Publications by authors named "Alfred Tiono"

100 Publications

Safety and immunogenicity of Vi-typhoid conjugate vaccine co-administration with routine 9-month vaccination in Burkina Faso: A randomized controlled phase 2 trial.

Int J Infect Dis 2021 Jul 1;108:465-472. Epub 2021 Jun 1.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Objectives: In 2017, the World Health Organisation (WHO) pre-qualified a single-dose typhoid conjugate vaccine (TCV) and identified TCV co-administration studies as a research priority. Accordingly, we tested co-administration of Typbar TCV® (Bharat Biotech International) with measles-rubella (MR) and yellow fever (YF) vaccines.

Methods: We conducted a randomized, double-blind, and controlled, phase 2 trial in Ouagadougou, Burkina Faso. Healthy children aged 9-11 months were randomized 1:1 to receive TCV (Group 1) or control vaccine (inactivated polio vaccine (IPV), Group 2). Vaccines were administered intramuscularly with routine MR and YF vaccines. Safety was assessed by (1) local and systemic reactions on days 0, 3, and 7; (2) unsolicited adverse events within 28 days; and (3) serious adverse events (SAEs) within six months after immunization.

Results: We enrolled, randomized, and vaccinated 100 eligible children (49 Group 1 and 51 Group 2). Safety outcomes occurred with similar frequency in both groups: local/solicited reactions (Group 1: 1/49, Group 2: 3/50), systemic/solicited reactions (Group 1: 4/49, Group 2: 9/50), unsolicited adverse events (Group 1: 26/49, Group 2: 33/51), and SAEs (Group 1: 2/49, Group 2: 3/51). TCV conferred robust immunogenicity without interference with MR or YF vaccines.

Conclusion: TCV can be safely co-administered with MR and YF vaccines to children at the 9-month vaccination visit.
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http://dx.doi.org/10.1016/j.ijid.2021.05.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298254PMC
July 2021

A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria.

Malar J 2021 May 19;20(1):222. Epub 2021 May 19.

Kenya Medical Research Institute, Kisumu, Kenya.

Background: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia.

Methods: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored.

Results: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures.

Conclusion: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.
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http://dx.doi.org/10.1186/s12936-021-03749-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135182PMC
May 2021

Prevalence and predictors of vitamin D deficiency in young African children.

BMC Med 2021 May 20;19(1):115. Epub 2021 May 20.

Kenya Medical Research Institute (KEMRI) Centre for Geographic Medicine Coast, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

Background: Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children.

Methods: We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0-8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses.

Results: Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants.

Conclusions: Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa.
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http://dx.doi.org/10.1186/s12916-021-01985-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136043PMC
May 2021

Higher gametocyte production and mosquito infectivity in chronic compared to incident Plasmodium falciparum infections.

Nat Commun 2021 04 26;12(1):2443. Epub 2021 Apr 26.

Radboud Institute for Health Sciences and Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.

Plasmodium falciparum gametocyte kinetics and infectivity may differ between chronic and incident infections. In the current study, we assess parasite kinetics and infectivity to mosquitoes among children (aged 5-10 years) from Burkina Faso with (a) incident infections following parasite clearance (n = 48) and (b) chronic asymptomatic infections (n = 60). In the incident infection cohort, 92% (44/48) of children develop symptoms within 35 days, compared to 23% (14/60) in the chronic cohort. All individuals with chronic infection carried gametocytes or developed them during follow-up, whereas only 35% (17/48) in the incident cohort produce gametocytes before becoming symptomatic and receiving treatment. Parasite multiplication rate (PMR) and the relative abundance of ap2-g and gexp-5 transcripts are positively associated with gametocyte production. Antibody responses are higher and PMR lower in chronic infections. The presence of symptoms and sexual stage immune responses are associated with reductions in gametocyte infectivity to mosquitoes. We observe that most incident infections require treatment before the density of mature gametocytes is sufficient to infect mosquitoes. In contrast, chronic, asymptomatic infections represent a significant source of mosquito infections. Our observations support the notion that malaria transmission reduction may be expedited by enhanced case management, involving both symptom-screening and infection detection.
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http://dx.doi.org/10.1038/s41467-021-22573-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076179PMC
April 2021

G6PD Polymorphisms and Hemolysis After Antimalarial Treatment With Low Single-Dose Primaquine: A Pooled Analysis of Six African Clinical Trials.

Front Genet 2021 9;12:645688. Epub 2021 Apr 9.

Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Primaquine (PQ) is an antimalarial drug with the potential to reduce malaria transmission due to its capacity to clear mature gametocytes in the human host. However, the large-scale roll-out of PQ has to be counterbalanced by the additional risk of drug-induced hemolysis in individuals suffering from Glucose-6-phospate dehydrogenase (G6PD) deficiency, a genetic condition determined by polymorphisms on the X-linked gene. Most studies on G6PD deficiency and PQ-associated hemolysis focused on the G6PD A- variant, a combination of the two single nucleotide changes G202A (rs1050828) and A376G (rs1050829), although other polymorphisms may play a role. In this study, we tested the association of 20 G6PD single nucleotide polymorphisms (SNPs) with hemolysis measured seven days after low single dose of PQ given at the dose of 0.1 mg/kg to 0.75 mg/kg in 957 individuals from 6 previously published clinical trials investigating the safety and efficacy of this drug spanning five African countries. After adjusting for inter-study effects, age, gender, baseline hemoglobin level, PQ dose, and parasitemia at screening, our analysis showed putative association signals from the common G6PD mutation, A376G [-log(-value) = 2.44] and two less-known SNPs, rs2230037 [-log(-value] = 2.60), and rs28470352 [-log(-value) = 2.15]; A376G and rs2230037 were in very strong linkage disequilibrium with each other ( = 0.978). However, when the effects of these SNPs were included in the same regression model, the subsequent associations were in the borderline of statistical significance. In conclusion, whilst a role for the A- variant is well established, we did not observe an important additional role for other G6PD polymorphisms in determining post-treatment hemolysis in individuals treated with low single-dose PQ.
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http://dx.doi.org/10.3389/fgene.2021.645688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062977PMC
April 2021

Maintaining Plasmodium falciparum gametocyte infectivity during blood collection and transport for mosquito feeding assays in the field.

Malar J 2021 Apr 20;20(1):191. Epub 2021 Apr 20.

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Mosquito feeding assays using venous blood are commonly used for evaluating the transmission potential of malaria infected individuals. To improve the accuracy of these assays, care must be taken to prevent premature activation or inactivation of gametocytes before they are fed to mosquitoes. This can be challenging in the field where infected individuals and insectary facilities are sometimes very far apart. In this study, a simple, reliable, field applicable method is presented for storage and transport of gametocyte infected blood using a thermos flask.

Methods: The optimal storage conditions for maintaining the transmissibility of gametocytes were determined initially using cultured Plasmodium falciparum gametocytes in standard membrane feeding assays (SMFAs). The impact of both the internal thermos water temperature (35.5 to 37.8 °C), and the external environmental temperature (room temperature to 42 °C) during long-term (4 h) storage, and the impact of short-term (15 min) temperature changes (room temp to 40 °C) during membrane feeding assays was assessed. The optimal conditions were then evaluated in direct membrane feeding assays (DMFAs) in Burkina Faso and The Gambia where blood from naturally-infected gametocyte carriers was offered to mosquitoes immediately and after storage in thermos flasks.

Results: Using cultured gametocytes in SMFAs it was determined that an internal thermos water temperature of 35.5 °C and storage of the thermos flask between RT (~ 21.3 °C) and 32 °C was optimal for maintaining transmissibility of gametocytes for 4 h. Short-term storage of the gametocyte infected blood for 15 min at temperatures up to 40 °C (range: RT, 30 °C, 38 °C and 40 °C) did not negatively affect gametocyte infectivity. Using samples from natural gametocyte carriers (47 from Burkina Faso and 16 from The Gambia), the prevalence of infected mosquitoes and the intensity of oocyst infection was maintained when gametocyte infected blood was stored in a thermos flask in water at 35.5 °C for up to 4 h.

Conclusions: This study determines the optimal long-term (4 h) storage temperature for gametocyte infected blood and the external environment temperature range within which gametocyte infectivity is unaffected. This will improve the accuracy, reproducibility, and utility of DMFAs in the field, and permit reliable comparative assessments of malaria transmission epidemiology in different settings.
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http://dx.doi.org/10.1186/s12936-021-03725-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056727PMC
April 2021

Malaria is a cause of iron deficiency in African children.

Nat Med 2021 04 22;27(4):653-658. Epub 2021 Feb 22.

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.
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http://dx.doi.org/10.1038/s41591-021-01238-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610676PMC
April 2021

Protocol for a quasi-experimental study to assess the feasibility, acceptability and costs of multiple first-lines artemisinin-based combination therapies for uncomplicated malaria in the Kaya health district, Burkina Faso.

BMJ Open 2021 02 15;11(2):e040220. Epub 2021 Feb 15.

Département Biomédical et Santé Publique, Groupe de Recherche Action en Sante (GRAS), Ouagadougou, Burkina Faso.

Introduction: As demonstrated in mathematical models, the simultaneous deployment of multiple first-line therapies (MFT) for uncomplicated malaria, using artemisinin-based combination therapies (ACTs), may extend the useful therapeutic life of the current ACTs. This is possible by reducing drug pressure and slowing the spread of resistance without putting patients' life at risk. We hypothesised that a simultaneous deployment of three different ACTs is feasible, acceptable and can achieve high coverage rate if potential barriers are properly identified and addressed.

Methods And Analysis: We plan to conduct a quasi-experimental study in the Kaya health district in Burkina Faso. We will investigate a simultaneous deployment of three ACTs, artemether-lumefantrine, pyronaridine-artesunate, dihydroartesinin-piperaquine, targeting three segments of the population: pregnant women, children under five and individuals aged five years and above. The study will include four overlapping phases: the formative phase, the MFT deployment phase, the monitoring and evaluation phase and the post-evaluation phase. The formative phase will help generate baseline information and develop MFT deployment tools. It will be followed by the MFT deployment phase in the study area. The monitoring and evaluation phase will be conducted as the deployment of MFT progresses. Cross-sectional surveys including desk reviews as well as qualitative and quantitative research methods will be used to assess the study outcomes. Quantitatives study outcomes will be measured using univariate, bivariate and multivariate analysis, including logistic regression and interrupted time series analysis approach. Content analysis will be performed on the qualitative data.

Ethics And Dissemination: The Health Research Ethics Committee in Burkina Faso approved the study (Clearance no. 2018-8-113). Study findings will be disseminated through feedback meetings with local communities, national workshops, oral presentations at congresses, seminars and publications in peer-reviewed scientific journals.

Trial Registration Number: NCT04265573.
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http://dx.doi.org/10.1136/bmjopen-2020-040220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887347PMC
February 2021

Safety and immunogenicity of co-administration of meningococcal type A and measles-rubella vaccines with typhoid conjugate vaccine in children aged 15-23 months in Burkina Faso.

Int J Infect Dis 2021 Jan 8;102:517-523. Epub 2020 Nov 8.

Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address:

Objectives: The World Health Organization pre-qualified single-dose typhoid conjugate vaccine (TCV) and requested data on co-administration with routine vaccines. The co-administration of Typbar TCV (Bharat Biotech International) with routine group A meningococcal conjugate vaccine (MCV-A) and measles-rubella (MR) vaccine was tested.

Methods: This was a double-blind, randomized controlled trial performed in Ouagadougou, Burkina Faso. Children were recruited at the 15-month vaccination visit and were assigned randomly (1:1:1) to three groups. Group 1 children received TCV plus control vaccine (inactivated polio vaccine) and MCV-A 28 days later; group 2 children received TCV and MCV-A; group 3 children received MCV-A and control vaccine. Routine MR vaccine was administered to all participants. Safety was assessed at 0, 3, and 7 days after immunization, and unsolicited adverse events and serious adverse events were assessed for 28 days and 6 months after immunization, respectively.

Results: A total of 150 children were recruited and vaccinated. Solicited symptoms were infrequent and similar for TCV and control recipients, as were adverse events (group 1, 61.2%; group 2, 64.0%; group 3, 68.6%) and serious adverse events (group 1, 2.0%; group 2, 8.0%; group 3, 5.9%). TCV generated robust immunity without interference with MCV-A vaccine.

Conclusions: TCV can be safely co-administered at 15 months with MCV-A without interference. This novel study on the co-administration of TCV with MCV-A provides data to support large-scale uptake in sub-Saharan Africa.
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http://dx.doi.org/10.1016/j.ijid.2020.10.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762715PMC
January 2021

A cohort study to identify risk factors for Plasmodium falciparum infection in Burkinabe children: implications for other high burden high impact countries.

Malar J 2020 Oct 16;19(1):371. Epub 2020 Oct 16.

Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool, UK.

Background: Progress in controlling malaria has stalled in recent years. Today the malaria burden is increasingly concentrated in a few countries, including Burkina Faso, where malaria is not declining. A cohort study was conducted to identify risk factors for malaria infection in children in southwest Burkina Faso, an area with high insecticide-treated net (ITN) coverage and insecticide-resistant vectors.

Methods: Incidence of Plasmodium falciparum infection was measured in 252 children aged 5 to 15 years, using active and passive detection, during the 2017 transmission season, following clearance of infection. Demographic, socio-economic, environmental, and entomological risk factors, including use of ITNs and insecticide resistance were monitored.

Results: During the six-month follow-up period, the overall incidence of P. falciparum infection was 2.78 episodes per child (95% CI = 2.66-2.91) by microscopy, and 3.11 (95% CI = 2.95-3.28) by polymerase chain reaction (PCR). The entomological inoculation rate (EIR) was 80.4 infective bites per child over the six-month malaria transmission season. At baseline, 80.6% of children were reported as sleeping under an ITN the previous night, although at the last survey, 23.3% of nets were in poor condition and considered no longer protective. No association was found between the rate of P. falciparum infection and either EIR (incidence rate ratio (IRR): 1.00, 95% CI: 1.00-1.00, p = 0.08) or mortality in WHO tube tests when vectors were exposed to 0.05% deltamethrin (IRR: 1.05, 95% CI: 0.73-1.50, p = 0.79). Travel history (IRR: 1.52, 95% CI: 1.45-1.59, p < 0.001) and higher socio-economic status were associated with an increased risk of P. falciparum infection (IRR: 1.05, 95% CI: 1.00-1.11, p = 0.04).

Conclusions: Incidence of P. falciparum infection remains overwhelmingly high in the study area. The study findings suggest that because of the exceptionally high levels of malaria transmission in the study area, malaria elimination cannot be achieved solely by mass deployment of ITNs and additional control measures are needed.
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http://dx.doi.org/10.1186/s12936-020-03443-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565747PMC
October 2020

Integrative genomic analysis reveals mechanisms of immune evasion in P. falciparum malaria.

Nat Commun 2020 10 9;11(1):5093. Epub 2020 Oct 9.

Program in Biology, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi, UAE.

The mechanisms behind the ability of Plasmodium falciparum to evade host immune system are poorly understood and are a major roadblock in achieving malaria elimination. Here, we use integrative genomic profiling and a longitudinal pediatric cohort in Burkina Faso to demonstrate the role of post-transcriptional regulation in host immune response in malaria. We report a strong signature of miRNA expression differentiation associated with P. falciparum infection (127 out of 320 miRNAs, B-H FDR 5%) and parasitemia (72 miRNAs, B-H FDR 5%). Integrative miRNA-mRNA analysis implicates several infection-responsive miRNAs (e.g., miR-16-5p, miR-15a-5p and miR-181c-5p) promoting lymphocyte cell death. miRNA cis-eQTL analysis using whole-genome sequencing data identified 1,376 genetic variants associated with the expression of 34 miRNAs (B-H FDR 5%). We report a protective effect of rs114136945 minor allele on parasitemia mediated through miR-598-3p expression. These results highlight the impact of post-transcriptional regulation, immune cell death processes and host genetic regulatory control in malaria.
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http://dx.doi.org/10.1038/s41467-020-18915-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547729PMC
October 2020

Estimating Annual Fluctuations in Malaria Transmission Intensity and in the Use of Malaria Control Interventions in Five Sub-Saharan African Countries.

Am J Trop Med Hyg 2020 11;103(5):1883-1892

GSK, Wavre, Belgium.

RTS,S/AS01 malaria vaccine safety, effectiveness, and impact will be assessed in pre- and post-vaccine introduction studies, comparing the occurrence of malaria cases and adverse events in vaccinated versus unvaccinated children. Because those comparisons may be confounded by potential year-to-year fluctuations in malaria transmission intensity and malaria control intervention usage, the latter should be carefully monitored to adequately adjust the analyses. This observational cross-sectional study is assessing parasite prevalence (PR) and malaria control intervention usage over nine annual surveys performed at peak parasite transmission. parasite prevalence was measured by microscopy and nucleic acid amplification test (quantitative PCR) in parallel in all participants, and defined as the proportion of infected participants among participants tested. Results of surveys 1 (S1) and 2 (S2), conducted in five sub-Saharan African countries, including some participating in the Malaria Vaccine Implementation Programme (MVIP), are reported herein; 4,208 and 4,199 children were, respectively, included in the analyses. parasite prevalence estimated using microscopy varied between study sites in both surveys, with the lowest prevalence in Senegalese sites and the highest in Burkina Faso. In sites located in the MVIP areas (Kintampo and Kombewa), PR in children aged 6 months to 4 years ranged from 24.8% to 27.3%, depending on the study site and the survey. Overall, 89.5% and 86.4% of children used a bednet in S1 and S2, of whom 68.7% and 77.9% used impregnated bednets. No major difference was observed between the two surveys in terms of PR or use of malaria control interventions.
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http://dx.doi.org/10.4269/ajtmh.19-0795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646796PMC
November 2020

Efficacy of single dose primaquine with artemisinin combination therapy on P. falciparum gametocytes and transmission: A WWARN individual patient meta-analysis.

J Infect Dis 2020 Aug 11. Epub 2020 Aug 11.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

Background: Since the World Health Organization recommended single low-dose (0.25mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant P. falciparum, several single-site studies have been conducted to assess its efficacy.

Methods: An individual patient meta-analysis to assess the gametocytocidal and transmission-blocking efficacy of PQ used in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (i) gametocyte carriage in the first two weeks post-treatment; (ii) the probability of infecting at least one mosquito or of a mosquito becoming infected.

Results: In 2,574 participants from fourteen studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytaemia on day 0 (Odds Ratio (OR)=0.22; 95%CI 0.17-0.28 and OR=0.12; 95%CI 0.08-0.16, respectively). The rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (p=0.010 for day 7). Addition of 0.25mg/kg PQ was associated with near complete prevention of transmission to mosquitoes.

Conclusion: Primaquine's transmission-blocking effects are achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.
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http://dx.doi.org/10.1093/infdis/jiaa498DOI Listing
August 2020

Distance sampling for epidemiology: an interactive tool for estimating under-reporting of cases from clinic data.

Int J Health Geogr 2020 04 20;19(1):16. Epub 2020 Apr 20.

University of Glasgow, Institute of Biodiversity Animal Health and Comparative Medicine, Glasgow, UK.

Background: Distance sampling methods are widely used in ecology to estimate and map the abundance of animal and plant populations from spatial survey data. The key underlying concept in distance sampling is the detection function, the probability of detecting the occurrence of an event as a function of its distance from the observer, as well as other covariates that may influence detection. In epidemiology, the burden and distribution of infectious disease is often inferred from cases that are reported at clinics and hospitals. In areas with few public health facilities and low accessibility, the probability of detecting a case is also a function of the distance between an infected person and the "observer" (e.g. a health centre). While the problem of distance-related under-reporting is acknowledged in public health; there are few quantitative methods for assessing and correcting for this bias when mapping disease incidence. Here, we develop a modified version of distance sampling for prediction of infectious disease incidence by relaxing some of the framework's fundamental assumptions. We illustrate the utility of this approach using as our example malaria distribution in rural Burkina Faso, where there is a large population at risk but relatively low accessibility of health facilities.

Results: The modified distance-sampling framework was used to predict the probability of reporting malaria infection at 8 rural clinics, based on road-travel distances from villages. The rate at which reporting probability dropped with distance varied between clinics, depending on road and clinic positions. The probability of case detection was estimated as 0.3-1 in the immediate vicinity of the clinic, dropping to 0.1-0.6 at a travel distance of 10 km, and effectively zero at distances > 30-40 km.

Conclusions: To enhance the method's strategic impact, we provide an interactive mapping tool (as a self-contained R Shiny app) that can be used by non-specialists to interrogate model outputs and visualize how the overall probability of under-reporting and the catchment area of each clinic is influenced by changing the number and spatial allocation of health centres.
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http://dx.doi.org/10.1186/s12942-020-00209-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171748PMC
April 2020

Estimating the burden of iron deficiency among African children.

BMC Med 2020 02 27;18(1):31. Epub 2020 Feb 27.

Centre for Geographic Medicine Research-Coast, KEMRI-Wellcome Trust Research Programme, Kenya Medical Research Institute (KEMRI), Kilifi, Kenya.

Background: Iron deficiency (ID) is a major public health burden in African children and accurate prevalence estimates are important for effective nutritional interventions. However, ID may be incorrectly estimated in Africa because most measures of iron status are altered by inflammation and infections such as malaria. Through the current study, we have assessed different approaches to the prediction of iron status and estimated the burden of ID in African children.

Methods: We assayed iron and inflammatory biomarkers in 4853 children aged 0-8 years from Kenya, Uganda, Burkina Faso, South Africa, and The Gambia. We described iron status and its relationship with age, sex, inflammation, and malaria parasitemia. We defined ID using the WHO guideline (ferritin < 12 μg/L or < 30 μg/L in the presence of inflammation in children < 5 years old or < 15 μg/L in children ≥ 5 years old). We compared this with a recently proposed gold standard, which uses regression-correction for ferritin levels based on the relationship between ferritin levels, inflammatory markers, and malaria. We further investigated the utility of other iron biomarkers in predicting ID using the inflammation and malaria regression-corrected estimate as a gold standard.

Results: The prevalence of ID was highest at 1 year of age and in male infants. Inflammation and malaria parasitemia were associated with all iron biomarkers, although transferrin saturation was least affected. Overall prevalence of WHO-defined ID was 34% compared to 52% using the inflammation and malaria regression-corrected estimate. This unidentified burden of ID increased with age and was highest in countries with high prevalence of inflammation and malaria, where up to a quarter of iron-deficient children were misclassified as iron replete. Transferrin saturation < 11% most closely predicted the prevalence of ID according to the regression-correction gold standard.

Conclusions: The prevalence of ID is underestimated in African children when defined using the WHO guidelines, especially in malaria-endemic populations, and the use of transferrin saturation may provide a more accurate approach. Further research is needed to identify the most accurate measures for determining the prevalence of ID in sub-Saharan Africa.
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http://dx.doi.org/10.1186/s12916-020-1502-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045745PMC
February 2020

How delayed and non-adherent treatment contribute to onward transmission of malaria: a modelling study.

BMJ Glob Health 2019 10;4(6):e001856. Epub 2019 Dec 10.

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.

Introduction: Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated malaria. Its efficacy has been extensively assessed in clinical trials. In routine healthcare settings, however, its effectiveness can be diminished by delayed access to treatment and poor adherence. As well as affecting clinical outcomes, these factors can lead to increased transmission, which is the focus of this study.

Methods: We extend a within-host model of to include gametocytes, the parasite forms responsible for onward transmission. The model includes a pharmacokinetic-pharmacodynamic model of AL, calibrated against both immature and mature gametocytes using individual-level patient data, to estimate the impact that delayed access and imperfect adherence to treatment can have on onward transmission of the parasite to mosquitoes.

Results: Using survey data from seven African countries to determine the time taken to acquire antimalarials following fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-fold, compared with patients treated after 24 hours. Realistic adherence behaviour, based on data from a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold, compared with a perfectly-adherent cohort. This was driven largely by increased rates of treatment failure leading to chronic infection, rather than prolonged gametocytaemia in patients who have slower, but still successful, clearance of parasites after imperfect adherence to treatment. Our model estimated that the mean infectivity of untreated infections was 29-51 times higher than that of treated infections (assuming perfect drug adherence), underlining the importance of improving treatment coverage.

Conclusion: Using mathematical modelling, we quantify how delayed treatment and non-adherent treatment can increase transmission compared with prompt effective treatment. We also highlight that transmission from the large proportion of infections which never receive treatment is substantially higher than those treated.
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http://dx.doi.org/10.1136/bmjgh-2019-001856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936434PMC
December 2019

Plasmodium falciparum Gametocyte Density and Infectivity in Peripheral Blood and Skin Tissue of Naturally Infected Parasite Carriers in Burkina Faso.

J Infect Dis 2021 May;223(10):1822-1830

Radboud Institute for Health Sciences, Radboud University Medical Center, the Netherlands.

Background: Plasmodium falciparum transmission depends on mature gametocytes that can be ingested by mosquitoes taking a blood meal on human skin. Although gametocyte skin sequestration has long been hypothesized as important contributor to efficient malaria transmission, this has never been formally tested.

Methods: In naturally infected gametocyte carriers from Burkina Faso, we assessed infectivity to mosquitoes by direct skin feeding and membrane feeding. We directly quantified male and female gametocytes and asexual parasites in finger-prick and venous blood samples, skin biopsy samples, and in of mosquitoes that fed on venous blood or directly on skin. Gametocytes were visualized in skin tissue with confocal microscopy.

Results: Although more mosquitoes became infected when feeding directly on skin then when feeding on venous blood (odds ratio, 2.01; 95% confidence interval, 1.21-3.33; P = .007), concentrations of gametocytes were not higher in the subdermal skin vasculature than in other blood compartments; only sparse gametocytes were observed in skin tissue.

Discussion: Our data strongly suggest that there is no significant skin sequestration of P. falciparum gametocytes. Gametocyte densities in peripheral blood are thus informative for predicting onward transmission potential to mosquitoes and can be used to target and monitor malaria elimination initiatives.
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http://dx.doi.org/10.1093/infdis/jiz680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161640PMC
May 2021

Assessing the impact of the addition of pyriproxyfen on the durability of permethrin-treated bed nets in Burkina Faso: a compound-randomized controlled trial.

Malar J 2019 Dec 2;18(1):383. Epub 2019 Dec 2.

Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.

Background: Long-lasting insecticidal nets (LLINs) treated with pyrethroids are the foundation of malaria control in sub-Saharan Africa. Rising pyrethroid resistance in vectors, however, has driven the development of alternative net formulations. Here the durability of polyethylene nets with a novel combination of a pyrethroid, permethrin, and the insect juvenile hormone mimic, pyriproxyfen (PPF), compared to a standard permethrin LLIN, was assessed in rural Burkina Faso.

Methods: A compound-randomized controlled trial was completed in two villages. In one village 326 of the PPF-permethrin nets (Olyset Duo) and 327 standard LLINs (Olyset) were distributed to assess bioefficacy. In a second village, 170 PPF-permethrin nets and 376 LLINs were distributed to assess survivorship. Nets were followed at 6-monthly intervals for 3 years. Bioefficacy was assessed by exposing permethrin-susceptible and resistant Anopheles gambiae sensu lato mosquito strains to standard World Health Organization (WHO) cone and tunnel tests with impacts on fertility measured in the resistant strain. Insecticide content was measured using high-performance liquid chromatography. LLIN survivorship was recorded with a questionnaire and assessed by comparing the physical integrity using the proportionate hole index (pHI).

Results: The PPF-permethrin net met WHO bioefficacy criteria (≥ 80% mortality or ≥ 95% knockdown) for the first 18 months, compared to 6 months for the standard LLIN. Mean mosquito mortality for PPF-permethrin nets, across all time points, was 8.6% (CI 2.6-14.6%) higher than the standard LLIN. Fertility rates were reduced after PPF-permethrin net exposure at 1-month post distribution, but not later. Permethrin content of both types of nets remained within the target range of 20 g/kg ± 25% for 242/248 nets tested. The pyriproxyfen content of PPF-permethrin nets declined by 54%, from 10.4 g/kg (CI 10.2-10.6) to 4.7 g/kg (CI 3.5-6.0, p < 0.001) over 36 months. Net survivorship was poor, with only 13% of PPF-permethrin nets and 12% of LLINs still present in the original household after 36 months. There was no difference in the fabric integrity or survivorship between the two net types.

Conclusion: The PPF-permethrin net, Olyset Duo, met or exceeded the performance of the WHO-recommended standard LLIN (Olyset) in the current study but both net types failed the 3-year WHO bioefficacy criteria.
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http://dx.doi.org/10.1186/s12936-019-3018-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889366PMC
December 2019

Investigating the impact of enhanced community case management and monthly screening and treatment on the transmissibility of malaria infections in Burkina Faso: study protocol for a cluster-randomised trial.

BMJ Open 2019 09 13;9(9):e030598. Epub 2019 Sep 13.

Department of Biomedical Sciences, Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.

Introduction: A large proportion of malaria-infected individuals in endemic areas do not experience symptoms that prompt treatment-seeking. These asymptomatically infected individuals may retain their infections for many months during which sexual-stage parasites (gametocytes) are produced that may be transmissible to mosquitoes. Reductions in malaria transmission could be achieved by detecting and treating these infections early. This study assesses the impact of enhanced community case management (CCM) and monthly screening and treatment (MSAT) on the prevalence and transmissibility of malaria infections.

Methods And Analysis: This cluster-randomised trial will take place in Sapone, an area of intense, highly seasonal malaria in Burkina Faso. In total, 180 compounds will be randomised to one of three interventions: arm 1 - current standard of care with passively monitored malaria infections; arm 2 - standard of care plus enhanced CCM, comprising active weekly screening for fever, and detection and treatment of infections in fever positive individuals using conventional rapid diagnostic tests (RDTs); or arm 3 - standard of care and enhanced CCM, plus MSAT using RDTs. The study will be conducted over approximately 18 months covering two high-transmission seasons and the intervening dry season. The recruitment strategy aims to ensure that overall transmission and force of infection is not affected so we are able to continuously evaluate the impact of interventions in the context of ongoing intense malaria transmission. The main objectives of the study are to determine the impact of enhanced CCM and MSAT on the prevalence and density of parasitaemia and gametocytaemia and the transmissibility of infections. This will be achieved by molecular detection of infections in all study participants during start and end season cross-sectional surveys and routine sampling of malaria-positive individuals to assess their infectiousness to mosquitoes.

Ethics And Dissemination: The study has been reviewed and approved by the London School of Hygiene and Tropical Medicine (LSHTM) (Review number: 14724) and The Centre National de Recherche et de Formation sur le Paludisme institutional review board (IRB) (Deliberation N° 2018/000002/MS/SG/CNRFP/CIB) and Burkina Faso national medical ethics committees (Deliberation N° 2018-01-010).Findings of the study will be shared with the community via local opinion leaders and community meetings. Results may also be shared through conferences, seminars, reports, theses and peer-reviewed publications; disease occurrence data and study outcomes will be shared with the Ministry of Health. Data will be published in an online digital repository.

Trial Registration Number: NCT03705624.
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http://dx.doi.org/10.1136/bmjopen-2019-030598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747640PMC
September 2019

Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum.

Antimicrob Agents Chemother 2019 10 23;63(10). Epub 2019 Sep 23.

Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands

Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of after artemisinin combination therapy. Genetic variation in , the gene producing the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa ( = 1,076), we were able to genotype for 774 samples (72%). We determined whether genetic variation in has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration ( = 554) and for safety in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals treated with PQ ( = 110). Individuals with a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90];  = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 11.8 g/dl for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dl for CYP2D6 poor/intermediate metabolizers ( = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anemia following PQ treatment ( = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single-low-dose PQ but not with treatment safety.
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http://dx.doi.org/10.1128/AAC.00538-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761544PMC
October 2019

Functional antibodies against sporozoites are associated with a longer time to qPCR-detected infection among schoolchildren in Burkina Faso.

Wellcome Open Res 2018 1;3:159. Epub 2019 May 1.

Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK.

Individuals living in malaria-endemic regions develop immunity against severe malaria, but it is unclear whether immunity against pre-erythrocytic stages that blocks initiation of blood-stage infection after parasite inoculation develops following continuous natural exposure. We cleared schoolchildren living in an area (health district of Saponé, Burkina Faso) with highly endemic seasonal malaria of possible sub-patent infections and examined them weekly for incident infections by nested PCR. Plasma samples collected at enrolment were used to quantify antibodies to the pre-eryhrocytic-stage antigens circumsporozoite protein (CSP) and Liver stage antigen 1 (LSA-1). sporozoite gliding inhibition and hepatocyte invasion inhibition by naturally acquired antibodies were assessed using NF54 sporozoites. Associations between antibody responses, functional pre-erythrocytic immunity phenotypes and time to infection detected by quantitative PCR were studied. A total of 51 children were monitored. Anti-CSP antibody titres showed a positive association with sporozoite gliding motility inhibition (P<0.0001, Spearman's ρ=0.76). hepatocyte invasion was inhibited by naturally acquired antibodies (median inhibition, 19.4% [IQR 15.2-40.9%]), and there were positive correlations between invasion inhibition and gliding inhibition (P=0.005, Spearman's ρ=0.67) and between invasion inhibition and CSP-specific antibodies (P=0.002, Spearman's ρ=0.76). Survival analysis indicated longer time to infection in individuals displaying higher-than-median sporozoite gliding inhibition activity (P=0.01), although this association became non-significant after adjustment for blood-stage immunity (P = 0.06). In summary, functional antibodies against the pre-erythrocytic stages of malaria infection are acquired in children who are repeatedly exposed to parasites. This immune response does not prevent them from becoming infected during a malaria transmission season, but might delay the appearance of blood stage parasitaemia. Our approach could not fully separate the effects of pre-erythrocytic-specific and blood-stage-specific antibody-mediated immune responses ; epidemiological studies powered and designed to address this important question should become a research priority.
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http://dx.doi.org/10.12688/wellcomeopenres.14932.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381444PMC
May 2019

The temporal dynamics and infectiousness of subpatent Plasmodium falciparum infections in relation to parasite density.

Nat Commun 2019 03 29;10(1):1433. Epub 2019 Mar 29.

Department of Disease Control, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.
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http://dx.doi.org/10.1038/s41467-019-09441-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440965PMC
March 2019

A Phase II, Randomized, Double-blind, Controlled Safety and Immunogenicity Trial of Typhoid Conjugate Vaccine in Children Under 2 Years of Age in Ouagadougou, Burkina Faso: A Methods Paper.

Clin Infect Dis 2019 03;68(Suppl 2):S59-S66

Center for Vaccine Development and Global Health at the University of Maryland School of Medicine, Baltimore, MD.

The recent Typhoid Fever Surveillance in Africa Program demonstrated an overall adjusted incidence of typhoid fever 2-3 times higher than previous estimates in Africa. Recently, a single-dose typhoid conjugate vaccine that allows infants as young as 6 months old to be vaccinated was prequalified by the World Health Organization (WHO). This Vi-based conjugate vaccine demonstrated robust immunogenicity after 1 dose in infants and children 6 through 23 months of age in India with no safety signal, and is currently being tested for the first time on the African continent in Malawi. The WHO Strategic Advisory Group of Experts recommends studies to evaluate co-administering Vi-typhoid conjugate vaccine (Vi-TCV) with routine childhood vaccines in typhoid-endemic countries. The Burkina Faso immunization schedule includes yellow fever vaccine (YFV) at 9 months and meningococcal A conjugate vaccine (MCV-A) at 15 months, in addition to measles-rubella vaccine at both 9 and 15 months. Co-administration testing of Vi-TCV with these routine vaccinations will provide the data needed to support large-scale uptake of Vi-TCV in sub-Saharan Africa. A randomized, controlled, Phase II trial of Vi-TCV co-administration with the vaccinations routinely given at 9 and 15 months of age is planned in Burkina Faso. The overall aim is to assess the safety and immunogenicity of Vi-TCV when co-administered with YFV at 9 months of age and with MCV-A at 15 months of age. A total of 250 participants (100 infants aged 9-11 months and 150 children aged 15-23 months) will be enrolled. Clinical Trials Registration. NCT03614533.
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http://dx.doi.org/10.1093/cid/ciy1104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405275PMC
March 2019

Bead-based assays to simultaneously detect multiple human inherited blood disorders associated with malaria.

Malar J 2019 Jan 21;18(1):14. Epub 2019 Jan 21.

Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, UK.

Background: Glucose-6-phosphate dehydrogenase deficiency (G6PDd), haemoglobin C (HbC) and S (HbS) are inherited blood disorders (IBD) common in populations in malaria endemic areas. All are associated to some degree with protection against clinical malaria whilst additionally G6PDd is associated with haemolysis following treatment with 8-aminoquinolines. Measuring the prevalence of these inherited blood disorders in affected populations can improve understanding of disease epidemiology. Current methodologies in epidemiological studies commonly rely on individual target amplification and visualization; here a method is presented to simultaneously detect the polymorphisms and that can be expanded to include other single nucleotide polymorphisms (SNPs) of interest.

Methods: Human DNA from whole blood samples was amplified in a novel, multiplex PCR reaction and extended with SNP-specific probes in an allele specific primer extension (ASPE) to simultaneously detect four epidemiologically important human markers including G6PD SNPs (G202A and A376G) and common haemoglobin mutations (HbS and HbC). The products were hybridized to magnetic beads and the median fluorescence intensity (MFI) was read on MAGPIX (Luminex corp.). Genotyping data was compared to phenotypical data generated by flow cytometry and to established genotyping methods.

Results: Seventy-five samples from Burkina Faso (n = 75/78, 96.2%) and 58 samples from The Gambia (n = 58/61, 95.1%) had a G6PD and a HBB genotype successfully assigned by the bead-based assay. Flow cytometry data available for n = 61 samples further supported the concordance between % G6PD normal/deficient cells and genotype.

Conclusions: The bead based assay compares well to alternative measures of genotyping and phenotyping for G6PD. The screening is high throughput, adaptable to inclusion of multiple targets of interest and easily standardized.
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http://dx.doi.org/10.1186/s12936-019-2648-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341711PMC
January 2019

First field efficacy trial of the ChAd63 MVA ME-TRAP vectored malaria vaccine candidate in 5-17 months old infants and children.

PLoS One 2018 12;13(12):e0208328. Epub 2018 Dec 12.

Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso.

Background: Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified Vaccinia Virus Ankara (MVA) vectored vaccines is a strategy previously shown to provide substantial protective efficacy against P. falciparum infection in United Kingdom adult Phase IIa sporozoite challenge studies (approximately 20-25% sterile protection with similar numbers showing clear delay in time to patency), and greater point efficacy in a trial in Kenyan adults.

Methodology: We conducted the first Phase IIb clinical trial assessing the safety, immunogenicity and efficacy of ChAd63 MVA ME-TRAP in 700 healthy malaria exposed children aged 5-17 months in a highly endemic malaria transmission area of Burkina Faso.

Results: ChAd63 MVA ME-TRAP was shown to be safe and immunogenic but induced only moderate T cell responses (median 326 SFU/106 PBMC (95% CI 290-387)) many fold lower than in previous trials. No significant efficacy was observed against clinical malaria during the follow up period, with efficacy against the primary endpoint estimate by proportional analysis being 13.8% (95%CI -42.4 to 47.9) at sixth month post MVA ME-TRAP and 3.1% (95%CI -15.0 to 18.3; p = 0.72) by Cox regression.

Conclusions: This study has confirmed ChAd63 MVA ME-TRAP is a safe and immunogenic vaccine regimen in children and infants with prior exposure to malaria. But no significant protective efficacy was observed in this very highly malaria-endemic setting.

Trial Registration: ClinicalTrials.gov NCT01635647. Pactr.org PACTR201208000404131.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208328PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291132PMC
May 2019

Efficacy of Olyset Duo, a bednet containing pyriproxyfen and permethrin, versus a permethrin-only net against clinical malaria in an area with highly pyrethroid-resistant vectors in rural Burkina Faso: a cluster-randomised controlled trial.

Lancet 2018 08 10;392(10147):569-580. Epub 2018 Aug 10.

Department of Biosciences, Durham University, Durham, UK. Electronic address:

Background: Substantial reductions in malaria incidence in sub-Saharan Africa have been achieved with massive deployment of long-lasting insecticidal nets (LLINs), but pyrethroid resistance threatens control. Burkina Faso is an area with intense malaria transmission and highly pyrethroid-resistant vectors. We assessed the effectiveness of bednets containing permethrin, a pyrethroid, and pyriproxyfen, an insect growth regulator, versus permethrin-only (standard) LLINs against clinical malaria in children younger than 5 years in Banfora, Burkina Faso.

Methods: In this two-group, step-wedge, cluster-randomised, controlled, superiority trial, standard LLINs were incrementally replaced with LLINs treated with permethrin plus pyriproxyfen (PPF) in 40 rural clusters in Burkina Faso. In each cluster, 50 children (aged 6 months to 5 years) were followed up by passive case detection for clinical malaria. Cross-sectional surveys were done at the start and the end of the transmission seasons in 2014 and 2015. We did monthly collections from indoor light traps to estimate vector densities. Primary endpoints were the incidence of clinical malaria, measured by passive case detection, and the entomological inoculation rate. Analyses were adjusted for clustering and for month and health centre. This trial is registered as ISRCTN21853394.

Findings: 1980 children were enrolled in the cohort in 2014 and 2157 in 2015. At the end of the study, more than 99% of children slept under a bednet. The incidence of clinical malaria was 2·0 episodes per child-year in the standard LLIN group and 1·5 episodes per child-year in the PPF-treated LLIN group (incidence rate ratio 0·88 [95% CI 0·77-0·99; p=0·04]). The entomological inoculation rate was 85 (95% CI 63-108) infective bites per transmission season in the standard LLIN group versus 42 (32-52) infective bites per transmission season in the PPF-treated LLIN group (rate ratio 0·49, 95% CI 0·32-0·66; p<0·0001).

Interpretation: PPF-treated LLINs provide greater protection against clinical malaria than do standard LLINs and could be used as an alternative to standard LLINs in areas with intense transmission of Plasmodium falciparum malaria and highly pyrethroid-resistant vectors.

Funding: EU Seventh Framework Programme.
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http://dx.doi.org/10.1016/S0140-6736(18)31711-2DOI Listing
August 2018

Haemolysis and haem oxygenase-1 induction during persistent "asymptomatic" malaria infection in Burkinabé children.

Malar J 2018 Jul 6;17(1):253. Epub 2018 Jul 6.

Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, UK.

Background: The haemolysis associated with clinical episodes of malaria results in the liberation of haem, which activates the enzyme haem oxygenase-1 (HO-1). HO-1 has been shown to reduce neutrophil function and increase susceptibility to invasive bacterial disease. However, the majority of community-associated malaria infections are subclinical, often termed "asymptomatic" and the consequences of low-grade haemolysis during subclinical malaria infection are unknown.

Study Design And Results: As part of an ongoing study of subclinical malaria in Burkina Faso, 23 children with subclinical Plasmodium falciparum infections (determined by qPCR) were compared with 21 village-matched uninfected control children. Infected children showed evidence of persistent haemolysis over 35 days, with raised plasma haem and HO-1 concentrations. Concentrations of IL-10, which can also directly activate HO-1, were also higher in infected children compared to uninfected children. Regression analysis revealed that HO-1 was associated with haemolysis, but not with parasite density, anaemia or IL-10 concentration.

Conclusions: This study reveals that subclinical P. falciparum malaria infection is associated with sustained haemolysis and the induction of HO-1. Given the association between HO-1, neutrophil dysfunction and increased risk of Salmonella bacteraemia, prolonged HO-1 induction may explain epidemiological associations and geographic overlap between malaria and invasive bacterial disease. Further studies are needed to understand the consequences of persistent subclinical malaria infection, low-grade haemolysis and raised HO-1 on immune cell function and risk of comorbidities.
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http://dx.doi.org/10.1186/s12936-018-2402-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035425PMC
July 2018

Predicting the likelihood and intensity of mosquito infection from sex specific gametocyte density.

Elife 2018 05 31;7. Epub 2018 May 31.

Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

Understanding the importance of gametocyte density on human-to-mosquito transmission is of immediate relevance to malaria control. Previous work (Churcher et al., 2013) indicated a complex relationship between gametocyte density and mosquito infection. Here we use data from 148 feeding experiments on naturally infected gametocyte carriers to show that the relationship is much simpler and depends on both female and male parasite density. The proportion of mosquitoes infected is primarily determined by the density of female gametocytes though transmission from low gametocyte densities may be impeded by a lack of male parasites. Improved precision of gametocyte quantification simplifies the shape of the relationship with infection increasing rapidly before plateauing at higher densities. The mean number of oocysts per mosquito rises quickly with gametocyte density but continues to increase across densities examined. The work highlights the importance of measuring both female and male gametocyte density when estimating the human reservoir of infection.
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http://dx.doi.org/10.7554/eLife.34463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013255PMC
May 2018
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