Phase 3 evaluation of an innovative simple molecular test for the diagnosis of malaria in different endemic and health settings in sub-Saharan Africa (DIAGMAL)

Background Rapid Diagnostic Tests (RDTs) have become the cornerstone for the management of malaria in many endemic settings, but their use is constrained for several reasons: (i) persistent malaria antigen (histidine-rich protein 2; HRP2) leading to false positive test results; (ii) hrp2 deletions leading to false negative PfHRP2 results; and (iii) limited sensitivity with a detection threshold of around 100 parasites/μl blood (pLDH- and HRP2-based) leading to false negative tests. Microscopy is still the gold standard for malaria diagnosis, and allows for species determination and quantitation, but requires trained microscopists, maintained microscopes and has detection limit issues. Consequently, there is a pressing need to develop and evaluate more sensitive and accurate diagnostic tests. To address this need we have developed a direct on blood mini PCR-NALFIA test that combines the benefits of molecular biology with low infrastructural requirements and extensive training. Methods This is a Phase 3 diagnostic evaluation in 5 African countries. Study sites (Sudan, Ethiopia, Burkina, Kenya and Namibia) were selected to ensure wide geographical coverage of Africa and to address various malaria epidemiological contexts ranging from high transmission to near elimination settings with different clinical scenarios and diagnostic challenges. Study participants will be enrolled at the study health facilities after obtaining written informed consent. Diagnostic accuracy will be assessed following the WHO/TDR guidelines for the evaluation of diagnostics and reported according to STARD principles. Due to the lack of a 100% specific and sensitive standard diagnostic test for malaria, the sensitivity and specificity of the new test will be compared to the available diagnostic practices in place at the selected sites and to quantitative PCR as the reference test. Discussion This phase 3 study is designed to validate the clinical performance and feasibility of implementing a new diagnostic tool for the detection of malaria in real clinical settings. If successful, the proposed technology will improve the diagnosis of malaria. Enrolment started in November 2022 (Kenya) with assessment of long term outcome to be completed by 2023 at all recruitment sites

Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial

BACKGROUND: Malaria is a leading cause of morbidity and mortality worldwide. We previously reported the efficacy of the R21/Matrix-M malaria vaccine, which reached the WHO-specified goal of 75% or greater efficacy over 12 months in the target population of African children. Here, we report the safety, immunogenicity, and efficacy results at 12 months following administration of a booster vaccination. METHODS: This double-blind phase 1/2b randomised controlled trial was done in children aged 5-17 months in Nanoro, Burkina Faso. Eligible children were enrolled and randomly assigned (1:1:1) to receive three vaccinations of either 5 μg R21/25 μg Matrix-M, 5 μg R21/50 μg Matrix-M, or a control vaccine (the Rabivax-S rabies vaccine) before the malaria season, with a booster dose 12 months later. Children were eligible for inclusion if written informed consent could be provided by a parent or guardian. Exclusion criteria included any existing clinically significant comorbidity or receipt of other investigational products. A random allocation list was generated by an independent statistician by use of block randomisation with variable block sizes. A research assistant from the University of Oxford, independent of the trial team, prepared sealed envelopes using this list, which was then provided to the study pharmacists to assign participants. All vaccines were prepared by the study pharmacists by use of the same type of syringe, and the contents were covered with an opaque label. Vaccine safety, efficacy, and a potential correlate of efficacy with immunogenicity, measured as anti-NANP antibody titres, were evaluated over 1 year following the first booster vaccination. The population in which the efficacy analyses were done comprised all participants who received the primary series of vaccinations and a booster vaccination. Participants were excluded from the efficacy analysis if they withdrew from the trial within the first 2 weeks of receiving the booster vaccine. This trial is registered with ClinicalTrials.gov (NCT03896724), and is continuing for a further 2 years to assess both the potential value of additional booster vaccine doses and longer-term safety. FINDINGS: Between June 2, and July 2, 2020, 409 children returned to receive a booster vaccine. Each child received the same vaccination for the booster as they received in the primary series of vaccinations; 132 participants received 5 μg R21 adjuvanted with 25 μg Matrix-M, 137 received 5 μg R21 adjuvanted with 50 μg Matrix-M, and 140 received the control vaccine. R21/Matrix-M had a favourable safety profile and was well tolerated. Vaccine efficacy remained high in the high adjuvant dose (50 μg) group, similar to previous findings at 1 year after the primary series of vaccinations. Following the booster vaccination, 67 (51%) of 132 children who received R21/Matrix-M with low-dose adjuvant, 54 (39%) of 137 children who received R21/Matrix-M with high-dose adjuvant, and 121 (86%) of 140 children who received the rabies vaccine developed clinical malaria by 12 months. Vaccine efficacy was 71% (95% CI 60 to 78) in the low-dose adjuvant group and 80% (72 to 85) in the high-dose adjuvant group. In the high-dose adjuvant group, vaccine efficacy against multiple episodes of malaria was 78% (95% CI 71 to 83), and 2285 (95% CI 1911 to 2568) cases of malaria were averted per 1000 child-years at risk among vaccinated children in the second year of follow-up. Among these participants, at 28 days following their last R21/Matrix-M vaccination, titres of malaria-specific anti-NANP antibodies correlated positively with protection against malaria in both the first year of follow-up (Spearman's ρ -0·32 [95% CI -0·45 to -0·19]; p=0·0001) and second year of follow-up (-0·20 [-0·34 to -0·06]; p=0·02). INTERPRETATION: A booster dose of R21/Matrix-M at 1 year following the primary three-dose regimen maintained high efficacy against first and multiple episodes of clinical malaria. Furthermore, the booster vaccine induced antibody concentrations that correlated with vaccine efficacy. The trial is ongoing to assess long-term follow-up of these participants and the value of further booster vaccinations. FUNDING: European and Developing Countries Clinical Trials Partnership 2 (EDCTP2), Wellcome Trust, and NIHR Oxford Biomedical Research Centre. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial.

BACKGROUND: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy. METHODS: In this double-blind, randomised, controlled, phase 2b trial, the low-dose circumsporozoite protein-based vaccine R21, with two different doses of adjuvant Matrix-M (MM), was given to children aged 5-17 months in Nanoro, Burkina Faso-a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals before the malaria season, with a fourth dose 1 year later. All vaccines were administered intramuscularly into the thigh. Group 1 received 5 μg R21 plus 25 μg MM, group 2 received 5 μg R21 plus 50 μg MM, and group 3, the control group, received rabies vaccinations. Children were randomly assigned (1:1:1) to groups 1-3. An independent statistician generated a random allocation list, using block randomisation with variable block sizes, which was used to assign participants. Participants, their families, and the local study team were all masked to group allocation. Only the pharmacists preparing the vaccine were unmasked to group allocation. Vaccine safety, immunogenicity, and efficacy were evaluated over 1 year. The primary objective assessed protective efficacy of R21 plus MM (R21/MM) from 14 days after the third vaccination to 6 months. Primary analyses of vaccine efficacy were based on a modified intention-to-treat population, which included all participants who received three vaccinations, allowing for inclusion of participants who received the wrong vaccine at any timepoint. This trial is registered with ClinicalTrials.gov, NCT03896724. FINDINGS: From May 7 to June 13, 2019, 498 children aged 5-17 months were screened, and 48 were excluded. 450 children were enrolled and received at least one vaccination. 150 children were allocated to group 1, 150 children were allocated to group 2, and 150 children were allocated to group 3. The final vaccination of the primary series was administered on Aug 7, 2019. R21/MM had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the seven serious adverse events were attributed to the vaccine. At the 6-month primary efficacy analysis, 43 (29%) of 146 participants in group 1, 38 (26%) of 146 participants in group 2, and 105 (71%) of 147 participants in group 3 developed clinical malaria. Vaccine efficacy was 74% (95% CI 63-82) in group 1 and 77% (67-84) in group 2 at 6 months. At 1 year, vaccine efficacy remained high, at 77% (67-84) in group 1. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered 1 year later. INTERPRETATION: R21/MM appears safe and very immunogenic in African children, and shows promising high-level efficacy. FUNDING: The European & Developing Countries Clinical Trials Partnership, Wellcome Trust, and National Institute for Health Research Oxford Biomedical Research Centre

Pregnancy outcomes after first-trimester treatment with artemisinin derivatives versus non-artemisinin antimalarials: A systematic review and individual patient data meta-analysis

Background Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We compared adverse pregnancy outcomes after artemisinin-based treatment (ABT) versus non-ABTs in the first trimester of pregnancy. Methods For this systematic review and individual patient data (IPD) meta-analysis, we searched MEDLINE, Embase, and the Malaria in Pregnancy Library for prospective cohort studies published between Nov 1, 2015, and Dec 21, 2021, containing data on outcomes of pregnancies exposed to ABT and non-ABT in the first trimester. The results of this search were added to those of a previous systematic review that included publications published up until November, 2015. We included pregnancies enrolled before the pregnancy outcome was known. We excluded pregnancies with missing estimated gestational age or exposure information, multiple gestation pregnancies, and if the fetus was confirmed to be unviable before antimalarial treatment. The primary endpoint was adverse pregnancy outcome, defined as a composite of either miscarriage, stillbirth, or major congenital anomalies. A one-stage IPD meta-analysis was done by use of shared-frailty Cox models. This study is registered with PROSPERO, number CRD42015032371. Findings We identified seven eligible studies that included 12 cohorts. All 12 cohorts contributed IPD, including 34 178 pregnancies, 737 with confirmed first-trimester exposure to ABTs and 1076 with confirmed first-trimester exposure to non-ABTs. Adverse pregnancy outcomes occurred in 42 (5·7%) of 736 ABT-exposed pregnancies compared with 96 (8·9%) of 1074 non-ABT-exposed pregnancies in the first trimester (adjusted hazard ratio [aHR] 0·71, 95% CI 0·49–1·03). Similar results were seen for the individual components of miscarriage (aHR=0·74, 0·47–1·17), stillbirth (aHR=0·71, 0·32–1·57), and major congenital anomalies (aHR=0·60, 0·13–2·87). The risk of adverse pregnancy outcomes was lower with artemether–lumefantrine than with oral quinine in the first trimester of pregnancy (25 [4·8%] of 524 vs 84 [9·2%] of 915; aHR 0·58, 0·36–0·92). Interpretation We found no evidence of embryotoxicity or teratogenicity based on the risk of miscarriage, stillbirth, or major congenital anomalies associated with ABT during the first trimester of pregnancy. Given that treatment with artemether–lumefantrine was associated with fewer adverse pregnancy outcomes than quinine, and because of the known superior tolerability and antimalarial effectiveness of ACTs, artemether–lumefantrine should be considered the preferred treatment for uncomplicated P falciparum malaria in the first trimester. If artemether–lumefantrine is unavailable, other ACTs (except artesunate–sulfadoxine–pyrimethamine) should be preferred to quinine. Continued active pharmacovigilance is warranted

Paludisme, Femmes Enceintes et Risques pour les Enfants

info:eu-repo/semantics/publishe

Optimal use of routinely collected data among pregnant women to improve malaria surveillance in Burkina Faso: Contribution of Bayesian spatiotemporal modelling

Background: The control of malaria in pregnancy remains a large challenge in Burkina Faso, despite the adoption of control measures known to be effective. Known effective programs include individual measures, such as intermittent preventive treatment during pregnancy, and the use of long lasting insecticide nets and daily supplementation of ferrous sulphate (200 mg) along with folic acid. Besides these measures, health programs that aim at enhancing the well-being of the population and improve maternal and child health have emerged, including results-based financing (in 2014), a project promoting health in 130 communities (implemented in 2015), and free health care (implemented in 2016). This thesis attempts to assess the effects of health programs on the space–time patterns of malaria (morbidity and mortality) through routinely collected data in pregnancy and explore the various prediction approaches to address challenges in routine health data reporting. Methods: We utilized a substantial range of data and applied advanced quantitative approaches while considering the specific distribution of the data. Our thesis is based on the valorization (analyses) of malaria surveillance data (aggregated by space and time units) recorded in the health information system of Burkina Faso between 2011 and 2019. These analyses also integrate environmental remote sensing data, data from periodic surveys, and data from other sources. These data were coupled into a database. After performing appropriate descriptive analyses considering the complexity of the data design, we performed spatio-temporal Bayesian modeling to determine areas with high risk and assess the effect of health programs on the space–time patterns of malaria incidence among pregnant women at the community-level; to explore an approach to estimate health facility readiness from survey data designed to be regionally representative (and then quantify the effect of this readiness on severe-malaria cases and case fatality); and to explore the prediction approaches used to address challenges in routine health data reporting, thereby supporting a malaria early warning system. Results: Our results show spatial and temporal heterogeneity and indicate that the annual incidence of malaria increased between 2013 and 2018, while the mortality rate decreased significantly. Some communities with a high malaria burden experienced a reduction in their risk through the deployment of the health programs mentioned above. The risk of a pregnant woman dying from severe malaria was 2.5 times higher in districts with low operational capacity. Finally, our thesis proposed an approach to respond to crisis situations that would affect data collection and could be used to set the target or provide early warnings for epidemics or other notifications. Conclusion: Our thesis provides useful tools for disease surveillance in developing countries to help optimize the scarce resources in malaria high burden areas. The results of our thesis could be used by the Ministry of Health to strengthen the capacity of existing surveillance tools and to develop rational strategies and/or new tools for monitoring malaria cases and associated deaths in communities.Contexte :La lutte contre le paludisme pendant la grossesse reste un grand défi au Burkina Faso, malgré l'adoption de mesures de contrôle dont l'efficacité est reconnue. Les programmes dont l'efficacité est reconnue comprennent des mesures individuelles, telles que le traitement préventif intermittent pendant la grossesse, l'utilisation de moustiquaires imprégnées d'insecticide de longue durée et la supplémentation quotidienne en sulfate ferreux (200 mg) ainsi qu'en acide folique. Outre ces mesures, des programmes de santé visant à accroître le bien-être de la population et à améliorer la santé maternelle et infantile ont vu le jour, notamment le financement basé sur les résultats (en 2014), le projet de promotion de la santé dans 130 communes (mis en œuvre en 2015) et la gratuité des soins de santé (mise en œuvre en 2016). Cette thèse tente d'évaluer les effets des programmes de santé sur les caractéristiques spatio-temporelles du paludisme (morbidité et mortalité) par le biais de données de routine collectées pendant la grossesse et d'explorer les différentes approches de prévision pour relever les défis de la rapportage systématique des données de santé. Méthodes :Nous avons utilisé un large éventail de données et appliqué des approches quantitatives avancées tout en tenant compte de la distribution spécifique des données. Notre thèse est basée sur la valorisation (analyses) des données de surveillance du paludisme (agrégées par unités spatiales et temporelles) enregistrées dans le système d'information sanitaire du Burkina Faso entre 2011 et 2019. Ces analyses intègrent également des données de télédétection environnementale, des données issues d'enquêtes périodiques et des données provenant d'autres sources. Ces données ont été couplées pour constituer une base de données. Après avoir effectué des analyses descriptives appropriées en tenant compte de la complexité de la conception des données, nous avons procédé à une modélisation bayésienne spatio-temporelle pour déterminer les zones à haut risque et évaluer l'effet des programmes de santé sur les tendances spatio-temporelles de l'incidence du paludisme chez les femmes enceintes au niveau communautaire ;pour explorer une approche permettant d'estimer la capacité opérationnelle des établissements de santé à partir de données d'enquête conçues pour être représentatives au niveau régional (et ensuite quantifier l'effet de cette capacité opérationnelle sur les cas de paludisme grave et la mortalité) ;et pour explorer les approches de prévision utilisées pour relever les défis relatifs au rapportaga systématique des données de santé, pouvant aussi servir à un système d'alerte précoce du paludisme. Résultats :Nos résultats montrent une hétérogénéité spatiale et temporelle et indiquent que l'incidence annuelle du paludisme a augmenté entre 2013 et 2018, tandis que le taux de mortalité a diminué de manière significative. Certaines communes où la charge du paludisme est élevée ont connu une réduction de leur risque grâce au déploiement des programmes de santé mentionnés ci-dessus. Le risque qu'une femme enceinte meure d'un paludisme grave était 2,5 fois plus élevé dans les districts ayant une faible capacité opérationnelle. Enfin, notre thèse a proposé une approche pour répondre aux situations de crise qui affecterait la collecte de données et pourrait être utilisée pour fixer l'objectif ou fournir des alertes précoces pour les épidémies ou autres notifications. Conclusion :Notre thèse fournit des outils utiles pour la surveillance des maladies dans les pays en développement afin de contribuer à optimiser les ressources limitées dans les zones à forte incidence de paludisme. Les résultats de notre thèse pourraient être utilisés par le ministère de la santé pour renforcer la capacité des outils de surveillance existants et pour développer des stratégies rationnelles et/ou de nouveaux outils de surveillance des cas de paludisme et des décès associés dans les communautés.Doctorat en Sciences de la santé Publiqueinfo:eu-repo/semantics/nonPublishe

How to Estimate Optimal Malaria Readiness Indicators at Health-District Level: Findings from the Burkina Faso Service Availability and Readiness Assessment (SARA) Data

One of the major contributors of malaria-related deaths in Sub-Saharan African countries is the limited accessibility to quality care. In these countries, malaria control activities are implemented at the health-district level (operational entity of the national health system), while malaria readiness indicators are regionally representative. This study provides an approach for estimating health district-level malaria readiness indicators from survey data designed to provide regionally representative estimates. A binomial-hierarchical Bayesian spatial prediction method was applied to Burkina Faso Service Availability and Readiness Assessment (SARA) survey data to provide estimates of essential equipment availability and readiness for malaria care. Predicted values of each indicator were adjusted by the type of health facility, location, and population density. Then, a health district composite readiness profile was built via hierarchical ascendant classification. All surveyed health-facilities were mandated by the Ministry of Health to manage malaria cases. The spatial distribution of essential equipment and malaria readiness was heterogeneous. Around 62.9% of health districts had a high level of readiness to provide malaria care and prevention during pregnancy. Low-performance scores for managing malaria cases were found in big cities. Health districts with low coverage for both first-line antimalarial drugs and rapid diagnostic tests were Baskuy, Bogodogo, Boulmiougou, Nongr-Massoum, Sig-Nonghin, Dafra, and Do. We provide health district estimates and reveal gaps in basic equipment and malaria management resources in some districts that need to be filled. By providing local-scale estimates, this approach could be replicated for other types of indicators to inform decision makers and health program managers and to identify priority areas

Addressing challenges in routine health data reporting in Burkina Faso through Bayesian spatiotemporal prediction of weekly clinical malaria incidence

Abstract Sub-Saharan African (SSA) countries’ health systems are often vulnerable to unplanned situations that can hinder their effectiveness in terms of data completeness and disease control. For instance, in Burkina Faso following a workers' strike, comprehensive data on several diseases were unavailable for a long period in 2019. Weather, seasonal-malaria-chemoprevention (SMC), free healthcare, and other contextual data, which are purported to influence malarial disease, provide opportunities to fit models to describe the clinical malaria data and predict the disease spread. Bayesian spatiotemporal modeling was applied to weekly malaria surveillance data from Burkina Faso (2011–2018) while considering the effects of weather, health programs and contextual factors. Then, a prediction was used to deal with weekly missing data for the entire year of 2019, and SMC and free healthcare effects were quantified. Our proposed model accurately predicted weekly clinical malaria incidence (correlation coefficient, r = 0.90). The distribution of clinical malaria incidence was heterogeneous across the country. Overall, national predicted clinical malaria incidence in 2019 (605 per 1000 [95% CrI: 360–990]) increased by 24.7% compared with the year 2015. SMC and the interaction between free healthcare and health facility attendance were associated with a reduction in clinical malaria incidence. Our modeling approach could be a useful tool for strengthening health systems’ resilience by addressing data completeness and could support SSA countries in developing appropriate targets and indicators to facilitate the subnational control effort.info:eu-repo/semantics/publishe

Caractérisation de la sécurité d’usage des médicaments chez la femme enceinte au Burkina Faso :Utilisation de la classification US FDA et AU TGA

0info:eu-repo/semantics/nonPublishe

Incidence of adverse drug reactions resulting from the use of Amodiaquine-Artesunate in Nanoro, Burkina Faso

0info:eu-repo/semantics/nonPublishe