Publications

@article{Datoo2024,

title = {Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial},

author = {Mehreen S. Datoo and Alassane Dicko and Halidou Tinto and Jean Bosco Ou\'{e}draogo and Mainga Hamaluba and Ally Olotu and Emma Beaumont and Fernando Ramos Lopez and Hamtandi Magloire Natama and Sophie Weston and Mwajuma Chemba and Yves Daniel Compaore and Djibrilla Issiaka and Diallo Salou and Athanase M. Some and Sharon Omenda and Alison Lawrie and Philip Bejon and Harish Rao and Daniel Chandramohan and Rachel Roberts and Sandesh Bharati and Lisa Stockdale and Sunil Gairola and Brian M. Greenwood and Katie J. Ewer and John Bradley and Prasad S. Kulkarni and Umesh Shaligram and Adrian V. S. Hill and Almahamoudou Mahamar and Koualy Sanogo and Youssoufa Sidibe and Kalifa Diarra and Mamoudou Samassekou and Oumar Attaher and Amadou Tapily and Makonon Diallo and Oumar Mohamed Dicko and Mahamadou Kaya and Seydina Oumar Maguiraga and Yaya Sankare and Hama Yalcouye and Soumaila Diarra and Sidi Mohamed Niambele and Ismaila Thera and Issaka Sagara and Mala Sylla and Amagana Dolo and Nsajigwa Misidai and Sylvester Simando and Hania Msami and Omary Juma and Nicolaus Gutapaka and Rose Paul and Sarah Mswata and Ibrahim Sasamalo and Kasmir Johaness and Mwantumu Sultan and Annastazia Alexander and Isaac Kimaro and Kauye Lwanga and Mwajuma Mtungwe and Kassim Khamis and Lighton Rugarabam and Wilmina Kalinga and Mohammed Mohammed and Janeth Kamange and Jubilate Msangi and Batuli Mwaijande and Ivanny Mtaka and Matilda Mhapa and Tarsis Mlaganile and Thabit Mbaga and Rakiswende Serge Yerbanga and Wendkouni Samtouma and Abdoul Aziz Sienou and Zachari Kabre and Wendinpui Jedida Muriel Ouedraogo and G. Armel Bienvenu Yarbanga and Issaka Zongo and Hamade Savadogo and Joseph Sanon and Judicael Compaore and Idrissa Kere and Ferdinand Lionel Yoni and Tewende Martine Sanre and Seydou Bienvenu Ouattara and Samuel Provstgaard-Morys and Danielle Woods and Robert W. Snow and Nyaguara Amek and Caroline J. Ngetsa and Lynette Isabella Ochola-Oyier and Jennifer Musyoki and Marianne Munene and Noni Mumba and Uche Jane Adetifa and Charles Mwangi Muiruri and Jimmy Shangala Mwawaka and Mwatasa Hussein Mwaganyuma and Martha Njeri Ndichu and Joseph Ochieng Weya and Kelvin Njogu and Jane Grant and Jayne Webster and Anand Lakhkar and N. F\'{e}lix Andr\'{e} Ido and Ousmane Traore and Marc Christian Tahita and Massa Achille Bonko and Toussaint Rouamba and D. Florence Ouedraogo and Rachidatou Soma and Aida Millogo and Edouard Ouedraogo and Faizatou Sorgho and Fab\'{e} Konate and Innocent Valea},

url = {https://pubmed.ncbi.nlm.nih.gov/38310910/},

doi = {10.1016/S0140-6736(23)02511-4},

issn = {1474-547X},

year  = {2024},

date = {2024-01-01},

journal = {Lancet (London, England)},

volume = {403},

issue = {10426},

pages = {533-544},

publisher = {Lancet},

abstract = {Background: Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. Methods: We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5\textendash36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing. Findings: From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71\textendash79; p\<0·0001) at the seasonal sites and 68% (61\textendash74; p\<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71\textendash78; p\<0·0001) at the seasonal sites and 67% (59\textendash73; p\<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762\textendash974) cases per 1000 children-years at seasonal sites and 296 (231\textendash362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5\textendash17 month age group compared with 18\textendash36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73\textendash84]; p\<0·001) and standard (75% [65\textendash83]; p\<0·001) sites. Interpretation: R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. Funding: The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.},

keywords = {{Alassane Dicko, Antibodies, Burkina Faso, Child, Clinical Trial, Double-Blind Method, Female, Humans, Immunization, Infant, Malaria Vaccines* / adverse effects, Malaria* / drug therapy, Male, MEDLINE, Mehreen S Datoo, Multicenter Study, Nanoparticles*, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase III, Preschool, PubMed Abstract, Randomized controlled trial, Research Support, Saponins*},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Evaluating the effect of a behavioural intervention bundle on antibiotic use, quality of care, and household transmission of resistant Enterobacteriaceae in intervention versus control clusters in rural Burkina Faso and DR Congo (CABU-EICO)},

author = {CABU-EICO consortium},

url = {https://pubmed.ncbi.nlm.nih.gov/38281023/},

doi = {10.1186/S13063-023-07856-2},

issn = {1745-6215},

year  = {2024},

date = {2024-01-01},

journal = {Trials},

volume = {25},

issue = {1},

pages = {91},

publisher = {Trials},

abstract = {BACKGROUND: Antimicrobial resistance (AMR) is a rising threat in low-resource settings, largely driven by transmission in the community, outside health facilities. Inappropriate antibiotic use is one of the main modifiable drivers of AMR. Its risk is especially high in poor resource settings, with limited diagnostic and surveillance capacities, and many informal medicine vendors determining community use. We hypothesise that to optimise community antibiotic use, especially Watch antibiotics (recommended only as first-choice for more severe clinical presentations or for causative pathogens likely to be resistant to Access antibiotics), both the supply side (medicine vendors) and the demand side (communities) should be pro-actively involved in any intervention. METHODS: In two existing demographic health surveillance sites (HDSS) in Burkina Faso and in the Democratic Republic of Congo, behavioural intervention bundles were co-created in a participatory approach, aiming to rationalise (Watch) antibiotic use and improve hygiene and sanitation practices. Bundles consisted of interactive interventions, including theatre, posters, discussions, etc. To evaluate impact, 11 of 22 clusters (a HDSS community with at least one (in)formal medicine vendor) were randomly assigned to this intervention, which will run over a year. The effect of the intervention will be evaluated by comparing outcomes before and after in intervention and control villages from a) exit interviews of clients from vendors, b) mystery patients presenting to vendors with a set of predefined symptoms, c) household interviews to assess behavioural changes related to antibiotic use, health literacy and water-sanitation-hygiene indicators. Long-term impact on AMR will be estimated by modelling changes in resistant Enterobacteriaceae carriage from repeated household surveys before, during and after the intervention in both arms. DISCUSSION: Most existing interventions aimed at improving antibiotic use focus on health care use, but in resource-limited settings, community use is highly prevalent. Previous studies targeting only providers failed to show an effect on antibiotic use. Evaluation will be done with before-after epidemiological measurements of actual prescriptions and use. If effective in reducing (Watch) antibiotic use, this would be an empowering methodology for communities, which has significant promise for long-term impact. TRIAL REGISTRATION: ClinicalTrials.gov NCT05378880 . 13 May 2022.},

keywords = {{Anti-Bacterial Agents* / adverse effects, Burkina Faso / epidemiology, Democratic Republic of the Congo / epidemiology, Enterobacteriaceae*, Humans, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, PMC10821568, PubMed Abstract, Randomized controlled trial, Surveys and Questionnaires},

pubstate = {published},

tppubtype = {article}

}

@article{Kiemde2024,

title = {Impact of a package of point-of-care diagnostic tests, a clinical diagnostic algorithm and adherence training on antibiotic prescriptions for the management of non-severe acute febrile illness in primary health facilities during the COVID-19 pandemic in Burkina Faso},

author = {Francois Kiemde and Juvenal Nkeramahame and Ana Belen Ibarz and Sabine Dittrich and Piero Olliaro and Daniel Valia and Toussaint Rouamba and Berenger Kabore and Alima Nadine Kone and Seydou Sawadogo and Antonia Windkouni Bere and Diane Yirgnur Some and Athanase Mwinessobaonfou Some and Adelaide Compaore and Philip Horgan and Stephan Weber and Thomas Keller and Halidou Tinto},

url = {https://pubmed.ncbi.nlm.nih.gov/39192209/},

doi = {10.1186/S12879-024-09787-Y},

issn = {1471-2334},

year  = {2024},

date = {2024-01-01},

journal = {BMC infectious diseases},

volume = {24},

issue = {1},

publisher = {BMC Infect Dis},

abstract = {Objective: To assess the impact of an intervention package on the prescription of antibiotic and subsequently the rate of clinical recovery for non-severe acute febrile illnesses at primary health centers. Methods: Patients over 6 months of age presenting to primary health care centres with fever or history of fever within the past 7 days were randomized to receive either the intervention package constituted of point-of-care tests including COVID-19 antigen tests, a diagnostic algorithm and training and communication packages, or the standard practice. The primary outcomes were antibiotic prescriptions at Day 0 (D0) and the clinical recovery at Day 7 (D7). Secondary outcomes were non-adherence of participants and parents/caregivers to prescriptions, health workers’ non-adherence to the algorithm, and the safety of the intervention. Results: A total of 1098 patients were enrolled. 551 (50.2%) were randomized to receive the intervention versus 547 (49.8%) received standard care. 1054 (96.0%) completed follow-up and all of them recovered at D7 in both arms. The proportion of patients with antibiotic prescriptions at D0 were 33.2% (183/551) in the intervention arm versus 58.1% (318/547) under standard care, risk difference (RD) -24.9 (95% CI -30.6 to -19.2, p \< 0.001), corresponding to one more antibiotic saved every four (95% CI: 3 to 5) consultations. This reduction was also statistically significant in children from 6 to 59 months (RD -34.5; 95% CI -41.7 to -27.3; p \< 0.001), patients over 18 years (RD -35.9; 95%CI -58.5 to -13.4; p = 0.002), patients with negative malaria test (RD -46.9; 95% CI -53.9 to -39.8; p \< 0.001), those with a respiratory diagnosis (RD -48.9; 95% CI -56.9 to -41.0, p \< 0.001) and those not vaccinated against COVID-19 (-24.8% 95%CI -30.7 to -18.9, p-value: \<0.001). A significant reduction in non-adherence to prescription by patients was reported (RD -7.1; 95% CI -10.9 to -3.3; p \< 0.001). Conclusion: The intervention was associated with significant reductions of antibiotic prescriptions and non-adherence, chiefly among patients with non-malaria fever, those with respiratory symptoms and children below 5 years of age. The addition of COVID-19 testing did not have a major impact on antibiotic use at primary health centers. Trial registration: Clinitrial.gov; NCT04081051 registered on 06/09/2019.},

keywords = {Adolescent, Adult, Algorithms*, Anti-Bacterial Agents* / therapeutic use, Burkina Faso, Child, COVID-19* / diagnosis, doi:10.1186/s12879-024-09787-y, Female, Fever* / drug therapy, Francois Kiemde, Halidou Tinto, Humans, Infant, Juvenal Nkeramahame, Male, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, PMC11351252, pmid:39192209, Point-of-Care Systems, Point-of-Care Testing, Preschool, Primary Health Care*, PubMed Abstract, Randomized controlled trial, SARS-Cov-2},

pubstate = {published},

tppubtype = {article}

}

@article{Gansane2023,

title = {Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria},

author = {Adama Gansane and Moussa Lingani and Adoke Yeka and Alain Nahum and Marielle Bouyou-Akotet and Ghyslain Mombo-Ngoma and Grace Kaguthi and Catalina Barcel\'{o} and Bart Laurijssens and Cathy Cantalloube and Fiona Macintyre and Elhadj Djeriou and Andreas Jessel and Rapha\"{e}l Bejuit and Helen Demarest and Anne Claire Marrast and Siaka Debe and Halidou Tinto and Afizi Kibuuka and Diolinda Nahum and Denise Patricia Mawili-Mboumba and Rella Zoleko-Manego and Irene Mugenya and Frederick Olewe and Stephan Duparc and Bernhards Ogutu},

url = {https://pubmed.ncbi.nlm.nih.gov/36597076/},

doi = {10.1186/S12936-022-04420-2},

issn = {1475-2875},

year  = {2023},

date = {2023-01-01},

journal = {Malaria journal},

volume = {22},

issue = {1},

publisher = {Malar J},

abstract = {Background: The contribution of artefenomel to the clinical and parasiticidal activity of ferroquine and artefenomel in combination in uncomplicated Plasmodium falciparum malaria was investigated. Methods: This Phase 2a, randomized, open-label, parallel-group study was conducted from 11th September 2018 to 6th November 2019 across seven centres in Benin, Burkina Faso, Gabon, Kenya, and Uganda. Patients aged ≥ 14\textendash69 years with microscopically confirmed infection (≥ 3000 to ≤ 50,000 parasites/µL blood) were randomized 1:1:1:1 to 400 mg ferroquine, or 400 mg ferroquine plus artefenomel 300, 600, or 1000 mg, administered as a single oral dose. The primary efficacy analysis was a logistic regression evaluating the contribution of artefenomel exposure to Day 28 PCR-adjusted adequate clinical and parasitological response (ACPR). Safety was also evaluated. Results: The randomized population included 140 patients. For the primary analysis in the pharmacokinetic/pharmacodynamic efficacy population (N = 121), the contribution of artefenomel AUC0\textendash∞ to Day 28 PCR-adjusted ACPR was not demonstrated when accounting for ferroquine AUC0\textendashd28, baseline parasitaemia, and other model covariates: odds ratio 1.1 (95% CI 0.98, 1.2; P = 0.245). In the per-protocol population, Day 28 PCR-adjusted ACPR was 80.8% (21/26; 95% CI 60.6, 93.4) with ferroquine alone and 90.3% (28/31; 95% CI 74.2, 98.0), 90.9% (30/33; 95% CI 75.7, 98.1) and 87.1% (27/31; 95% CI 70.2, 96.4) with 300, 600, and 1000 mg artefenomel, respectively. Median time to parasite clearance (Kaplan\textendashMeier) was 56.1 h with ferroquine, more rapid with artefenomel, but similar for all doses (30.0 h). There were no deaths. Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively. All AEs were of mild-to-moderate severity, and consistent with the known profiles of the compounds. Vomiting was the most reported AE. There were no cases of QTcF prolongation ≥ 500 ms or \> 60 ms from baseline. Conclusion: The contribution of artefenomel exposure to the clinical and parasitological activity of ferroquine/artefenomel could not be demonstrated in this study. Parasite clearance was faster with ferroquine/artefenomel versus ferroquine alone. All treatments were well tolerated. Trial registration: ClinicalTrials.gov, NCT03660839 (7 September, 2018).},

keywords = {Adama Gansane, Aminoquinolines / therapeutic use, Antimalarials* / pharmacology, Bernhards Ogutu, Clinical Trial, doi:10.1186/s12936-022-04420-2, Drug Combinations, Falciparum* / drug therapy, Falciparum* / parasitology, Humans, Malaria, MEDLINE, Moussa Lingani, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Phase II, Plasmodium falciparum, PMC9809015, pmid:36597076, PubMed Abstract, Randomized controlled trial, Treatment Outcome},

pubstate = {published},

tppubtype = {article}

}

@article{Kiemde2023,

title = {A Randomized Trial to Assess the Impact of a Package of Diagnostic Tools and Diagnostic Algorithm on Antibiotic Prescriptions for the Management of Febrile Illnesses Among Children and Adolescents in Primary Health Facilities in Burkina Faso},

author = {Francois Kiemde and Daniel Valia and Berenger Kabore and Toussaint Rouamba and Alima Nadine Kone and Seydou Sawadogo and Adelaide Compaore and Olawale Salami and Philip Horgan and Catrin E. Moore and Sabine Dittrich and Juvenal Nkeramahame and Piero Olliaro and Halidou Tinto},

url = {https://pubmed.ncbi.nlm.nih.gov/37490742/},

doi = {10.1093/CID/CIAD331},

issn = {1537-6591},

year  = {2023},

date = {2023-01-01},

journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},

volume = {77},

issue = {Suppl 2},

pages = {S134-S144},

publisher = {Clin Infect Dis},

abstract = {Background: Low- and middle-income countries face significant challenges in differentiating bacterial from viral causes of febrile illnesses, leading to inappropriate use of antibiotics. This trial aimed to evaluate the impact of an intervention package comprising diagnostic tests, a diagnostic algorithm, and a training-and-communication package on antibiotic prescriptions and clinical outcomes. Methods: Patients aged 6 months to 18 years with fever or history of fever within the past 7 days with no focus, or a suspected respiratory tract infection, arriving at 2 health facilities were randomized to either the intervention package or standard practice. The primary outcomes were the proportions of patients who recovered at day 7 (D7) and patients prescribed antibiotics at day 0. Results: Of 1718 patients randomized, 1681 (97.8%; intervention: 844; control: 837) completed follow-up: 99.5% recovered at D7 in the intervention arm versus 100% in standard practice (P =. 135). Antibiotics were prescribed to 40.6% of patients in the intervention group versus 57.5% in the control arm (risk ratio: 29.3%; 95% CI: 21.8-36.0%; risk difference [RD]: -16.8%; 95% CI: -21.7% to -12.0%; P \<. 001), which translates to 1 additional antibiotic prescription saved every 6 (95% CI: 5-8) consultations. This reduction was significant regardless of test results for malaria, but was greater in patients without malaria (RD: -46.0%; -54.7% to -37.4%; P \<. 001), those with a respiratory diagnosis (RD: -38.2%; -43.8% to -32.6%; P \<. 001), and in children 6-59 months old (RD: -20.4%; -26.0% to -14.9%; P \<. 001). Except for the period July-September, the reduction was consistent across the other quarters (P \<. 001). Conclusions: The implementation of the package can reduce inappropriate antibiotic prescription without compromising clinical outcomes. Clinical Trials Registration: clinicaltrials.gov; NCT04081051.},

keywords = {Adolescent, Algorithms, Anti-Bacterial Agents* / therapeutic use, Burkina Faso, Child, Daniel Valia, doi:10.1093/cid/ciad331, Francois Kiemde, Halidou Tinto, Health Facilities, Humans, Infant, Malaria* / drug therapy, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, PMC10368409, pmid:37490742, Preschool, Prescriptions, PubMed Abstract, Randomized controlled trial, Research Support},

pubstate = {published},

tppubtype = {article}

}

@article{Agnandji2023,

title = {Prostration and the prognosis of death in African children with severe malaria},

author = {Selidji T. Agnandji and Mario Recker and Benjamin Mordm\"{u}ller and Stephan Gl\"{o}ckner and Akim A. Adegnika and Bertrand Lell and Lucas Otieno and Walter Otieno and Seth Owusu-Agyei and Kwaku P. Asante and Tsiri Agbenyega and Daniel Ansong and Eusebio Macete and Pedro Aide and Hermann Sorgho and Halidou Tinto and Neema Mturi and John P. A. Lusingu and Samwel Gesase and Irving Hoffman and Nahya Salim Masoud and Charles R. Newton and Kalifa Bojang and G\'{e}rard Krause and Peter Gottfried Kremsner},

url = {https://pubmed.ncbi.nlm.nih.gov/37414210/},

doi = {10.1016/J.IJID.2023.06.022},

issn = {1878-3511},

year  = {2023},

date = {2023-01-01},

journal = {International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases},

volume = {134},

pages = {240-247},

publisher = {Int J Infect Dis},

abstract = {Objectives: Malaria is still one of the main reasons for hospitalization in children living in sub-Saharan Africa. Rapid risk stratification at admission is essential for optimal medical care and improved prognosis. Whereas coma, deep breathing, and, to a lesser degree, severe anemia are established predictors of malaria-related death, the value of assessing prostration for risk stratification is less certain. Methods: Here we used a retrospective multi-center analysis comprising over 33,000 hospitalized children from four large studies, including two observational studies from the Severe Malaria in African Children network, a randomized controlled treatment study, and the phase-3-clinical RTS,S-malaria vaccine trial, to evaluate known risk factors of mortality and with a specific emphasis on the role of prostration. Results: Despite comparable age profiles of the participants, we found significant inter- and intra-study variation in the incidence of fatal malaria as well as in the derived risk ratios associated with the four risk factors: coma, deep breathing, anemia, and prostration. Despite pronounced variations, prostration was significantly associated with an increased risk of mortality (P \<0.001) and its consideration resulted in improved predictive performance, both in a multivariate model and a univariate model based on the Lambar\'{e}n\'{e} Organ Dysfunction Score. Conclusion: Prostration is an important clinical criterion to determine severe pediatric malaria with possible fatal outcomes.},

keywords = {Anemia*, Child, Clinical Trial, Coma, doi:10.1016/j.ijid.2023.06.022, Falciparum* / drug therapy, Humans, Infant, Malaria, Malaria* / complications, Malaria* / diagnosis, Mario Recker, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Peter Gottfried Kremsner, Phase III, pmid:37414210, Prognosis, PubMed Abstract, Randomized controlled trial, Selidji T Agnandji},

pubstate = {published},

tppubtype = {article}

}

@article{Ogutu2023,

title = {Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial},

author = {Bernhards Ogutu and Adoke Yeka and Sylvia Kusemererwa and Ricardo Thompson and Halidou Tinto and Andre Offianan Toure and Chirapong Uthaisin and Amar Verma and Afizi Kibuuka and Moussa Lingani and Carlos Louren\c{c}o and Ghyslain Mombo-Ngoma and Videlis Nduba and Tiacoh Landry N'Guessan and Gu\'{e}tawend\'{e} Job Wilfried Nassa and Mary Nyantaro and Lucas Otieno Tina and Piyoosh K. Singh and Myriam El Gaaloul and Anne Claire Marrast and Havana Chikoto and Katalin Csermak and Ivan Demin and Dheeraj Mehta and Rashidkhan Pathan and Celine Risterucci and Guoqin Su and Cornelis Winnips and Grace Kaguthi and Bakary Fofana and Martin Peter Grobusch},

url = {https://pubmed.ncbi.nlm.nih.gov/37327809/},

doi = {10.1016/S1473-3099(23)00209-8},

issn = {1474-4457},

year  = {2023},

date = {2023-01-01},

journal = {The Lancet. Infectious diseases},

volume = {23},

issue = {9},

pages = {1051-1061},

publisher = {Lancet Infect Dis},

abstract = {Background: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. Methods: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (\>1000 and \<150 000 parasites per μL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and \<12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to \<6 years and 6 to \<12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020\textendash003284\textendash25) and ClinicalTrials.gov (NCT03167242). Findings: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81\textendash98] with 1 day, 47 of 48 [98%, 89\textendash100] with 2 days, and 42 of 43 [98%, 88\textendash100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83\textendash99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93\textendash100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92\textendash100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86\textendash100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83\textendash99] vs 21 of 22 [96%, 77\textendash100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. Interpretation: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). Funding: Novartis and Medicines for Malaria Venture.},

keywords = {Adoke Yeka, Adolescent, Adult, Antimalarials*, Artemether / pharmacology, Artemether / therapeutic use, Artemisinins*, Bernhards Ogutu, Child, Clinical Trial, doi:10.1016/S1473-3099(23)00209-8, Drug Combinations, Ethanolamines / pharmacology, Ethanolamines / therapeutic use, Falciparum* / drug therapy, Falciparum* / parasitology, Fluorenes / pharmacology, Fluorenes / therapeutic use, Humans, Lumefantrine / pharmacology, Lumefantrine / therapeutic use, Malaria, Malaria* / drug therapy, Martin Peter Grobusch, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase II, Plasmodium falciparum, pmid:37327809, PubMed Abstract, Randomized controlled trial, Research Support, Treatment Outcome},

pubstate = {published},

tppubtype = {article}

}

@article{Sondo2023,

title = {Enhanced effect of seasonal malaria chemoprevention when coupled with nutrients supplementation for preventing malaria in children under 5 years old in Burkina Faso: a randomized open label trial},

author = {Paul Sondo and B\'{e}renger Kabor\'{e} and Toussaint Rouamba and Eulalie Compaor\'{e} and Yssimini Nad\`{e}ge Guill\`{e}ne Tibiri and Hyacinthe Abd El Latif Fa\"{i}\c{c}al Kabor\'{e} and Karim Derra and Marc Christian Tahita and Hamidou Ilboudo and Gauthier Tougri and Isma\"{i}la Bouda and Tikanou Dakyo and Hyacinthe Kafando and Florence Ou\'{e}draogo and Eli Rouamba and So Franck Hien and Adama Kazienga and Cheick Sa\"{i}d Compaor\'{e} and Estelle Bambara and Macaire Nana and Prabin Dahal and Franck Garanet and William Kabor\'{e} and Thierry L\'{e}f\`{e}vre and Philippe Guerin and Halidou Tinto},

url = {https://pubmed.ncbi.nlm.nih.gov/37853408/},

doi = {10.1186/S12936-023-04745-6},

issn = {1475-2875},

year  = {2023},

date = {2023-01-01},

journal = {Malaria journal},

volume = {22},

issue = {1},

publisher = {Malar J},

abstract = {Background: In rural African settings, most of the children under the coverage of Seasonal Malaria Chemoprevention (SMC) are also undernourished at the time of SMC delivery, justifying the need for packaging malarial and nutritional interventions. This study aimed at assessing the impact of SMC by coupling the intervention with nutrients supplementation for preventing malaria in children less than 5 years old in Burkina Faso. Methods: A randomized trial was carried out between July 2020 and June 2021 in the health district of Nanoro, Burkina Faso. Children (n = 1059) under SMC coverage were randomly assigned to one of the three study arms SMC + Vitamin A (SMC-A},

keywords = {Antimalarials* / therapeutic use, B\'{e}renger Kabor\'{e}, Burkina Faso / epidemiology, Chemoprevention, Child, Cross-Sectional Studies, Dietary Supplements, doi:10.1186/s12936-023-04745-6, Halidou Tinto, Humans, Infant, Malaria* / epidemiology, MEDLINE, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Nutrients, Paul Sondo, PMC10585892, pmid:37853408, Preschool, PubMed Abstract, Randomized controlled trial, Seasons, Vitamin A / therapeutic use},

pubstate = {published},

tppubtype = {article}

}

@article{Sondo2021-kc,

title = {Assessment of a combined strategy of seasonal malaria  chemoprevention and supplementation with vitamin A, zinc and  Plumpy'Doz™ to prevent malaria and malnutrition in children  under 5 years old in Burkina Faso: a randomized open-label trial  (SMC-NUT)},

author = {Paul Sondo and Marc Christian Tahita and Toussaint Rouamba and Karim Derra and B\'{e}renger Kabor\'{e} and Cheick Sa"id Compaor\'{e} and Florence Ou\'{e}draogo and Eli Rouamba and Hamidou Ilboudo and Estelle A"issa Bambara and Macaire Nana and Edmond Yabr\'{e} Sawadogo and Hermann Sorgho and Athanase Mwinessobaonfou Som\'{e} and Innocent Val\'{e}a and Prabin Dahal and Maminata Traor\'{e}/Coulibaly and Halidou Tinto},

doi = {10.1186/s13063-021-05320-7},

issn = {1745-6215},

year  = {2021},

date = {2021-05-24},

urldate = {2021-05-24},

journal = {Trials},

volume = {22},

number = {1},

pages = {360},

publisher = {Springer Science and Business Media LLC},

abstract = {BACKGROUND: Malaria and malnutrition represent major public 

 health concerns worldwide especially in Sub-Sahara Africa. 

 Despite implementation of seasonal malaria chemoprophylaxis 

 (SMC), an intervention aimed at reducing malaria incidence among 

 children aged 3-59 months, the burden of malaria and associated 

 mortality among children below age 5 years remains high in 

 Burkina Faso. Malnutrition, in particular micronutrient 

 deficiency, appears to be one of the potential factors that can 

 negatively affect the effectiveness of SMC. Treating 

 micronutrient deficiencies is known to reduce the incidence of 

 malaria in highly prevalent malaria zone such as rural settings. 

 Therefore, we hypothesized that a combined strategy of SMC 

 together with a daily oral nutrients supplement will enhance the 

 immune response and decrease the incidence of malaria and 

 malnutrition among children under SMC coverage. METHODS: 

 Children (6-59 months) under SMC coverage receiving vitamin A 

 supplementation will be randomly assigned to one of the three 

 study arms (a) SMC + vitamin A alone, (b) SMC + vitamin A + 

 zinc, or (c) SMC + vitamin A + Plumpy'Doz™ using 1:1:1 

 allocation ratio. After each SMC monthly distribution, children 

 will be visited at home to confirm drug administration and 

 followed-up for 1 year. Anthropometric indicators will be 

 recorded at each visit and blood samples will be collected for 

 microscopy slides, haemoglobin measurement, and spotted onto 

 filter paper for further PCR analyses. The primary outcome 

 measure is the incidence of malaria in each arm. Secondary 

 outcome measures will include mid-upper arm circumference and 

 weight gain from baseline measurements, coverage and compliance 

 to SMC, occurrence of adverse events (AEs), and prevalence of 

 molecular markers of antimalarial resistance comprising Pfcrt, 

 Pfmdr1, Pfdhfr, and Pfdhps. DISCUSSION: This study will 

 demonstrate an integrated strategy of malaria and malnutrition 

 programmes in order to mutualize resources for best impact. By 

 relying on existing strategies, the policy implementation of 

 this joint intervention will be scalable at country and regional 

 levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT04238845 . 

 Registered on 23 January 2020 

 https://clinicaltrials.gov/ct2/show/NCT04238845.},

note = {PMID: 34030705 

PMCID: PMC8142067},

keywords = {Antimalarials/adverse effects, Burkina Faso/epidemiology, Chemoprevention, Child, Child Nutrition Disorders, Dietary Supplements, Humans, Infant, Malaria, Malaria/diagnosis/epidemiology/prevention \& control, Malnutrition, Malnutrition/diagnosis/drug therapy/prevention \& control, Pharmaceutical Preparations, Plumpy’Doz™, Preschool, Randomized controlled trial, Seasonal chemoprevention, Seasons, Vitamin A, Vitamin A/adverse effects, Zinc},

pubstate = {published},

tppubtype = {article}

}

@article{RTS2015,

title = {Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial},

author = {S Clinical Trials Partnership RTS},

url = {https://pubmed.ncbi.nlm.nih.gov/25913272/},

doi = {10.1016/S0140-6736(15)60721-8},

issn = {1474-547X},

year  = {2015},

date = {2015-01-01},

journal = {Lancet (London, England)},

volume = {386},

issue = {9988},

pages = {31-45},

publisher = {Lancet},

abstract = {Background The efficacy and safety of the RTS,S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose. Methods From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and young infants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and a booster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparator vaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severe malaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria. Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619. Findings 8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infants for 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36·3%, 95% CI 31·8-40·5) and 7396 occurred in the R3C group (28·3%, 23·3-32·9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32·2%, 13·7 to 46·9) and 169 in the R3C group (1·1%, -23·0 to 20·5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25·9%, 95% CI 19·9-31·5) and 5444 occurred in the R3C group (18·3%, 11·7-24·4); and compared with 116 infants who experienced at least one episode of severe malaria in the C3C group, 96 infants experienced at least one episode of severe malaria in the R3R group (17·3%, 95% CI -9·4 to 37·5) and 104 in the R3C group (10·3%, -17·9 to 31·8). In children, 1774 cases of clinical malaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 young infants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2·2 per 1000 doses in young infants and 2·5 per 1000 doses in children. Interpretation RTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3-4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. Funding GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.},

keywords = {{Africa South of the Sahara / epidemiology, Age Factors, Clinical Trial, Double-Blind Method, Falciparum / epidemiology, Falciparum / prevention \& control*, Female, Follow-Up Studies, Hospitalization / statistics \& numerical data, Humans, Immunization, Immunization Schedule, Incidence, Infant, Malaria, Malaria Vaccines*, Male, MEDLINE, Multicenter Study, National Center for Biotechnology Information, National Institutes of Health, National Library of Medicine, NCBI, NIH, NLM, Non-U.S. Gov't, Phase III, PMC5626001, PubMed Abstract, Randomized controlled trial, Research Support, S Clinical Trials Partnership'},

pubstate = {published},

tppubtype = {article}

}