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Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings. We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1–59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data. Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41·8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99·7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31·7%) of 1752 cases (range by site 10·6–97·3%). 30-day case-fatality ratio was 6·4% (114 of 1769 cases). Blood cultures were positive in 56 (3·2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33·9%] of 56). Almost all cases (98·9%) and controls (98·0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61·4% (95% credible interval [CrI] 57·3–65·6) of causes, whereas bacteria accounted for 27·3% (23·3–31·6) and Mycobacterium tuberculosis for 5·9% (3·9–8·3). Viruses were less common (54·5%, 95% CrI 47·4–61·5 vs 68·0%, 62·7–72·7) and bacteria more common (33·7%, 27·2–40·8 vs 22·8%, 18·3–27·6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31·1%, 95% CrI 28·4–34·2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus–enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site's aetiological fraction. In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes. Bill & Melinda Gates Foundation.

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.

In a phase 3 noninferiority trial, one dose of a new meningococcal vaccine (NmCV-5) elicited immune responses similar to those of MenACWY-D for the four serotypes in common and additional immune responses for serogroup X.

Malaria is a major cause of illness worldwide. In a phase 2 trial in Mali, one subcutaneous dose of L9LS, a monoclonal antibody targeting Plasmodium falciparum , reduced the incidence of clinical malaria among children.

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.

Pfs25H-EPA is a protein-protein conjugate transmission-blocking vaccine against Plasmodium falciparum that is safe and induces functional antibodies in malaria-naive individuals. In this field trial, we assessed Pfs25H-EPA/Alhydrogel for safety and functional immunogenicity in Malian adults. This double-blind, randomised, comparator-controlled, dose-escalation trial in Bancoumana, Mali, was done in two staggered phases, an initial pilot safety assessment and a subsequent main phase. Healthy village residents aged 18–45 years were eligible if they had normal laboratory results (including HIV, hepatitis B, hepatitis C tests) and had not received a previous malaria vaccine or recent immunosuppressive drugs, vaccines, or blood products. Participants in the pilot safety cohort and the main cohort were assigned (1:1) by block randomisation to a study vaccine group. Participants in the pilot safety cohort received two doses of Pfs25H-EPA/Alhydrogel 16 μg or Euvax B (comparator vaccine), and participants in the main cohort received Pfs25H-EPA/Alhydrogel 47 μg or comparator vaccine (Euvax B for the first, second, and third vaccinations and Menactra for the fourth vaccination). Participants and investigators were masked to group assignment, and randomisation codes in sealed envelopes held by a site pharmacist. Vials with study drug for injection were covered by opaque tape and labelled with a study identification number. Group assignments were unmasked at final study visit. The primary outcomes were safety and tolerability for all vaccinees. The secondary outcome measure was immunogenicity 14 days after vaccination in the per-protocol population, as confirmed by the presence of antibodies against Pfs25H measured by ELISA IgG and antibody functionality assessed by standard membrane feeding assays and by direct skin feeding assays. This trial is registered with ClinicalTrials.gov, number NCT01867463. Between May 15, and Jun 16, 2013, 230 individuals were screened for eligibility. 20 individuals were enrolled in the pilot safety cohort; ten participants were assigned to receive Pfs25H-EPA/Alhydrogel 16 μg, and ten participants were assigned to receive comparator vaccine. 100 individuals were enrolled in the main cohort; 50 participants were assigned to receive Pfs25H-EPA/Alhydrogel 47 μg, and 50 participants were assigned to receive comparator vaccine. Compared with comparator vaccinees, Pfs25H vaccinees had more solicited adverse events (137 events vs 86 events; p=0·022) and treatment-related adverse events (191 events vs 126 events, p=0·034), but the number of other adverse events did not differ between study vaccine groups (792 vs 683). Pfs25H antibody titres increased with each dose, with a peak geometric mean of 422·3 ELISA units (95% CI 290–615) after the fourth dose, but decreased relatively rapidly thereafter, with a half-life of 42 days for anti-Pfs25H and 59 days for anti-EPA (median ratio of titres at day 600 to peak, 0·19 for anti-Pfs25H vs 0·29 for anti-EPA; p=0·009). Serum transmission-reducing activity was greater for Pfs25H than for comparator vaccine after the fourth vaccine dose (p<0·001) but not after the third dose (p=0·09). Repeated direct skin feeds were well tolerated, but the number of participants who infected at least one mosquito did not differ between Pfs25H and comparator vaccinees after the fourth dose (p=1, conditional exact). Pfs25H-EPA/Alhydrogel was well tolerated and induced significant serum activity by standard membrane feeding assays but transmission blocking activity was not confirmed by weekly direct skin feed. This activity required four doses, and titres decreased rapidly after the fourth dose. Alternative antigens or combinations should be assessed to improve activity. Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

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.

Mass administration of azithromycin to children younger than 5 years has been reported to decrease child mortality. In this trial, limited to infants 1 to 11 months of age in Mali, azithromycin did not reduce infant or child mortality.

Background Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP + AQ) involves the monthly administration of therapeutic doses to children under five years of age during periods of high risk of malaria in regions where malaria transmission is highly seasonal. Current SMC guidelines recommend administering the same treatment to both non-infected and asymptomatic Plasmodium falciparum- infected children. However, a critical knowledge gap remains the impact asymptomatic infection on the efficacy of SMC in preventing clinical malaria over a four-week period. This study aimed to evaluate the risk of clinical malaria and its association with children's infection status during SMC treatment. Methods This study was conducted in the Koulikoro health district of Mali and focused on children under 10 years of age. A total of 726 children in 2019 and 1452 children in 2020 were randomly selected and followed throughout the SMC campaigns. The prevalence of asymptomatic P. falciparum infection was assessed in each round using microscopy prior to SMC drug administration. Children were passively monitored over a four-week period to record the incidence of clinical malaria. Data analysis was performed using R-Studio software. The risk of clinical malaria based on infection status was estimated through logistic regression analysis, and a Kaplan–Meier curve was used to compare survival times between infected and uninfected children. Proportions were compared using the Pearson Chi-square test, with statistical significance set at p < 0.05. Results The average prevalence of asymptomatic P. falciparum infection was 11.0% across study years. Prevalence was notably higher among children aged 5 to 9 years old in 2019 (p < 0.001) and 2020 (p = 0.016). Asymptomatic infected children had a significantly higher risk of clinical malaria during both transmission seasons: 2019: (RR = 3.05, CI [2.04–4.72]) and 2020 (RR = 1.43, CI [1.04–1.97]). Furthermore, the time to the first malaria episode was significantly shorter among infected children in both years (p < 0.001 for 2019, p = 0.01 for 2020). Conclusion These findings demonstrate an elevated risk of clinical malaria in asymptomatic infected children during SMC implementation. Screening and treating P. falciparum infections prior to SMC administration could substantially enhance the effectiveness of this strategy in reducing malaria morbidity in endemic areas.

A cluster‐randomised controlled trial was conducted in 60 communities in southern Mali to evaluate the impact of micronutrient powders (MNP) combined with seasonal malaria chemoprevention (SMC) on anaemia (primary endpoint), Plasmodium infection, stunting and cognitive function in children < 5 years. The 60 communities were randomly allocated to the intervention or control arm, and cross‐sectional biomedical and cognitive surveys were conducted after 1 and 3 years in a random sample of 3 and 5 years olds (1052 and 1081 children, respectively). All children aged 3–59 m in intervention and control communities received two rounds of SMC each year during the peak malaria season, and in intervention communities, all children aged 6–59 m additionally received 4 months of daily MNP after the peak malaria season. Despite a high baseline prevalence of anaemia and good fidelity to intervention, this trial found no evidence of impact on study outcomes. The prevalence of anaemia was similar in both arms for both age groups after 1 and 3 years of intervention—after 3 years, the prevalence of anaemia amongst 3‐year olds was 57.6% in the intervention arm versus 60.1% in the control group (p = 0.352). For 5‐year olds, it was 51.3% and 53.0%, respectively (p = 0.607). No effect was observed on stunting or cognitive function either. Globally nearly 40% of children under 5 years old are anaemic, which affects their ability to grow and develop. A cluster randomised trial was conducted in 60 communities in Southern Mali to evaluate the added impact of home fortification with micronutrient powders, delivered alongside seasonal malaria chemoprevention, on anaemia, malaria infection, stunting and cognitive function in early childhood. Summary Around 60% of children under 5 years in Africa are anaemic due to iron deficiency and disease. Home fortification with micronutrient powders (MNP) and seasonal malaria chemoprevention (SMC) are recommended interventions to prevent anaemia and malaria. A cluster randomised trial in 60 rural communities in Southern Mali found that MNP, combined with SMC, had no impact on anaemia, stunting or cognitive development despite relatively high adherence and a high burden of anaemia and malaria. While MNP are effective in most contexts, they are not effective in every context. More research is needed to assess MNP's capacity to prevent anaemia in a wider range of settings—addressing both the biological mechanisms that might hinder absorption, as well as the sociocultural aspects for maximal utilisation.