Publications by authors named "Teun Bousema"

243 Publications

Infectivity of patent Plasmodium falciparum gametocyte carriers to mosquitoes: establishing capacity to investigate the infectious reservoir of malaria in a low-transmission setting in The Gambia.

Trans R Soc Trop Med Hyg 2021 Jun 9. Epub 2021 Jun 9.

Department of Infection Biology, London School of Hygiene & Tropical Medicine, Keppel Street, WC1E 7HT, London, UK.

Background: Understanding the human malaria infectious reservoir is important for elimination initiatives. Here, we implemented mosquito membrane feeding experiments to prepare for larger studies to quantify the transmission potential and relative contribution of the human infectious reservoir.

Methods: Patients with clinical malaria attending four health facilities with at least 16 Plasmodium falciparum gametocytes per μL were recruited during the 2018 transmission season. Infectiousness to mosquitoes was assessed by direct membrane feeding assay (DMFA). We compared our results with a Bayesian predictive model to investigate the relationship between infectiousness and gametocyte density and explore the impact of fever on gametocyte infectivity.

Results: A total of 3177 suspected malaria cases were screened; 43.3% (1376) had microscopically patent P. falciparum parasites and 3.6% (114) of them had gametocytes. Out of 68 DMFAs, 38 (55.9%) resulted in at least one infected mosquito, with a total of 15.4% (1178/7667) of mosquitoes infected with 1-475 oocysts per gut. The relationship between mosquito infection prevalence and gametocytaemia was similar to other African settings and negatively associated with fever (OR: 0.188, 95% CI 0.0603 to 0.585, p=0.0039).

Conclusions: Among symptomatic malaria patients, fever is strongly associated with transmission failure. Future studies can use DMFA to better understand the human malaria reservoir in settings of low endemicity in The Gambia and inform malaria elimination initiatives.
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http://dx.doi.org/10.1093/trstmh/trab087DOI Listing
June 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

An open dataset of genome variation in 7,000 worldwide samples.

Wellcome Open Res 2021 24;6:42. Epub 2021 Feb 24.

Medical Research Council Unit The Gambia, at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed.  Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.
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http://dx.doi.org/10.12688/wellcomeopenres.16168.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008441PMC
February 2021

Gametocyte carriage after seasonal malaria chemoprevention in Plasmodium falciparum infected asymptomatic children.

Malar J 2021 Mar 26;20(1):169. Epub 2021 Mar 26.

Disease Control and Elimination Theme, Medical Research Council Unit The Gambia At London, School of Hygiene and Tropical Medicine, P.O Box 273, Banjul, The Gambia.

Background: Treatment of clinical Plasmodium falciparum malaria with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) is associated with increased post-treatment gametocyte carriage. The effect of seasonal malaria chemoprevention (SMC) with SP and AQ on gametocyte carriage was assessed in asymptomatic P. falciparum infected children.

Methods: The study was carried out in eastern Gambia. Asymptomatic P. falciparum malaria infected children aged 24-59 months old who were eligible to receive SMC (SMC group) and children 5-8 years that were not eligible to receive SMC (comparison group) were recruited. Gametocytaemia was determined by molecular methods before and after SMC administration. Gametocyte carriage between the groups was compared using the chi-squared test and within-person using conditional logistic regression.

Results: During the 2017 and 2018 malaria transmission seasons, 65 and 75 children were recruited in the SMC and comparison groups, respectively. Before SMC administration, gametocyte prevalence was 10.7% (7/65) in the SMC group and 13.3% (10/75) in the comparison group (p = 0.64). At day 13 (IQR 12, 13) after SMC administration, this was 9.4% (5/53) in children who received at least the first dose of SMC treatment and 12.7% (9/71) for those in the comparison group (p = 0.57). Similarly, there was no difference in prevalence of gametocytes between children that adhered to all 3-day doses of SMC treatment 15.6% (5/32) and those in the comparison group (p = 0.68). In the SMC group, within-group gametocyte carriage was similar before and after SMC administration in children that received at least the first dose of SMC treatment (OR 0.6, 95% CI 0.14-2.51; p = 0.48) and in those that adhered to all 3-day doses of SMC treatment (OR 1.0, 95% CI 0.20-4.95; p = 1.0).

Conclusion: In this study with relative low gametocyte prevalence prior to SMC treatment, no evidence was observed that SMC treatment increased gametocyte carriage in asymptomatic P. falciparum malaria infected children.
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http://dx.doi.org/10.1186/s12936-021-03706-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995796PMC
March 2021

Infection Manager System (IMS) as a new hemocytometry-based bacteremia detection tool: A diagnostic accuracy study in a malaria-endemic area of Burkina Faso.

PLoS Negl Trop Dis 2021 Mar 1;15(3):e0009187. Epub 2021 Mar 1.

Nijmegen Institute of International Health, Radboudumc, Nijmegen, the Netherlands.

Background: New hemocytometric parameters can be used to differentiate causes of acute febrile illness (AFI). We evaluated a software algorithm-Infection Manager System (IMS)-which uses hemocytometric data generated by Sysmex hematology analyzers, for its accuracy to detect bacteremia in AFI patients with and without malaria in Burkina Faso. Secondary aims included comparing the accuracy of IMS with C-reactive protein (CRP) and procalcitonin (PCT).

Methods: In a prospective observational study, patients of ≥ three-month-old (range 3 months- 90 years) presenting with AFI were enrolled. IMS, blood culture and malaria diagnostics were done upon inclusion and additional diagnostics on clinical indication. CRP, PCT, viral multiplex PCR on nasopharyngeal swabs and bacterial- and malaria PCR were batch-tested retrospectively. Diagnostic classification was done retrospectively using all available data except IMS, CRP and PCT results.

Findings: A diagnosis was affirmed in 549/914 (60.1%) patients and included malaria (n = 191) bacteremia (n = 69), viral infections (n = 145), and malaria-bacteremia co-infections (n = 47). The overall sensitivity, specificity, and negative predictive value (NPV) of IMS for detection of bacteremia in patients of ≥ 5 years were 97.0% (95% CI: 89.8-99.6), 68.2% (95% CI: 55.6-79.1) and 95.7% (95% CI: 85.5-99.5) respectively, compared to 93.9% (95% CI: 85.2-98.3), 39.4% (95% CI: 27.6-52.2), and 86.7% (95% CI: 69.3-96.2) for CRP at ≥20mg/L. The sensitivity, specificity and NPV of PCT at 0.5 ng/ml were lower at respectively 72.7% (95% CI: 60.4-83.0), 50.0% (95% CI: 37.4-62.6) and 64.7% (95% CI: 50.1-77.6) The diagnostic accuracy of IMS was lower among malaria cases and patients <5 years but remained equal to- or higher than the accuracy of CRP.

Interpretation: IMS is a new diagnostic tool to differentiate causes of AFI. Its high NPV for bacteremia has the potential to improve antibiotic dispensing practices in healthcare facilities with hematology analyzers. Future studies are needed to evaluate whether IMS, combined with malaria diagnostics, may be used to rationalize antimicrobial prescription in malaria endemic areas.

Trial Registration: ClinicalTrials.gov (NCT02669823) https://clinicaltrials.gov/ct2/show/NCT02669823.
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http://dx.doi.org/10.1371/journal.pntd.0009187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951874PMC
March 2021

Antibody Responses to Crude Gametocyte Extract Predict Gametocyte Carriage in Kenya.

Front Immunol 2020 3;11:609474. Epub 2021 Feb 3.

Department of Biosciences, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya.

Background: Malaria caused by remains a serious global public health challenge especially in Africa. Interventions that aim to reduce malaria transmission by targeting the gametocyte reservoir are key to malaria elimination and/or eradication. However, factors that are associated with gametocyte carriage have not been fully explored. Consequently, identifying predictors of the infectious reservoir is fundamental in the elimination campaign.

Methods: We cultured NF54 gametocytes (to stage V) and prepared crude gametocyte extract. Samples from a total of 687 participants (aged 6 months to 67 years) representing two cross-sectional study cohorts in Kilifi, Kenya were used to assess IgG antibody responses by ELISA. We also analyzed IgG antibody responses to the blood-stage antigen AMA1 as a marker of asexual parasite exposure. Gametocytemia and asexual parasitemia data quantified by microscopy and molecular detection (QT-NASBA) were used to determine the relationship with antibody responses, season, age, and transmission setting. Multivariable logistic regression models were used to study the association between antibody responses and gametocyte carriage. The predictive power of the models was tested using the receiver operating characteristic (ROC) curve.

Results: Multivariable logistic regression analysis showed that IgG antibody response to crude gametocyte extract predicted both microscopic (OR=1.81 95% CI: 1.06-3.07, =0.028) and molecular (OR=1.91, 95% CI: 1.11-3.29, =0.019) gametocyte carriage. Antibody responses to AMA1 were also associated with both microscopic (OR=1.61 95% CI: 1.08-2.42, =0.020) and molecular (OR=3.73 95% CI: 2.03-6.74, <0.001) gametocytemia. ROC analysis showed that molecular (AUC=0.897, 95% CI: 0.868-0.926) and microscopic (AUC=0.812, 95% CI: 0.758-0.865) multivariable models adjusted for gametocyte extract showed very high predictive power. Molecular (AUC=0.917, 95% CI: 0.891-0.943) and microscopic (AUC=0.806, 95% CI: 0.755-0.858) multivariable models adjusted for AMA1 were equally highly predictive.

Conclusion: In our study, it appears that IgG responses to crude gametocyte extract are not an independent predictor of gametocyte carriage after adjusting for AMA1 responses but may predict gametocyte carriage as a proxy marker of exposure to parasites. Serological responses to AMA1 or to gametocyte extract may facilitate identification of individuals within populations who contribute to malaria transmission and support implementation of transmission-blocking interventions.
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http://dx.doi.org/10.3389/fimmu.2020.609474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902058PMC
February 2021

Within-household clustering of genetically related Plasmodium falciparum infections in a moderate transmission area of Uganda.

Malar J 2021 Feb 2;20(1):68. Epub 2021 Feb 2.

Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Background: Evaluation of genetic relatedness of malaria parasites is a useful tool for understanding transmission patterns, but patterns are not easily detectable in areas with moderate to high malaria transmission. To evaluate the feasibility of detecting genetic relatedness in a moderate malaria transmission setting, relatedness of Plasmodium falciparum infections was measured in cohort participants from randomly selected households in the Kihihi sub-county of Uganda (annual entomological inoculation rate of 27 infectious bites per person).

Methods: All infections detected via microscopy or Plasmodium-specific loop mediated isothermal amplification from passive and active case detection during August 2011-March 2012 were genotyped at 26 microsatellite loci, providing data for 349 samples from 230 participants living in 80 households. Pairwise genetic relatedness was calculated using identity by state (IBS).

Results: As expected, genetic diversity was high (mean heterozygosity [H] = 0.73), and the majority (76.5 %) of samples were polyclonal. Despite the high genetic diversity, fine-scale population structure was detectable, with significant spatiotemporal clustering of highly related infections. Although the difference in malaria incidence between households at higher (mean 1127 metres) versus lower elevation (mean 1015 metres) was modest (1.4 malaria cases per person-year vs. 1.9 per person-year, respectively), there was a significant difference in multiplicity of infection (2.2 vs. 2.6, p = 0.008) and, more strikingly, a higher proportion of highly related infections within households (6.3 % vs. 0.9 %, p = 0.0005) at higher elevation compared to lower elevation.

Conclusions: Genetic data from a relatively small number of diverse, multiallelic loci reflected fine scale patterns of malaria transmission. Given the increasing interest in applying genetic data to augment malaria surveillance, this study provides evidence that genetic data can be used to inform transmission patterns at local spatial scales even in moderate transmission areas.
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http://dx.doi.org/10.1186/s12936-021-03603-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042884PMC
February 2021

Anopheles stephensi Mosquitoes as Vectors of Plasmodium vivax and falciparum, Horn of Africa, 2019.

Emerg Infect Dis 2021 02;27(2):603-607

Anopheles stephensi mosquitoes, efficient vectors in parts of Asia and Africa, were found in 75.3% of water sources surveyed and contributed to 80.9% of wild-caught Anopheles mosquitoes in Awash Sebat Kilo, Ethiopia. High susceptibility of these mosquitoes to Plasmodium falciparum and vivax infection presents a challenge for malaria control in the Horn of Africa.
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http://dx.doi.org/10.3201/eid2702.200019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853561PMC
February 2021

The epidemiology and detectability of asymptomatic plasmodium vivax and plasmodium falciparum infections in low, moderate and high transmission settings in Ethiopia.

Malar J 2021 Jan 22;20(1):59. Epub 2021 Jan 22.

Malaria and Neglected Tropical Diseases Directorate, Armauer Hansen Research Institute, PO Box 1005, Addis Ababa, Ethiopia.

Background: As countries move to malaria elimination, detecting and targeting asymptomatic malaria infections might be needed. Here, the epidemiology and detectability of asymptomatic Plasmodium falciparum and Plasmodium vivax infections were investigated in different transmission settings in Ethiopia.

Method: A total of 1093 dried blood spot (DBS) samples were collected from afebrile and apparently healthy individuals across ten study sites in Ethiopia from 2016 to 2020. Of these, 862 were from community and 231 from school based cross-sectional surveys. Malaria infection status was determined by microscopy or rapid diagnostics tests (RDT) and 18S rRNA-based nested PCR (nPCR). The annual parasite index (API) was used to classify endemicity as low (API > 0 and < 5), moderate (API ≥ 5 and < 100) and high transmission (API ≥ 100) and detectability of infections was assessed in these settings.

Results: In community surveys, the overall prevalence of asymptomatic Plasmodium infections by microscopy/RDT, nPCR and all methods combined was 12.2% (105/860), 21.6% (183/846) and 24.1% (208/862), respectively. The proportion of nPCR positive infections that was detectable by microscopy/RDT was 48.7% (73/150) for P. falciparum and 4.6% (2/44) for P. vivax. Compared to low transmission settings, the likelihood of detecting infections by microscopy/RDT was increased in moderate (Adjusted odds ratio [AOR]: 3.4; 95% confidence interval [95% CI] 1.6-7.2, P = 0.002) and high endemic settings (AOR = 5.1; 95% CI 2.6-9.9, P < 0.001). After adjustment for site and correlation between observations from the same survey, the likelihood of detecting asymptomatic infections by microscopy/RDT (AOR per year increase = 0.95, 95% CI 0.9-1.0, P = 0.013) declined with age.

Conclusions: Conventional diagnostics missed nearly half of the asymptomatic Plasmodium reservoir detected by nPCR. The detectability of infections was particularly low in older age groups and low transmission settings. These findings highlight the need for sensitive diagnostic tools to detect the entire parasite reservoir and potential infection transmitters.
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http://dx.doi.org/10.1186/s12936-021-03587-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821398PMC
January 2021

Persistence of mRNA indicative of Plasmodium falciparum ring-stage parasites 42 days after artemisinin and non-artemisinin combination therapy in naturally infected Malians.

Malar J 2021 Jan 9;20(1):34. Epub 2021 Jan 9.

Global Health Group, Malaria Elimination Initiative, University of California, San Francisco, CA, USA.

Background: Malaria control in sub-Saharan Africa relies upon prompt case management with artemisinin-based combination therapy (ACT). Ring-stage parasite mRNA, measured by sbp1 quantitative reverse-transcriptase PCR (qRT-PCR), was previously reported to persist after ACT treatment and hypothesized to reflect temporary arrest of the growth of ring-stage parasites (dormancy) following exposure to artemisinins. Here, the persistence of ring-stage parasitaemia following ACT and non-ACT treatment was examined.

Methods: Samples were used from naturally infected Malian gametocyte carriers who received dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP-AQ) with or without gametocytocidal drugs. Gametocytes and ring-stage parasites were quantified by qRT-PCR during 42 days of follow-up.

Results: At baseline, 89% (64/73) of participants had measurable ring-stage parasite mRNA. Following treatment, the proportion of ring-stage parasite-positive individuals and estimated densities declined for all four treatment groups. Ring-stage parasite prevalence and density was generally lower in arms that received DP compared to SP-AQ. This finding was most apparent days 1, 2, and 42 of follow-up (p < 0.01). Gametocytocidal drugs did not influence ring-stage parasite persistence. Ring-stage parasite density estimates on days 14 and 28 after initiation of treatment were higher among individuals who subsequently experienced recurrent parasitaemia compared to those who remained free of parasites until day 42 after initiation of treatment (p = 0.011 and p = 0.068). No association of ring-stage persistence with gametocyte carriage was observed.

Conclusions: The current findings of lower ring-stage persistence after ACT without an effect of gametocytocidal partner drugs affirms the use of sbp1 as ring-stage marker. Lower persistence of ring-stage mRNA after ACT treatment suggests the marker may not reflect dormant parasites whilst it was predictive of re-appearance of parasitaemia.
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http://dx.doi.org/10.1186/s12936-020-03576-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797096PMC
January 2021

Spatial-temporal patterns of malaria incidence in Uganda using HMIS data from 2015 to 2019.

BMC Public Health 2020 Dec 14;20(1):1913. Epub 2020 Dec 14.

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

Background: As global progress to reduce malaria transmission continues, it is increasingly important to track changes in malaria incidence rather than prevalence. Risk estimates for Africa have largely underutilized available health management information systems (HMIS) data to monitor trends. This study uses national HMIS data, together with environmental and geographical data, to assess spatial-temporal patterns of malaria incidence at facility catchment level in Uganda, over a recent 5-year period.

Methods: Data reported by 3446 health facilities in Uganda, between July 2015 and September 2019, was analysed. To assess the geographic accessibility of the health facilities network, AccessMod was employed to determine a three-hour cost-distance catchment around each facility. Using confirmed malaria cases and total catchment population by facility, an ecological Bayesian conditional autoregressive spatial-temporal Poisson model was fitted to generate monthly posterior incidence rate estimates, adjusted for caregiver education, rainfall, land surface temperature, night-time light (an indicator of urbanicity), and vegetation index.

Results: An estimated 38.8 million (95% Credible Interval [CI]: 37.9-40.9) confirmed cases of malaria occurred over the period, with a national mean monthly incidence rate of 20.4 (95% CI: 19.9-21.5) cases per 1000, ranging from 8.9 (95% CI: 8.7-9.4) to 36.6 (95% CI: 35.7-38.5) across the study period. Strong seasonality was observed, with June-July experiencing highest peaks and February-March the lowest peaks. There was also considerable geographic heterogeneity in incidence, with health facility catchment relative risk during peak transmission months ranging from 0 to 50.5 (95% CI: 49.0-50.8) times higher than national average. Both districts and health facility catchments showed significant positive spatial autocorrelation; health facility catchments had global Moran's I = 0.3 (p < 0.001) and districts Moran's I = 0.4 (p < 0.001). Notably, significant clusters of high-risk health facility catchments were concentrated in Acholi, West Nile, Karamoja, and East Central - Busoga regions.

Conclusion: Findings showed clear countrywide spatial-temporal patterns with clustering of malaria risk across districts and health facility catchments within high risk regions, which can facilitate targeting of interventions to those areas at highest risk. Moreover, despite high and perennial transmission, seasonality for malaria incidence highlights the potential for optimal and timely implementation of targeted interventions.
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http://dx.doi.org/10.1186/s12889-020-10007-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737387PMC
December 2020

Identification of main malaria vectors and their insecticide resistance profile in internally displaced and indigenous communities in Eastern Democratic Republic of the Congo (DRC).

Malar J 2020 Nov 23;19(1):425. Epub 2020 Nov 23.

Laboratory of Entomology, Wageningen University and Research, Wageningen, The Netherlands.

Background: Malaria remains a major public health concern in the Democratic Republic of the Congo (DRC) and its control is affected by recurrent conflicts. Médecins Sans Frontières (MSF) initiated several studies to better understand the unprecedented incidence of malaria to effectively target and implement interventions in emergency settings. The current study evaluated the main vector species involved in malaria transmission and their resistance to insecticides, with the aim to propose the most effective tools and strategies for control of local malaria vectors.

Methods: This study was performed in 52 households in Shamwana (Katanga, 2014), 168 households in Baraka (South Kivu, 2015) and 269 households in Kashuga (North Kivu, 2017). Anopheles vectors were collected and subjected to standardized Word Health Organization (WHO) and Center for Disease Control (CDC) insecticide susceptibility bioassays. Mosquito species determination was done using PCR and Plasmodium falciparum infection in mosquitoes was assessed by ELISA targeting circumsporozoite protein.

Results: Of 3517 Anopheles spp. mosquitoes collected, Anopheles gambiae sensu lato (s.l.) (29.6%) and Anopheles funestus (69.1%) were the main malaria vectors. Plasmodium falciparum infection rates for An. gambiae s.l. were 1.0, 2.1 and 13.9% for Shamwana, Baraka and Kashuga, respectively. Anopheles funestus showed positivity rates of 1.6% in Shamwana and 4.4% in Baraka. No An. funestus were collected in Kashuga. Insecticide susceptibility tests showed resistance development towards pyrethroids in all locations. Exposure to bendiocarb, malathion and pirimiphos-methyl still resulted in high mosquito mortality.

Conclusions: This is one of only few studies from these conflict areas in DRC to report insecticide resistance in local malaria vectors. The data suggest that current malaria prevention methods in these populations are only partially effective, and require additional tools and strategies. Importantly, the results triggered MSF to consider the selection of a new insecticide for indoor residual spraying (IRS) and a new long-lasting insecticide-treated net (LLIN). The reinforcement of correct usage of LLINs and the introduction of targeted larviciding were also included as additional vector control tools as a result of the studies.
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http://dx.doi.org/10.1186/s12936-020-03497-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684733PMC
November 2020

Mass Drug Administration With High-Dose Ivermectin and Dihydroartemisinin-Piperaquine for Malaria Elimination in an Area of Low Transmission With High Coverage of Malaria Control Interventions: Protocol for the MASSIV Cluster Randomized Clinical Trial.

JMIR Res Protoc 2020 Nov 19;9(11):e20904. Epub 2020 Nov 19.

Medical Research Council Unit Gambia, London School of Hygiene and Tropical Medicine, Banjul, Gambia.

Background: With a decline in malaria burden, innovative interventions and tools are required to reduce malaria transmission further. Mass drug administration (MDA) of artemisinin-based combination therapy (ACT) has been identified as a potential tool to further reduce malaria transmission, where coverage of vector control interventions is already high. However, the impact is limited in time. Combining an ACT with an endectocide treatment that is able to reduce vector survival, such as ivermectin (IVM), could increase the impact of MDA and offer a new tool to reduce malaria transmission.

Objective: The study objective is to evaluate the impact of MDA with IVM plus dihydroartemisinin-piperaquine (DP) on malaria transmission in an area with high coverage of malaria control interventions.

Methods: The study is a cluster randomized trial in the Upper River Region of The Gambia and included 32 villages (16 control and 16 intervention). A buffer zone of ~2 km was created around all intervention clusters. MDA with IVM plus DP was implemented in all intervention villages and the buffer zones; control villages received standard malaria interventions according to the Gambian National Malaria Control Program plans.

Results: The MDA campaigns were carried out from August to October 2018 for the first year and from July to September 2019 for the second year. Statistical analysis will commence once the database is completed, cleaned, and locked.

Conclusions: This is the first cluster randomized clinical trial of MDA with IVM plus DP. The results will provide evidence on the impact of MDA with IVM plus DP on malaria transmission.

Trial Registration: ClinicalTrials.gov NCT03576313; https://clinicaltrials.gov/ct2/show/NCT03576313.

International Registered Report Identifier (irrid): DERR1-10.2196/20904.
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http://dx.doi.org/10.2196/20904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714640PMC
November 2020

Spatial and genetic clustering of Plasmodium falciparum and Plasmodium vivax infections in a low-transmission area of Ethiopia.

Sci Rep 2020 11 17;10(1):19975. Epub 2020 Nov 17.

Armauer Hansen Research Institute, PO Box 1005, Addis Ababa, Ethiopia.

The distribution of malaria infections is heterogeneous in space and time, especially in low transmission settings. Understanding this clustering may allow identification and targeting of pockets of transmission. In Adama district, Ethiopia, Plasmodium falciparum and P. vivax malaria patients and controls were examined, together with household members and immediate neighbors. Rapid diagnostic test and quantitative PCR (qPCR) were used for the detection of infections that were genetically characterized by a panel of microsatellite loci for P. falciparum (26) and P. vivax (11), respectively. Individuals living in households of clinical P. falciparum patients were more likely to have qPCR detected P. falciparum infections (22.0%, 9/41) compared to individuals in control households (8.7%, 37/426; odds ratio, 2.9; 95% confidence interval, 1.3-6.4; P = .007). Genetically related P. falciparum, but not P. vivax infections showed strong clustering within households. Genotyping revealed a marked temporal cluster of P. falciparum infections, almost exclusively comprised of clinical cases. These findings uncover previously unappreciated transmission dynamics and support a rational approach to reactive case detection strategies for P. falciparum in Ethiopia.
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http://dx.doi.org/10.1038/s41598-020-77031-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672087PMC
November 2020

Quantifying Plasmodium falciparum infections clustering within households to inform household-based intervention strategies for malaria control programs: An observational study and meta-analysis from 41 malaria-endemic countries.

PLoS Med 2020 10 29;17(10):e1003370. Epub 2020 Oct 29.

MRC Tropical Epidemiology Group, London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: Reactive malaria strategies are predicated on the assumption that individuals infected with malaria are clustered within households or neighbourhoods. Despite the widespread programmatic implementation of reactive strategies, little empirical evidence exists as to whether such strategies are appropriate and, if so, how they should be most effectively implemented.

Methods And Findings: We collated 2 different datasets to assess clustering of malaria infections within households: (i) demographic health survey (DHS) data, integrating household information and patent malaria infection, recent fever, and recent treatment status in children; and (ii) data from cross-sectional and reactive detection studies containing information on the household and malaria infection status (patent and subpatent) of all-aged individuals. Both datasets were used to assess the odds of infections clustering within index households, where index households were defined based on whether they contained infections detectable through one of 3 programmatic strategies: (a) Reactive Case Detection (RACD) classifed by confirmed clinical cases, (b) Mass Screen and Treat (MSAT) classifed by febrile, symptomatic infections, and (c) Mass Test and Treat (MTAT) classifed by infections detectable using routine diagnostics. Data included 59,050 infections in 208,140 children under 7 years old (median age = 2 years, minimum = 2, maximum = 7) by microscopy/rapid diagnostic test (RDT) from 57 DHSs conducted between November 2006 and December 2018 from 23 African countries. Data representing 11,349 infections across all ages (median age = 22 years, minimum = 0.5, maximum = 100) detected by molecular tools in 132,590 individuals in 43 studies published between April 2006 and May 2019 in 20 African, American, Asian, and Middle Eastern countries were obtained from the published literature. Extensive clustering was observed-overall, there was a 20.40 greater (95% credible interval [CrI] 0.35-20.45; P < 0.001) odds of patent infections (according to the DHS data) and 5.13 greater odds (95% CI 3.85-6.84; P < 0.001) of molecularly detected infections (from the published literature) detected within households in which a programmatically detectable infection resides. The strongest degree of clustering identified by polymerase chain reaction (PCR)/ loop mediated isothermal amplification (LAMP) was observed using the MTAT strategy (odds ratio [OR] = 6.79, 95% CI 4.42-10.43) but was not significantly different when compared to MSAT (OR = 5.2, 95% CI 3.22-8.37; P-difference = 0.883) and RACD (OR = 4.08, 95% CI 2.55-6.53; P-difference = 0.29). Across both datasets, clustering became more prominent when transmission was low. However, limitations to our analysis include not accounting for any malaria control interventions in place, malaria seasonality, or the likely heterogeneity of transmission within study sites. Clustering may thus have been underestimated.

Conclusions: In areas where malaria transmission is peri-domestic, there are programmatic options for identifying households where residual infections are likely to be found. Combining these detection strategies with presumptively treating residents of index households over a sustained time period could contribute to malaria elimination efforts.
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http://dx.doi.org/10.1371/journal.pmed.1003370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595326PMC
October 2020

Sex-based differences in clearance of chronic infection.

Elife 2020 10 27;9. Epub 2020 Oct 27.

Department of Medicine, University of California San Francisco, San Francisco, United States.

Multiple studies have reported a male bias in incidence and/or prevalence of malaria infection in males compared to females. To test the hypothesis that sex-based differences in host-parasite interactions affect the epidemiology of malaria, we intensively followed infections in a cohort in a malaria endemic area of eastern Uganda and estimated both force of infection (FOI) and rate of clearance using amplicon deep-sequencing. We found no evidence of differences in behavioral risk factors, incidence of malaria, or FOI by sex. In contrast, females cleared asymptomatic infections at a faster rate than males (hazard ratio [HR]=1.82, 95% CI 1.20 to 2.75 by clone and HR = 2.07, 95% CI 1.24 to 3.47 by infection event) in multivariate models adjusted for age, timing of infection onset, and parasite density. These findings implicate biological sex-based differences as an important factor in the host response to this globally important pathogen.
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http://dx.doi.org/10.7554/eLife.59872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591246PMC
October 2020

Chloroquine Potentiates Primaquine Activity against Active and Latent Hepatic Plasmodia : Potentials and Pitfalls.

Antimicrob Agents Chemother 2020 12 16;65(1). Epub 2020 Dec 16.

Sorbonne Université, INSERM, CNRS, INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, Paris, France.

For a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of , , , and within several systems-primary hepatocytes of , primary human hepatocytes, and stably transformed human hepatocarcinoma cell line HepG2. Primaquine exposures to formed hepatic schizonts and hypnozoites of in primary simian hepatocytes exhibited similar 50% inhibitory concentration (IC) values near 0.4 μM, whereas chloroquine in the same system exhibited no inhibitory activities. Combining chloroquine and primaquine in this system decreased the observed primaquine IC for all parasite forms in a chloroquine dose-dependent manner by an average of 18-fold. Chloroquine also decreased the primaquine IC against hepatic in primary human hepatocytes, in simian primary hepatocytes, and in primary human hepatocytes. Chloroquine had no impact on primaquine IC against in HepG2 cells and, likewise, had no impact on the IC of atovaquone (hepatic schizontocide) against in human hepatocytes. We describe important sources of variability in the potentiation of primaquine activity by chloroquine in these systems. Chloroquine potentiated primaquine activity against hepatic forms of several plasmodia. We conclude that chloroquine specifically potentiated 8-aminoquinoline activities against active and dormant hepatic-stage plasmodia in normal primary hepatocytes but not in a hepatocarcinoma cell line.
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http://dx.doi.org/10.1128/AAC.01416-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927800PMC
December 2020

Reducing the Carbon Footprint of Academic Conferences: The Example of the American Society of Tropical Medicine and Hygiene.

Am J Trop Med Hyg 2020 11;103(5):1758-1761

Clinton Health Access Initiative, Boston, Massachusetts.

We calculated carbon emissions associated with air travel of 4,834 participants at the 2019 annual conference of the American Society of Tropical Medicine and Hygiene (ASTMH). Together, participants traveled a total of 27.7 million miles or 44.6 million kilometers. This equates to 58 return trips to the moon. Estimated carbon dioxide equivalent (COe) emissions were 8,646 metric tons or the total weekly carbon footprint of approximately 9,366 average American households. These emissions contribute to climate change and thus may exacerbate many of the global diseases that conference attendees seek to combat. Options to reduce conference travel-associated emissions include 1) alternating in-person and online conferences, 2) offering a hybrid in-person/online conference, and 3) decentralizing the conference with multiple conference venues. Decentralized ASTMH conferences may allow for up to 64% reduction in travel distance and 58% reduction in COe emissions. Given the urgency of the climate crisis and the clear association between global warming and global health, ways to reduce carbon emissions should be considered.
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http://dx.doi.org/10.4269/ajtmh.20-1013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646750PMC
November 2020

Antibody Therapy Goes to Insects: Monoclonal Antibodies Can Block Plasmodium Transmission to Mosquitoes.

Trends Parasitol 2020 11 6;36(11):880-883. Epub 2020 Oct 6.

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Malaria eradication is a global priority but requires innovative strategies. Humoral immune responses attack different parasite stages, and antibody-based therapy may prevent malaria infection or transmission. Here, we discuss targets of monoclonal antibodies in mosquito sexual stages of Plasmodium.
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http://dx.doi.org/10.1016/j.pt.2020.08.009DOI Listing
November 2020

How the COVID-19 pandemic highlights the necessity of animal research.

Curr Biol 2020 09 10;30(18):R1014-R1018. Epub 2020 Aug 10.

Maastricht University, 6211 LK Maastricht, The Netherlands.

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health.
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http://dx.doi.org/10.1016/j.cub.2020.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416712PMC
September 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

A mosquito feeding assay to examine Plasmodium transmission to mosquitoes using small blood volumes in 3D printed nano-feeders.

Parasit Vectors 2020 Aug 8;13(1):401. Epub 2020 Aug 8.

Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Background: To understand the dynamics of malaria transmission, membrane feeding assays with glass feeders are used to assess the transmission potential of malaria infected individuals to mosquitoes. However, in some circumstances, use of these assays is hindered by both the blood volume requirement and the availability of fragile, specially crafted glass feeders. 3D printed plastic feeders that require very small volumes of blood would thus expand the utility of membrane feeding assays.

Methods: Using two 3D printing production methods, MultiJet (MJ) and Digital Light Processing (DLP), we developed a plastic version of the most commonly used standard glass feeder (the mini-feeder) with an improved design, and also a smaller feeder requiring only 60 µl of blood (the nano-feeder). Performance of the 3D printed feeders was compared to standard glass mini-feeders by assessing infectivity of gametocytes to mosquitoes in standard membrane feeding assays with laboratory reared Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. In addition, the optimum number of mosquitoes that can feed on the nano-feeder was determined by evaluating fully fed mosquitoes visually and by assessing blood- meal volume with a colorimetric haemoglobin assay.

Results: The 3D printing methods allowed quick and inexpensive production of durable feeders. Infectivity of gametocytes to mosquitoes was comparable for MJ and DLP 3D printed feeders and glass feeders, and the performance of the 3D printed feeders was not influenced by repeated washing with bleach. There was no loss in transmission efficiency when the feeder size was reduced from mini-feeder to nano-feeder, and blood-meal volume assessment indicated ~10 An. stephensi mosquitoes can take a full blood-meal (median volume 3.44 µl) on a nano-feeder.

Conclusions: Here we present 3D printed mini- and nano-feeders with comparable performance to the currently used glass mini-feeders. These feeders do not require specialized glass craftsmanship, making them easily accessible. Moreover, the smaller nano-feeders will enable evaluation of smaller blood volumes that can be collected from finger prick, thus expanding the utility of membrane feeding assays and facilitating a more thorough evaluation of the human infectious reservoir for malaria.
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http://dx.doi.org/10.1186/s13071-020-04269-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414548PMC
August 2020

Malaria Transmission, Infection, and Disease following Sustained Indoor Residual Spraying of Insecticide in Tororo, Uganda.

Am J Trop Med Hyg 2020 10;103(4):1525-1533

Department of Medicine, University of California San Francisco, San Francisco, California.

Tororo, a district in Uganda with historically high malaria transmission intensity, has recently scaled up control interventions, including universal long-lasting insecticidal net distribution in 2013 and 2017, and sustained indoor residual spraying (IRS) of insecticide since December 2014. We describe the burden of malaria in Tororo 5 years following the initiation of IRS. We followed a cohort of 531 participants from 80 randomly selected households in Nagongera subcounty, Tororo district, from October 2017 to October 2019. Mosquitoes were collected every 2 weeks using CDC light traps in all rooms where participants slept, symptomatic malaria was identified by passive surveillance, and microscopic and submicroscopic parasitemia were measured every 4 weeks using active surveillance. Over the 2 years of follow-up, 15,780 female anopheline mosquitos were collected, the majority (98.0%) of which were . The daily human biting rate was 2.07, and the annual entomological inoculation rate was 0.43 infective bites/person/year. Only 38 episodes of malaria were diagnosed (incidence 0.04 episodes/person/year), and there were no cases of severe malaria or malarial deaths. The prevalence of microscopic parasitemia was 1.9%, and the combined prevalence of microscopic and submicroscopic parasitemia was 10.4%, each highest in children aged 5-15 years (3.3% and 14.0%, respectively). After 5 years of intensive vector control measures in Tororo, the burden of malaria was reduced to very low transmission levels. However, a significant proportion of the population remained parasitemic, primarily school-aged children with submicroscopic parasitemia, providing a potential reservoir for malaria transmission.
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http://dx.doi.org/10.4269/ajtmh.20-0250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543828PMC
October 2020

Optimizing RTS,S Vaccination Strategies: Give It Your Best Parting Shot.

J Infect Dis 2020 10;222(10):1581-1584

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

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http://dx.doi.org/10.1093/infdis/jiaa423DOI Listing
October 2020

Reply to Gautret et al: hydroxychloroquine sulfate and azithromycin for COVID-19: what is the evidence and what are the risks?

Int J Antimicrob Agents 2020 Jul 13;56(1):106056. Epub 2020 Jul 13.

Department of Medical Microbiology & Radboudumc Center for Infectious Diseases, the Netherlands. Electronic address:

The severity of COVID-19 has resulted in a global rush to find the right antiviral treatment to conquer the pandemic and to treat patients. This requires reliable studies to support treatment. In a recently published study by Gautret et al. the authors concluded that hydroxychloroquine monotherapy and hydroxychloroquine in combination with azithromycin reduced viral load. However, this trial has several major methodological issues, including the design, outcome measure and the statistical analyses. In this paper we discuss the background, clinical evidence, pharmacology and methodological issues related to this clinical trial. We understand the rush to release results, however in case conclusions are far reaching the evidence needs to be robust.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357524PMC
July 2020

When Is a Plasmodium-Infected Mosquito an Infectious Mosquito?

Trends Parasitol 2020 08 1;36(8):705-716. Epub 2020 Jul 1.

Department of Molecular Microbiology and Immunology, and Johns Hopkins Malaria Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

Plasmodium parasites experience significant bottlenecks as they transit through the mosquito and are transmitted to their mammalian host. Oocyst prevalence on mosquito midguts and sporozoite prevalence in salivary glands are nevertheless commonly used to confirm successful malaria transmission, assuming that these are reliable indicators of the mosquito's capacity to give rise to secondary infections. Here we discuss recent insights in sporogonic development and transmission bottlenecks for Plasmodium. We highlight critical gaps in our knowledge and frame their importance in understanding the human and mosquito reservoirs of infection. A better understanding of the events that lead to successful inoculation of infectious sporozoites by mosquitoes is critical to designing effective interventions to shrink the malaria map.
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http://dx.doi.org/10.1016/j.pt.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386819PMC
August 2020