55) versus AL = 96% (55/57) (aRR = 0.86, 0.58-1.29, p = 0.47). Median (IQR) viral load on day 7 was higher with PA (855 [30-2883] versus AL:81 [12-209] copies/mL, p = 0.023). Time to SARS-CoV-2 clearance over 28 days was slower with PA (adjusted hazard ratio [aHR]: 0.55, 0.37-0.83, p = 0.004). Time to symptom clearance between treatments was similar (aHR = 1.01, 0.91-1.13, p = 0.79). Parasitological cure rates by day 42 were PA = 100% and AL = 99%. Five serious adverse events occurred (PA = 2, AL = 3) in three participants (PA = 1, AL = 2), including three hospitalisations (PA = 1, AL = 2), resulting in two deaths, both from respiratory failure (PA = 1, AL = 1). No serious adverse events (SAEs) were considered treatment-related. Interpretation:Pyronaridine-artesunate in COVID-19 patients co-infected with malaria was associated with slower viral clearance than standard treatment with artemether-lumefantrine but similar symptom resolution. Both treatments were highly effective as antimalarials and should continue to be considered first- or second-line treatment options for uncomplicated malaria in patients with mild to moderate COVID-19. Funding:Gates Foundation.

BACKGROUND:Malaria remains a major cause of mortality globally, especially among young children in sub-Saharan Africa. The long-acting monoclonal antibody L9LS has shown high efficacy in preventing malaria in children aged 6-10 years exposed to seasonal transmission but remains untested in perennial transmission settings and younger children. We assessed the safety, tolerability, and efficacy of L9LS in infants and children in a high perennial malaria transmission setting. METHODS:This double-blind, two-part, randomised, placebo-controlled, phase 2 trial was done in Siaya county in western Kenya. In parts 1a and 1b, we tested the safety and tolerability of L9LS using an age de-escalation and dose escalation approach and randomly assigned (3:1) cohorts of healthy children (three cohorts aged 5-10 years, three cohorts aged 5-59 months, and two cohorts aged 5-71 months) to L9LS at doses of 5, 10, 20, 30, or 40 mg/kg subcutaneously or to placebo (normal saline). In part 2, healthy children aged 5-59 months were randomly assigned (1:1:1) by use of centralised computer-generated lists to receive two doses of L9LS at 10-20 mg/kg at baseline and month 6, one dose of L9LS at baseline and placebo at month 6, or placebo at both timepoints. Children were followed up for 12 months with monthly clinic visits and blood smear collections. Primary safety outcomes were incidence and severity of local and systemic solicited adverse events within 7 days of dosing and serious adverse events throughout follow-up. The primary efficacy endpoint was Plasmodium falciparum infection detected by blood smear over 12 months. Primary analyses were done in the modified intention-to-treat population, consisting of all randomly assigned participants who received the study intervention. This trial is registered with ClinicalTrials.gov (NCT05400655) and is complete. FINDINGS:In parts 1a and 1b, 96 children were enrolled and randomly assigned between Oct 1, 2022, and Jan 16, 2024; 72 participants were assigned to L9LS and 24 were assigned to placebo. In part 2, 324 children aged 5-59 months were enrolled and randomly assigned between Jan 26 and June 2, 2023; 108 children were assigned to one-dose L9LS, 106 to two-dose L9LS, and 110 to placebo. Across all study parts, grade 3 or worse treatment-related adverse events occurred after four (1%) of 384 L9LS injections and two (1%) of 338 placebo injections; these events all resolved by study end. The proportion of solicited and unsolicited adverse events was similar across all L9LS dose groups. There were no serious adverse events related to the trial. In part 2, 70 (66%) of 106 children in the two-dose L9LS group had at least one P falciparum infection during the 12-month follow-up versus 91 (83%) of 110 children in the placebo group (protective efficacy 42·7%, 95% CI 22·5-57·7; p=0·0003). INTERPRETATION:L9LS was protective against malaria in young children in western Kenya without evident safety concerns over 6-12 months. A higher dose of L9LS might be needed to achieve high-level efficacy against malaria in young children exposed to intense perennial P falciparum transmission. FUNDING:Gates Foundation.

Environmental enteric dysfunction, universal in young children exposed to poor sanitation and hygiene, impairs growth and development through malabsorption and as a driver of chronic systemic inflammation (CSI). In an open-label, randomized, four-arm, phase II clinical trial, infants with birthweight ≥2000 g in Homa Bay County, western Kenya receive live, multi-strain Bifidobacterium spp. and Lactobacillaceae pro/synbiotics from 0 to 6 months. CSI (plasma α1-acid glycoprotein >1 g/L) at age 6 months (primary outcome) occurs in 60/138 (43%) controls versus 4/144 (3%; risk ratio [RR], 0.06; 95% confidence interval [CI], 0.02-0.17) infants in the Labinic synbiotic arm, 3/132 (2%; RR = 0.05; 95% CI, 0.02-0.16) in the Lab4b synbiotic arm, and 3/141 (2%; RR, 0.05; 95% CI, 0.02-0.15) in the Lab4b probiotic arm. Biomarkers of gut health and growth hormones also improve, and no serious adverse events are attributed to the interventions. Pro/synbiotics safely and markedly reduce CSI in a highly disadvantaged population, warranting further investigation of health impacts. The trial is registered at https://pactr.samrc.ac.za; identifier: PACTR202003893276712.

Background. There is paucity of information on the role of cytomegalovirus (CMV) infection as a cause of stillbirths or childhood deaths in low- and middle-income countries (LMICs). We investigated attribution of CMV disease in the causal pathway to stillbirths and deaths in children <5 years of age in 7 LMICs participating in the Child Health and Mortality Prevention Surveillance (CHAMPS) network. Methods. We analyzed stillbirths and decedents enrolled between December 2016 and July 2023. Deaths were investigated using postmortem minimally invasive tissue sampling with histopathology and molecular diagnostic investigations of tissues and body fluids, along with review of clinical records. Multidisciplinary expert panels reviewed findings and reported on the causal pathway to death. Results. CMV was detected in 19.5% (1140/5841) of all evaluated deaths, including 5.0% (111/2204), 6.2% (139/2229), 41.2% (107/260), 68.1% (323/474), and 68.2% (460/674) of stillbirths, neonates (deaths <28 days postnatal), early infants (28 to <90 days), late infants (90 to <365 days), and children (12 to <60 months), respectively. CMV disease was attributed in the causal pathway to death in 0.9% (20/2204) of stillbirths, 0.8% (17/2229) of neonates, 13.1% (34/260) of early infants, 9.7% (46/474) of late infants, and 3.3% (22/674) of children. Decedents with CMV disease, compared with those without CMV disease in the causal pathway, were more likely to have severe microcephaly (38.2% vs 21.1%; adjusted odds ratio [aOR], 2.2 [95% confidence interval {CI}, 1.3-3.6]) and to have human immunodeficiency virus (HIV) (36.9% vs 6.2%; aOR, 10.9 [95% CI, 6.5-18.5]). Conclusions. CMV disease is an important contributor to deaths during infancy and childhood and is often associated with severe microcephaly and HIV infection. Improving management of CMV in children with HIV and a vaccine to prevent CMV are needed interventions.

BACKGROUND:The relationship between malaria and COVID-19 varies across different clinical scenarios; historical malaria exposure might protect against severe COVID-19, whereas co-infection in hospitalised patients with severe disease might increase mortality. Interactions between non-severe malaria and COVID-19 remain poorly understood. We conducted a cohort study among COVID-19 patients of all ages in western Kenya and Burkina Faso to assess the effects of acute, uncomplicated Plasmodium falciparum malaria co-infection on COVID-19 outcomes in ambulatory patients. METHODS:Participants with laboratory-confirmed SARS-CoV-2 infection (positive rapid antigen test or reverse transcription quantitative real-time PCR [RT-qPCR]) were tested for malaria by rapid antigen tests with confirmatory microscopy. Patients with COVID-19 and malaria co-infection received artemether-lumefantrine or pyronaridine-artesunate. COVID-19 symptom course was assessed daily using FLU-PRO Plus (a validated patient-reported outcome instrument) until day 14. Viral load was measured by RT-qPCR on days 0, 3, 7, 14, and 28. The primary endpoint was time to symptom resolution on the FLU-PRO Plus. Analyses were adjusted for country, age, disease severity, and viral load. FINDINGS:Between Jan 8, 2021 and Jan 24, 2022, we screened 5161 participants and recruited 756 with COVID-19. 742 participants with valid malaria tests were enrolled, of which 151 (20%) had malaria co-infection and the remaining 591 (80%) did not have malaria. Patients with malaria were younger (49 [32%] aged <15 years) than those without malaria (35 [6%]; p<0·0001). Time to symptom resolution was similar between those with malaria (median 9 days [IQR 5-13]) and those without (10 days [IQR 6-13]; adjusted hazard ratio [aHR] 1·14 [95% CI 0·91-1·42]; p=0·26). Three (2%) patients with malaria and nine (2%) without malaria were hospitalised; two (1%) with malaria and three (1%) without malaria died, four from acute respiratory distress syndrome and one (in the no malaria group) from perforated peptic ulcer complicated by anaemia. Participants with malaria more frequently reported moderate-to-severe symptoms at enrolment (68% vs 60%; p=0·074), but overall symptom duration was similar (adjusted incidence rate ratio 0·95 [95% CI 0·86-1·05]; p=0·31). Previous malaria exposure significantly modified outcomes, with patients with malaria co-infection and previous exposure having faster symptom clearance than those without previous exposure (pinteraction=0·042). SARS-CoV-2 clearance was slower in the malaria group by day 7 (aHR 0·69 [95% CI 0·51-0·94]; p=0·017) but was similar between groups by day 28 (adjusted risk ratio 0·99 [95% CI 0·79-1·24]; p=0·95). INTERPRETATION:This study shows that acute uncomplicated malaria co-infection does not adversely affect COVID-19 progression when appropriately treated. Moreover, serological evidence confirms that previous lifelong malaria exposure might provide some protection, with exposed individuals having faster symptom resolution. FUNDING:Gates Foundation. TRANSLATION:For the French translation of the abstract see Supplementary Materials section.

Abstract In sub-Saharan Africa, continental-scale genomic surveillance of Plasmodium falciparum malaria is needed to track the spread of drug and diagnostic resistance, as well as monitor parasite evolutionary responses to vaccine rollout. Yet continental-scale implementation is hindered by a lack of genomic approaches suitable for local laboratories, and the vastness of the continent. Here, we initiate a decentralised scale-up of P. falciparum genomic surveillance by locally sequencing and analysing 1065 samples across six African countries in one year. We achieve this with a novel nanopore sequencing protocol that is rapid (~5 hr) and cost-effective (<$25 USD/sample), providing surveillance of antimalarial drug resistance genes, hrp2/3 deletions, the vaccine target csp, and the polymorphic gene ama1. We couple this to a laptop-based bioinformatics dashboard that runs offline and displays mapping and variant calling results in real-time. We demonstrate robust sequencing coverage across parasitemia levels and laboratories, accurate identification of antimalarial resistance markers and hrp2/3 deletions; and, with a novel variant caller, sensitive detection of mutations carried by minor clones. Our approach will accelerate genomic surveillance of P. falciparum malaria across sub-Saharan Africa at a time of urgent need.

Infectious Pathogens (IP) remain a significant contributor to stillbirths and under-five deaths in resource-limited settings. Children with sickle cell disease (SCD) are susceptible due to weakened immunity, influencing infection outcomes. This sub-study, nested within the Kenya Child Health and Mortality Prevention Surveillance (CHAMPS) network, investigated infectious pathogens associated with stillbirths and under-five deaths in Western Kenya, as well as the role of the sickle cell condition. We analysed stillbirths (n = 387) and ≤ 5 child deaths (n = 945) enrolled in CHAMPS in Karemo (Siaya) and Manyatta (Kisumu), both in western Kenya, between May 2017 and Dec 2024. Minimally invasive tissue sampling (MITS) specimens were processed on a TaqMan Array Card using the QuantStudio 7 real-time PCR (TAC qPCR) and cultured. All participants were screened for sickle cell status using the point-of-care Gazelle™ Hb Variant device, and confirmed by High Performance Liquid Chromatography (HPLC) and pathological diagnosis. Statistical analyses were performed using R programming software (version 4.5.1). A total of 1,332 cases were investigated, 499, 37.5

Abstract Background Although rapid diagnostic tests (RDTs) are widely used for malaria diagnosis, they have notable limitations. Blood smear (BS) microscopy remains the gold standard, yet its reliability in public health facilities (HFs) across malaria-endemic regions of Kenya can be compromised by limited infrastructure, technical capacity, and quality assurance. Methods We assessed the quality of malaria microscopy in 29 HFs in Siaya County, western Kenya, from January–July 2024 by evaluating the concordance of routine HF BS results with expert microscopy. We evaluated the availability and quality of reagents, standard operating procedures, and infrastructure using the National Malaria Control Program (NMCP) technical supervision checklist which follows WHO-certified microscopy standards. Up to 60 participant slides were randomly selected over three visits and two slides were prepared for each participant. Slide 1 was prepared and read on-site as per routine HF practice, then re-examined by an expert microscopist using the HF microscope and again at the Kenya Medical Research Institute (KEMRI). Slide 2 was stained and read at KEMRI, serving as the gold standard. We evaluated factors and characteristics associated with accurate diagnosis using logistic regression. Results Of the 1,494 blood smears examined, 501 (34%) were positive. Concordance between routine microscopy and expert re-reading was 91% (1,289/1,414), ranging from 55% (6/11) to 100% (60/60) across health facilities. Percent agreement between HF slide 1 and slide 2 was 86% (1,276/1,485), with a range from 55% (6/11) to 98% (39/40) by HF. Compared to slide 2, sensitivity and specificity of HF results was 76% and 92%, respectively, resulting in undertreatment of 24% and overtreatment of 8% of patients. Those with parasitemia 1–100 p/μL had lower odds of accurate diagnosis (OR = 0.12; 95% CI: 0.05–0.29; p < 0.001) while specimens with parasite densities > 10,000 p/μL had higher odds of accurate diagnosis (OR = 6.08; 95% CI: 2.22–25.1; p = 0.002), indicating a positive association between parasite density and diagnostic accuracy. Six (21%) of HFs had poor quality BS with debris or contamination. Conclusions While overall concordance was high, the variability in results by HF, limited accuracy at low parasite densities, and challenges with required infrastructure highlight the need for ongoing malaria microscopy quality assurance to ensure proper case management.

Malaria in pregnancy is a major but poorly quantified contributor to maternal anaemia in sub-Saharan Africa. We combined individual-level data on haemoglobin (Hb), gravidity, gestational age and PCR-confirmed Plasmodium falciparum infection from 12,608 pregnancies in 7 African countries with a gravidity-specific model of malaria exposure and immunity linked to contemporary maps of transmission and fertility. For 2023, we estimate that 13.1 million pregnancies in malaria-endemic African regions were exposed to P. falciparum. In the absence of preventive measures, this exposure would have resulted in 2.41 million (95% credible interval 1.98-3.04 million) cases of moderate or severe anaemia (Hb < 9 g dl-1), including 600,000 (408,000-906,000) severe cases (Hb < 7 g dl-1). A counterfactual scenario using 2,000 transmission levels suggests that a 32% reduction in exposure during pregnancy translated into only a 22% decline in intrinsic anaemia burden, reflecting a shift from a concentration of risk in primigravidae to a more even distribution across gravidities as multigravid women acquire less pregnancy-specific immunity. Calibrating our model to randomized trials, we estimate that under current coverage, intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine averted around 1.10 million (0.72-1.61 million) cases of moderate or severe anaemia and 330,000 (225,000-523,000) severe cases in 2023. These findings show that although burden has declined substantially, malaria remains a major driver of maternal anaemia risk. Meanwhile, lower immunity across multigravidae means any interruption to intermittent preventive treatment of malaria in pregnancy using sulfadoxine-pyrimethamine, or other population-based malaria control efforts, risks rapid resurgence of severe maternal anaemia, with substantial consequences for maternal and neonatal health.

Caesarean section (CS) rates are rising globally, yet sub-Saharan Africa records among the lowest rates despite substantial unmet obstetric need. Understanding clinical decision-making trajectories and their determinants is essential to optimize obstetric practice and address service gaps in resource-limited settings. We conducted a secondary analysis of 2,400 deliveries from a prospective cohort enrolled in the Pregnancy Risk, Infant Surveillance and Measurement Alliance (PRISMA), recruited via a population-based Health and Demographic Surveillance System in Kenya. Sankey flow visualization, observed-to-expected ratios and mixed-effects modified Poisson regression were applied to characterize clinical trajectories and identify associated factors. The overall CS prevalence was 19.4% (n = 465), exceeding the WHO-recommended threshold of 10–15%. Sankey analysis highlighted over-represented trajectories: previous unplanned CS transitioning to planned repeat CS (O/E ratio: 3.25; p < 0.001), primigravid women progressing to emergent CS for failure to progress (O/E ratio: 3.50; p < 0.001) and previous obstructed labour associated with planned CS for prior caesarean indication (O/E ratio: 2.89; p < 0.001). In multivariable regression, history of unplanned CS (RR: 4.63; 95% CI: 4.53–4.73), preeclampsia (RR: 1.97; 95% CI: 1.85–2.10), multiple pregnancy (RR: 2.23; 95% CI: 1.84–2.70), nulliparity (RR: 1.79; 95% CI: 1.58–2.03), and women with BMI ≥ 30 kg/m² (RR: 1.79; 95% CI: 1.61–1.99) were significantly associated with CS delivery. Gestational hypertension, gestational diabetes, advanced maternal age, and tertiary education were associated with higher likelihood of CS, while greater maternal height and unskilled employment were inversely associated. CS in western Kenya follows structured clinical trajectories shaped by obstetric history and intrapartum indications. Most determinants are identifiable antenatally, underscoring the value of targeted risk stratification in antenatal care. Expanding access to monitored vaginal birth after caesarean and strengthened antenatal risk profiling represent critical leverage points for rationalizing CS rates in comparable low-resource settings.

BACKGROUND:Genomic surveillance of malaria parasites offers important insights into the impact of interventions on transmission reduction and changes in pathogen populations over time, especially in low-transmission areas. However, such surveillance faces challenges in high-transmission regions. Detecting temporal changes in transmission in high-transmission settings requires analytical methods tailored to high-diversity parasite populations that can differentiate between superinfection (infection through multiple mosquito bites, each bearing an unrelated strain) and co-transmission (infection through a single mosquito bite bearing more than one strain). METHODS:This study applied a previously developed novel Next Generation Sequencing (NGS) 24-SNP barcode assay for genotyping smear-positive samples obtained from a 2017 cross-sectional survey in the Asembo area, western Kenya, building on previous work on samples collected in the surveys conducted in 1996, 2001, 2007, and 2012. Algorithms StrainRecon and STIM were used to identify parasite strains within a sample and measure multiplicity of infection (MOI). Population genetic metrics of FST (Fixation Index), strain-relatedness by IBD (Identity by Descent), Hs (Modified Heterozygosity) and Ne (Effective Population Size) were evaluated using the same 24-SNP data. This study further explored a novel slope metric of the relationship between within-host strain relatedness and MOI to infer superinfection and co-transmission. Temporal changes in the above metrics were assessed. RESULTS:There was no significant differentiation in FST, Hs, Ne, and strain-relatedness at the population level over time. In contrast, the average MOI significantly decreased from 4.32 in 1996 to 3.34 in 2012, although it increased to 3.49 in 2017. Insecticide-treated bednet distribution campaigns from 1997 to 2017 did track these temporal changes in MOI. Additionally, the value of strain relatedness within-host (IBD) was inversely correlated with MOI (number of strains), and the change in the inverse relationship (within-host slopes) over time was verified by two different correlation analysis and modelling. The temporal trends in this within-host slope metric suggested that transmission dynamics shifted towards co-transmission from 2001 to 2012, and then returned to similar levels of superinfection in 2017 as in 1996. CONCLUSION:The within-host MOI, IBD-based strain-relatedness, and their mathematical relationship (slope) provide useful metrics for understanding the transmission dynamics in our study. Notably, this study presents the first simple slope-based method using 24-SNP barcodes to distinguish superinfection from co-transmission in a high transmission area, warranting further evaluation of the novel tool in other high transmission settings.

BACKGROUND:We conducted a phase 2b trial evaluating fractional-dose and full-dose regimens of the RTS,S/AS01E vaccine (RTS,S). All regimens provided substantial protection against clinical malaria in natural exposure settings, over 21 and 32 months of follow-up. Here, we present end-of-study results, after 50 months of follow-up. METHODS:This open-label, randomised controlled trial was conducted at two research centres in Agogo (Ghana) and Siaya County (Kenya) between Sept 28, 2017, and Nov 14, 2022. Children aged 5-17 months were randomly assigned (1:1:1:1:1) to one of five groups to receive rabies vaccine (the control group) at months 0, 1, and 2; or full doses of RTS,S at months 0, 1, and 2, followed by either full doses (R) at month 20 (group R012-20) or months 14, 26, and 38 (R012-14-26-38); or full doses at months 0 and 1, followed by fractional doses (Fx; one-fifth of full dose) at months 2, 14, 26, and 38 (Fx012-14-26-38) or months 7, 20, and 32 (Fx017-20-32). We present results of secondary objectives, evaluating vaccine efficacy, impact, immunogenicity, and harms up to month 50. Endpoints were the occurrence of clinical malaria meeting the primary and secondary case definitions and antibody responses at predefined timepoints, and the occurrence of solicited adverse events within 7 days from vaccination and serious adverse events and adverse events of special interest up to study end. This trial is registered at ClinicalTrials.gov (NCT03276962) and is complete. FINDINGS:Between Sept 28, 2017, and Sept 25, 2018, 2157 children were enrolled, of whom 1609 were randomly assigned (322 to each RTS,S group and 321 to the control group). Of these 1609 children, 1500 received at least one study vaccine dose (exposed set), and 1333 were included in the per-protocol set for efficacy. Among children in the exposed set, to month 50, vaccine efficacy against all episodes of clinical malaria was 36% (95% CI 19-50), 51% (37-61), 43% (28-55), and 41% (26-53) in groups R012-20, R012-14-26-38, Fx012-14-26-38, and Fx017-20-32, respectively (p<0·001 for all). The numbers of cases averted per 1000 RTS,S full-dose equivalents were 353 (R012-20 group), 544 (R012-14-26-38 group), 1151 (Fx012-14-26-38 group), and 1134 (Fx017-20-32 group). Vaccine efficacy and impact and immune responses were maintained over 50 months of follow-up in groups who received additional vaccine doses after the fourth dose. The vaccine was well tolerated; only five serious adverse events were considered to be related to vaccination. There were no deaths considered to be related to vaccination. INTERPRETATION:All RTS,S regimens provided substantial protection against clinical malaria, with additional yearly doses maintaining vaccine efficacy and impact up to 50 months. Using fractional-dose regimens could increase the availability of RTS,S and reduce vaccination cost. FUNDING:GSK; PATH (through the Bill & Melinda Gates Foundation and the German Federal Ministry of Education and Research).

Environmental enteric dysfunction (EED) in early life, caused by gut pathogen colonisation, contributes to chronic systemic inflammation (CSI) which impairs growth and organ development and increases non-communicable disease risk. Pro/synbiotics may prevent or ameliorate EED, and thereby reduce CSI, through boosting colonisation resistance against enteropathogens and provide other intestinal and immune benefits. We evaluated three pro/synbiotics consisting of live, multi-strain Bifidobacterium spp. and Lactobacillaceae in reducing CSI. In this open-label, randomised, four-arm, phase II trial, 600 healthy Kenyan newborns (1–3 days old, birthweight ≥2000g) were allocated 1:1:1:1, stratified by HIV exposure, to receive Labinic synbiotic, Lab4b synbiotic or Lab4b probiotic or no intervention daily for ten days, then weekly until six months. The primary outcome was CSI (plasma α1-acid glycoprotein > 1g/L) at six months with blinded laboratory assessments. At six months, CSI occurred in 60/138 (43%) controls versus 4/144 (3%; relative risk (RR) 0.06, 95% CI 0.02–0.17; p < 0.0001) infants in the Labinic synbiotic, 3/132 (2%; RR = 0.05, 0.02–0.16; P < 0.0001) in the Lab4b synbiotic, and 3/141 (2%; RR = 0.05, 0.02–0.15; P < 0.0001) in the Lab4b probiotic arm. Serious adverse events and mortality over 0–24 months were similar across study arms. Pro/synbiotics safely and markedly reduced CSI in this disadvantaged population, warranting investigation of health impacts.

In western Kenya, a cluster-randomized trial is assessing the impact of attractive targeted sugar baits (ATSBs) on malaria in children enrolled in three consecutive cohorts. Here, characteristics of children and households at enrolment, and factors associated with baseline malaria prevalence are described. Children aged 1 to < 15 years were randomly selected by cluster (n = 70) from a census database. Cohorts were enrolled in March–April 2022, September–October 2022, and March–April 2023. ATSBs were deployed in March 2022. At enrolment, all participants were tested for malaria by rapid diagnostic test (RDT). After enrolment a household survey was conducted. Household structures were classified as ‘improved’ (finished walls and roofs, and closed eaves) or ‘traditional’ (all other construction). A generalized linear mixed model was used to assess factors associated with malaria prevalence. Of 3705 children screened, 220 declined and 523 were excluded, due to plans to leave the study area (n = 392), ineligible age (n = 64) or other reason (n = 67). Overall, 2962 children were enrolled. Bed net use the previous night was more common in children aged 1–4 years (746/777 [96

Background: In sub-Saharan Africa as much as 60% of children with sickle cell disease (SCD) die before the age of five. Despite high mortality rates among children with SCD in sub-Saharan Africa, there is little understanding of specific causes of death in these children. Prior studies assessing causes of death among children with SCD have largely relied on clinical diagnoses and have not utilized postmortem examinations to determine definitive causes of death. Our objectives were to describe causes of death among children with SCD and children with sickle cell trait who died. Methods: We conducted a descriptive analysis using data collected in a prospective childhood mortality surveillance network (Child Health and Mortality Prevention Surveillance [CHAMPS]) from 2016 through 2024. CHAMPS conducts surveillance for stillbirths and deaths in children aged <5 years in healthcare facilities and communities in high childhood mortality regions in six sub-Saharan African countries, Bangladesh, and Pakistan. CHAMPS collects antemortem clinical data, interviews families using a standardized verbal autopsy form, and conducts microbiological and histopathological postmortem examinations using minimally invasive tissue sampling. These data are then reviewed by an expert panel at each site to determine causes of death. For this study, blood samples were tested for SCD and sickle cell trait using the Gazelle® Hb Variant point-of-care (POC) test (Hemex Health, Portland, Oregon, USA), which is a miniaturized version of the reference standard cellulose acetate electrophoresis. We restricted our analyses to infants and children aged 3-59 months who enrolled in CHAMPS because high concentration of fetal hemoglobin affects the accuracy of the Gazelle® Hb Variant POC test. We used descriptive statistics for demographics, proportions, and causes of death. Comparisons were made using chi-square testing and the Mann-Whitney U test where appropriate. Results: CHAMPS enrolled 719 children aged 3-59 months who were tested for SCD and had cause of death determined during the study period. Of these, 36 (5.0%) tested positive for SCD, 112 (15.6%) tested positive for sickle cell trait, 18 (2.5%) had indeterminate results, and 553 (76.9%) had normal hemoglobin. The median age of cases with SCD was 19 months (interquartile range 13, 34 months) and 53.3% were male. CHAMPS sites in Kenya and Sierra Leone contributed the largest proportion of cases of SCD (n=20, 55.6% and n=10, 27.8%, respectively) and sickle cell trait (n=49, 43.8% and n=46, 41.1%, respectively). Of deaths with SCD, only 8.3% had documentation of an antemortem diagnosis of SCD. The most common underlying causes of death among cases with SCD were malaria (22.2%), malnutrition (16.7%), and sepsis (5.6%). For cases that tested positive for sickle cell trait, the most common underlying causes of death were malnutrition (25.0%), malaria (13.4%), and HIV (11.6%). The most common bacterial pathogens identified postmortem among cases with SCD and sickle cell trait were Streptococcus pneumoniae (13.9% and 11.6% of all cases, respectively), Klebsiella pneumoniae (5.6% and 12.5% of all cases, respectively), and Salmonella species (5.6% and 3.6% of all cases, respectively). We found no difference in the number of causes of death among cases that were positive for SCD (median 2, IQR 1, 2) compared to those with sickle cell trait (median 2, IQR 1, 3), and those who had normal hemoglobin (median 2, IQR 1, 3; P=0.33). Conclusions: SCD and sickle cell trait were commonly identified postmortem in a large, multi-country childhood mortality surveillance network, yet antemortem diagnosis of SCD was rare among these cases. Malaria was a common cause of death among children both with SCD and sickle cell trait. Enhanced screening for SCD in sub-Saharan Africa may allow for early initiation of prophylaxis, treatment and potential prevention of mortality.

BACKGROUND:Environmental enteric dysfunction is associated with chronic systemic inflammation that results in growth hormone resistance and impaired growth although associations differ between settings. OBJECTIVES:We aimed to describe the time of onset and progression of intestinal pathology and explore associations between biomarkers of environmental enteric dysfunction, systemic inflammation, growth hormones, and linear growth in infants in western Kenya. METHODS:In this prospective, observational cohort study, analysis is limited to infants recruited to the control arm (no intervention) of the PROSYNK trial between 28 October, 2020, and 13 January, 2022. Biomarkers of environmental enteric dysfunction, systemic inflammation, growth hormones, and infant length were measured at 6 wk and 3, 6, and 12 mo. Associations between biomarkers, growth hormones, and linear growth between time points were explored. RESULTS:In 149 infants at age 6 wk, fecal myeloperoxidase (a biomarker of intestinal inflammation) was raised (≥0.2 mg/dL) in 47 of 143 (32.9%) and fecal α1-antitrypsin (intestinal permeability; ≥26.8 mg/dL) in 26 of 142 (18.3%) infants. Chronic systemic inflammation (plasma α1-acid glycoprotein, >1 g/dL) occurred from age 3 mo (33/140 infants; 23.6%). Once detected, intestinal inflammation, increased intestinal permeability, and chronic systemic inflammation persisted in most infants. Fecal myeloperoxidase, fecal α1-antitrypsin, and plasma intestinal fatty acid-binding protein (intestinal integrity) were significantly positively associated with chronic systemic inflammation at some time points. Chronic systemic inflammation was significantly negatively associated with insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 at 3, 6, and 12 mo. In multiple regression analysis, fecal α1-antitrypsin at age 6 mo was negatively associated with subsequent change in length-for-age z-score (n = 124; coefficient: -0.32; 95% CI: -0.50, -0.13; P = 0.001). CONCLUSIONS:Targeting young infants with environmental enteric dysfunction, and especially increased gut permeability, may prevent or ameliorate chronic systemic inflammation and improve growth and development in infants in western Kenya. The PROSYNK trial was registered at the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za/) as PACTR202003893276712 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=9798).

Introduction: Digital health interventions can potentially improve research-related procedures and outcomes. However, many fall short of the expected benefits. Implementing user-centred design (UCD) in their development increases their relevance and adoption. Here we describe a UCD approach in building a data collection platform for use in a research trial requiring timely management of malaria microscopy results. Methodology: UCD was used to transform a paper-based laboratory information system used to manage malaria microscopy to an end-to-end digital equivalent. The approach was based on the three cycles of the information systems research framework i.e. relevance, prototype design and rigour. In the relevance cycle, the paper-based workflow was evaluated and a needs assessment conducted. In the prototype design cycle, a set of electronic case report forms, a revised laboratory request form and an online data dashboard were developed. In the rigour cycle, interviews were held with the relevant users to gain insight on design of each prototype iteration. All staff were trained and the deployment of the finalised digital platform was launched at a single point in time. Three months after implementation of the finalised system, users' experiences were assessed. Results: Turnaround time on reporting microscopy results reduced from a median of 15 days to 3 days(p value < 0.0001). The amount of paper used was reduced to eight times less than before. Redundant data entry activities were removed, and labour-intensive clerical activities were replaced with automated digital processes. Users reported improved work productivity and efficiency in managing microscopy results. Conclusion: The UCD data platform enabled the design of a contextually relevant, successfully adopted and clinically impactful laboratory information system. The manner in which digital health data collections systems are developed, and introduced to users is as critical as their features and functions ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Unitaid. Unitaid is a global health organization that saves lives by making new health products available and affordable for people in low- and middle-income countries. Unitaid works with partners to identify innovative treatments, tests and tools, help tackle the market barriers that are holding them back, and get them to the people who need them most - fast. Since Unitaid was created in 2006, the organization has unlocked access to more than 100 groundbreaking health products to help address the world's biggest health challenges, including HIV, TB, and malaria; women's and children's health; and pandemic prevention, preparedness and response. Every year, more than 300 million people benefit from the products Unitaid has helped roll out. Unitaid is hosted partnership by the World Health Organization. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Kenya Medical Research Institute Scientific Ethics Research Unit (protocol 3870, reference KEMRI/RES/7/3/1), the Institutional Review Boards of Centers for Disease Control and Prevention (protocol number: 7252), the University of Notre Dame (protocol number: 19-08-5506), and the World Health Organization Ethical Review Committee (ERC.0003185) gave ethical approval for the clinical trial which this work fell under. The clinical trial this manuscript references was registered with clinicaltrials.gov [NCT04766879][1]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04766879&atom=%2Fmedrxiv%2Fearly%2F2025%2F04%2F26%2F2025.04.24.25326358.atom

Attractive targeted sugar baits (ATSBs) are a novel malaria control tool designed to target mosquitoes outdoors. We conducted a cluster-randomised trial to evaluate the impact of ATSBs on malaria indicators in Kenya. Seventy clusters (≥100 households/cluster) in Siaya county were randomly assigned (1:1) to intervention or control. Pyrethroid-only long-lasting insecticidal nets were distributed to all clusters, aiming for universal coverage. Two ATSBs containing dinotefuran were hung outside household structures in intervention clusters. ATSBs were monitored every two months and replaced every six months over two years. Three consecutive cohorts of randomly selected children (1- < 15 years) were enrolled, aiming to accrue 1,260 person-years over two years of follow-up. Incidence of clinical malaria (fever with a positive malaria test) was the primary outcome. A multilevel Poisson regression model was applied, with clusters as a random intercept and study arm as a fixed effect. Secondary outcomes were malaria prevalence in community residents (≥1 month), and parity of mosquitos captured through human landing catches. In March 2022, ATSBs were delivered to 33,180 of 33,419 (99.3%) household structures in intervention clusters. Overall, 268,268 ATSBs were deployed over two years. Of 2,962 cohort children enrolled (intervention = 1,497; control = 1,465), 2,869 (96.9%) were included in the primary analysis (intervention = 1,461; control = 1,408), contributing 1,445 person-years of follow-up. Malaria incidence was 1.32 episodes per person-years in the intervention arm versus 1.20 in the control (unadjusted incidence rate ratio 1.11; 95% CI: 0.75-1.65; p = 0.598). Of 7,488 community residents surveyed (intervention = 3,760; control = 3,728), 1,474 (39.2%) intervention and 1,461 (39.2%) control participants tested positive for malaria (unadjusted odds ratio [OR] 0.98; 95% CI: 0.60-1.59; p = 0.93). Of 6,457 female anopheles mosquitoes collected (intervention = 4,058; control = 2,399), 3,579 (88.2%) intervention and 1,973 (82.2%) control mosquitoes were parous (OR 1.34; 95% CI: 0.91-1.99; p = 0.14). In Kenya, we found no evidence that ATSBs reduced clinical malaria incidence, malaria prevalence, or vector parity. Trial registration Clinicaltrials.gov (NCT05219565), 22 January 2022.