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2. Live Attenuated Malaria Vaccine Designed to Protect Through Hepatic CD8⁺ T Cell Immunity

Author

Epstein, J. E., Tewari, K., Lyke, K. E., Sim, B. K. L., Billingsley, P. F., Laurens, M. B., Gunasekera, A., Chakravarty, S., James, E. R., Sedegah, M., Richman, A., Velmurugan, S., Reyes, S., Li, M., Tucker, K., Ahumada, A., Ruben, A. J., Li, T., Stafford, R., Eappen, A. G., Tamminga, C., Bennett, J. W., Ockenhouse, C. F., Murphy, J. R., Komisar, J., Thomas, N., Loyevsky, M., Birkett, A., Plowe, C. V., Loucq, C., Edelman, R., Richie, T. L., Seder, R. A., and Hoffman, S. L.

Published
2011

3. Malaria chemoprevention and drug resistance

Author

Plowe C

Subjects
parasitic diseases
Abstract

This report was considered by the WHO/GMP Guideline Development Group on Malaria Chemoprevention for “Section 4.2 Preventive chemotherapies” of the WHO Guidelines for malaria, 3 June 2022., Review subsequently published on 24 March 2022 in Malaria Journal: https://doi.org/10.1186/s12936-022-04115-8

Published
2022
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4. Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis

Author

Dahal, P, Simpson, JA, Abdulla, S, Achan, J, Adam, I, Agarwal, A, Allan, R, Anvikar, AR, Ashley, EA, Bassat, Q, Borrmann, S, Bousema, T, Bukirwa, H, Carrara, V, Corsi, M, D'Alessandro, U, Davis, TME, Deloron, P, Desai, M, Dimbu, PR, Djalle, D, Djimde, A, Dorsey, G, Drakeley, CJ, Duparc, S, Edstein, MD, Espie, E, Abul, F, Falade, C, Fanello, C, Faucher, J-F, Faye, B, Fortes, FDJ, Gadalla, NB, Gaye, O, Gil, JP, Gilayeneh, J, Greenwood, B, Grivoyannis, A, Hien, TT, Hwang, J, Janssens, B, Juma, E, Kamugisha, E, Karema, C, Karunajeewa, HA, Kiechel, JR, Kironde, F, Kofoed, P-E, Kremsner, PG, Lee, SJ, Marsh, K, Martensson, A, Mayxay, M, Menan, H, Mens, P, Mutabingwa, TK, Ndiaye, J-L, Ngasala, BE, Noedl, H, Nosten, F, Offianan, AT, Ogutu, BR, Olliaro, PL, Ouedraogo, JB, Piola, P, Plowe, C, Plucinski, MM, Pratt, OJ, Premji, Z, Ramharter, M, Rogier, C, Vitare, P, Rombo, L, Rosenthal, PJ, Sibley, C, Sirima, S, Smithuis, F, Staedke, SG, Sutanto, I, Talisuna, AO, Tarning, J, Taylor, WRJ, Temu, E, Thriemer, K, Thuy-Nhien, N, Udhayakumar, V, Ursing, JD, van Herp, M, van Lenthe, M, van Vugt, M, William, Y, Winnips, C, Zaloumis, S, Zongo, I, White, NJ, Guerin, PJ, Stepniewska, K, Price, RN, Arinaitwe, E, Dahal, P, Simpson, JA, Abdulla, S, Achan, J, Adam, I, Agarwal, A, Allan, R, Anvikar, AR, Ashley, EA, Bassat, Q, Borrmann, S, Bousema, T, Bukirwa, H, Carrara, V, Corsi, M, D'Alessandro, U, Davis, TME, Deloron, P, Desai, M, Dimbu, PR, Djalle, D, Djimde, A, Dorsey, G, Drakeley, CJ, Duparc, S, Edstein, MD, Espie, E, Abul, F, Falade, C, Fanello, C, Faucher, J-F, Faye, B, Fortes, FDJ, Gadalla, NB, Gaye, O, Gil, JP, Gilayeneh, J, Greenwood, B, Grivoyannis, A, Hien, TT, Hwang, J, Janssens, B, Juma, E, Kamugisha, E, Karema, C, Karunajeewa, HA, Kiechel, JR, Kironde, F, Kofoed, P-E, Kremsner, PG, Lee, SJ, Marsh, K, Martensson, A, Mayxay, M, Menan, H, Mens, P, Mutabingwa, TK, Ndiaye, J-L, Ngasala, BE, Noedl, H, Nosten, F, Offianan, AT, Ogutu, BR, Olliaro, PL, Ouedraogo, JB, Piola, P, Plowe, C, Plucinski, MM, Pratt, OJ, Premji, Z, Ramharter, M, Rogier, C, Vitare, P, Rombo, L, Rosenthal, PJ, Sibley, C, Sirima, S, Smithuis, F, Staedke, SG, Sutanto, I, Talisuna, AO, Tarning, J, Taylor, WRJ, Temu, E, Thriemer, K, Thuy-Nhien, N, Udhayakumar, V, Ursing, JD, van Herp, M, van Lenthe, M, van Vugt, M, William, Y, Winnips, C, Zaloumis, S, Zongo, I, White, NJ, Guerin, PJ, Stepniewska, K, Price, RN, and Arinaitwe, E

Abstract

BACKGROUND: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria. METHODS: Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up. RESULTS: Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47-74%] of recrudescences in African children and 32% [95% CI 15-45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19-90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0-22%] in those treated with ≤ 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up

Published
2022

8. Genomic structure and diversity of Plasmodium falciparum in Southeast Asia reveal recent parasite migration patterns

Author

Shetty, A, Jacob, C, Huang, F, Li, Y, Agrawal, S, Saunders, D, Lon, C, Fukuda, M, Ringwald, P, Ashley, E, Han, K, Hlaing, T, Nyunt, M, Silva, J, Stewart, K, Plowe, C, O'Connor, T, Takala-Harrison, S, White, N, Artemisinin Resistance Confirmation, Characterization, and Containment (ARC3), (ARCE), Artemisinin Resistance Containment and Elimination, and (TRAC), Tracking Resistance to Artemisinin Collaboration

Subjects
0301 basic medicine, Genotype, Population genetics, Science, Plasmodium falciparum, Biodiversity, Drug Resistance, General Physics and Astronomy, Single-nucleotide polymorphism, 02 engineering and technology, Drug resistance, Biology, Genome, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Antimalarials, parasitic diseases, medicine, Parasite hosting, Geography, Medical, Malaria, Falciparum, lcsh:Science, Asia, Southeastern, Infectious-disease epidemiology, Multidisciplinary, Parasite genomics, General Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, biology.organism_classification, Artemisinins, 3. Good health, Malaria, 030104 developmental biology, Evolutionary biology, Epidemiological Monitoring, lcsh:Q, 0210 nano-technology, Genome, Protozoan
Abstract

Estimates of Plasmodium falciparum migration may inform strategies for malaria elimination. Here we elucidate fine-scale parasite population structure and infer recent migration across Southeast Asia using identity-by-descent (IBD) approaches based on genome-wide single nucleotide polymorphisms called in 1722 samples from 54 districts. IBD estimates are consistent with isolation-by-distance. We observe greater sharing of larger IBD segments between artemisinin-resistant parasites versus sensitive parasites, which is consistent with the recent spread of drug resistance. Our IBD analyses reveal actionable patterns, including isolated parasite populations, which may be prioritized for malaria elimination, as well as asymmetrical migration identifying potential sources and sinks of migrating parasites., Understanding genomic variation in Plasmodium falciparum parasites and inferring migration patterns can guide malaria elimination strategies. Using genome-wide data for 1722 parasites collected from 54 districts, the authors use identity-by-descent approaches to estimate regional parasite migration and spread of artemisinin drug resistance.

Published
2019

13. Genome-wide and fine-resolution association analysis of malaria in West Africa

Author

Muminatou, Jallow, Yik Ying Teo, Small, Kerrin S., Rockett, Kirk A., Panos, Deloukas, Clark, Taane G., Katja, Kivinen, Bojang, Kalifa A., Conway, David J., Margaret, Pinder, Giorgio, Sirugo, Fatou Sisay Joof, Stanley, Usen, Sarah, Auburn, Bumpstead, Suzannah J., Susana, Campino, Alison, Coffey, Andrew, Dunham, Fry, Andrew E., Angela, Green, Rhian, Gwilliam, Hunt, Sarah E., Michael, Inouye, Jeffreys, Anna E., Alieu, Mendy, Aarno, Palotie, Simon, Potter, Jiannis, Ragoussis, Jane, Rogers, Kate, Rowlands, Elilan, Somaskantharajah, Pamela, Whittaker, Claire, Widden, Peter, Donnelly, Bryan, Howie, Jonathan, Marchini, Andrew, Morris, Miguel, Sanjoaquin, Eric Akum Achidi, Tsiri, Agbenyega, Angela, Allen, Olukemi, Amodu, Patrick, Corran, Abdoulaye, Djimde, Amagana, Dolo, Doumbo, Ogobara K., Chris, Drakeley, Sarah, Dunstan, Jennifer, Evans, Jeremy, Farrar, Hien Tt, Fernando D., Horstmann, R. D., Ibrahim, M., Karunaweera, N., Kokwaro, G., Koram, K. A., Lemnge, M., Makani, J., Marsh, K., Michon, P., David, Modiano, Molyneux, M. E., Mueller, I., Parker, M., Peshu, N., Plowe, C. V., Puijalon, O., Reeder, J., Reyburn, H., Riley, E. M., Sakuntabhai, A., Singhasivanon, P., Sirima, S., Tall, A., Taylor, T. E., Thera, M., Troye Blomberg, M., Williams, T. N., Wilson, M., Wellcome Trust Case Control Consortium Kwiatkowski, D. P., Epidemiology Network: Achidi, Malaria Genomic E. A., Agbenyega, T., Ahmad, T., Alcock, D., Allen, S., Amenga Etego, L., Amodu, O., Apinjoh, T. O., Attwood, A. P., Auburn, S., Ball, S. G., Balmforth, A. J., Ban, M., Barbour, J., Barnwell, D., Barrett, J. C., Barrett, J. H., Barton, A., Bentley, D., Bishop, D. T., Bojang, K., Boorman, J. P., Bougouma, E., Bradbury, L. A., Braga Marcano, C. A., Braund, P. S., Bredin, F., Breen, G., Brown, M. A., Brown, M. J., Bruce, I. N., Bryan, C., Bull, S., Bumpstead, S. J., Burke, B., Burton, P. R., Caesar, S., Campino, S., Cant, B., Cardin, N. J., Cardon, L. R., Carucci, D., Caulfield, M., Chaney, A., Clark, T., Clayton, D. G., Collier, D. A., Compston, A., Compston, D. A., Connell, J., Conway, D., Cook, K., Corran, P., Craddock, N., Cummings, F. R., Davison, D., Deloukas, P., Devries, J., Dewasurendra, R., Diakite, M., Dixon, R. J., Djimde, A., Dobson, R., Dolo, A., Dominiczak, A., Donnelly, P., Donovan, H., Doumbo, O., Downes, K., Doyle, A., Drakeley, C., Drummond, H., Duffy, P., Duncanson, A., Dunger, D. B., Dunstan, S., Duombo, O., Easton, D., Elkin, A., Elliott, K. S., Elzein, A., Enimil, A., Evans, D., Evans, J., Everson, U., Eyre, S., Farmer, A., Farrall, M., Farrar, C., Farrar, J., Fernando, D., Ferreira, T., Ferrier, I. N., Fisher, S. A., Fitzpatrick, K., Forbes, A., Franklyn, J. A., Fraser, C., Frayling, T. M., Freathy, R. M., Ghansah, A., Ghori, J., Gilbert, P. D., Gordon Smith, K., Goris, A., Gottlieb, M., Gough, S. C., Green, A., Green, E. K., Groves, C. J., Grozeva, D., Gungadoo, J., Gwilliam, R., Hall, A. S., Hallgrimsdóttir, I. B., Hamshere, M. L., Hart, L., Hattersley, A. T., Heward, J. M., Hider, S. L., Tran Tinh Hien, Hill, A. V., Hilton, E., Hinks, A. M., Hitman, G. A., Holmans, P. A., Horstmann, Rolf D., Howie, B. N., Hubbart, C., Hughes, C., Hunt, S. E., Hussein, A., Hussey, J. M., Muntaser, Ibrahim, Iles, M. M., Inouye, M., Ishengoma, D., Jallow, M., Jeffreys, A. E., Jewell, D. P., John, Sl, Jolley, J. D., Jones, I. R., Jones, L., Jones, R. W., Nadira, Karunaweera, Keniry, A., King, E., Kirov, G., Kivinen, K., Knight, A. S., Koch, K., Gilbert, Kokwaro, Koram, Kwadwo A., Lango, H., Lathrop, G. M., Lee, K. L., Lees, C. W., Martha, Lemnge, Leung, H. T., Lewis, C. M., Lin, E., Lindgren, C. M., Ly, A., Macinnis, B., Julie, Makani, Mangano, Valentina, Mangino, M., Manjurano, A., Manning, L., Mansfield, J. C., Manske, M., Maqbool, A., Marchini, J. L., Kevin, Marsh, Maslen, G., Mathew, C. G., Mcardle, W. L., Mccarthy, M. I., Mccreight, M., Mcginnis, R., Mcguffin, P., Meech, E., Mendy, A., Pascal, Michon, Mohiuddin, M. K., Molyneux, Malcolm E., Morris, A. P., Moskvina, V., Moyes, C., Ivo, Mueller, Munroe, P. B., Mutabingwa, T., Ndila, C. M., Newhouse, S. J., Newport, M., Nikolov, I., Nimmo, E. R., Nutland, S., Nyirongo, V., O'Donovan, M. C., Oluoch, T., Onipinla, A., Onnie, C. M., Ouwehand, W. H., Owen, M. J., Michael, Parker, Parkes, M., Pembrey, M., Pereira Gale, J., Perry, J. R., Norbert, Peshu, Plowe, Christopher V., Pointon, J. J., Potter, C., Potter, S., Prescott, N. J., Prowse, C. V., Odile, Puijalon, Quyen, N. T., Ragoussis, J., Rahman, N., Ravindrarajah, R., Rayner, N. W., John, Reeder, Hugh, Reyburn, Riley, Eleanor M., Ring, S. M., Risley, P., Rockett, K. A., Rogers, J., Rowlands, K., Anavaj, Sakuntabhai, Samani, N. J., Sanderson, J., Sanjoaquin, M., Satsangi, J., Sawcer, S. J., Seal, S., Shields, B. M., Silman, A. J., Simmonds, M. J., Pratap, Singhasivanon, Sodiomon, Sirima, Sirugo, G., Small, K. S., Somaskantharajah, E., Spencer, C. C., St Clair, D., Stevens, H. E., Stevens, M., Stevens, S., Strachan, D. P., Stratton, M. R., Su, Z., Suriyaphol, P., Symmons, D. P., Adama, Tall, Taylor, N. C., Taylor, Terrie E., Teo, Y., Teo, Y. Y., Mahamadou, Thera, Thompson, J. R., Thomson, W., Timpson, N. J., Tobin, M. D., Todd, J. A., Todhunter, C. E., Toure, O., Tremelling, M., Marita Troye Blomberg, Vanderwal, A., Vukcevic, D., Walker, M., Walker, N. M., Wallace, C., Walters, G. R., Walton, R., Watkins, N. A., Watson, R., Webster, J., Weedon, M. N., Whittaker, P., Widmer, B., Williams, Thomas N., Williamson, R., Michael, Wilson, Winzer, T., Withers, D., Wordsworth, P., Worthington, J., Wrigley, R., Xue, M., Young, A. H., Yuldasheva, N., and Zeggini, E.

Subjects
Linkage disequilibrium, Hemoglobin, Sickle, Population, Genome-wide association study, Locus (genetics), Biology, Population stratification, Polymorphism, Single Nucleotide, Severity of Illness Index, Linkage Disequilibrium, Article, Gene mapping, Reference Values, Ethnicity, Genetics, Humans, education, Genetic association, education.field_of_study, Polymorphism, Genetic, Chromosome Mapping, Genetic Variation, Malaria, Gambia, Imputation (genetics), Genome-Wide Association Study
Abstract

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Published
2009
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14. Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data

Author

Abdulla, S, Adam, I, Adjei, G, Adjuik, M, Alemayehu, B, Allan, R, Arinaitwe, E, Ashley, E, Ba, MS, Barennes, H, Barnes, K, Bassat, Q, Baudin, E, Berens-Riha, N, Bjoerkman, A, Bompart, F, Bonnet, M, Borrmann, S, Bousema, T, Brasseur, P, Bukirwa, H, Checchi, F, Dahal, P, D'Alessandro, U, Desai, M, Dicko, A, Djimde, A, Dorsey, G, Doumbo, O, Drakeley, C, Duparc, S, Eshetu, T, Espie, E, Etard, J, Faiz, A, Falade, C, Fanello, C, Faucher, J, Faye, B, Faye, O, Filler, S, Flegg, J, Fofana, B, Fogg, C, Gadalla, N, Gaye, O, Genton, B, Gething, P, Gil, J, Gonzalez, R, Grandesso, F, Greenhouse, B, Greenwood, B, Grivoyannis, A, Guerin, P, Guthmann, J, Hamed, K, Hamour, S, Hay, S, Hodel, E, Humphreys, G, Hwang, J, Ibrahim, M, Jima, D, Jones, J, Jullien, V, Juma, E, Kachur, P, Kager, P, Kamugisha, E, Kamya, MR, Karema, C, Kayentao, K, Kiechel, J, Kironde, F, Kofoed, P, Kremsner, P, Krishna, S, Lameyre, V, Lell, B, Lima, A, Makanga, M, Malik, E, Marsh, K, Martensson, A, Massougbodji, A, Menan, H, Menard, D, Menendez, C, Mens, P, Meremikwu, M, Moreira, C, Nabasumba, C, Nambozi, M, Ndiaye, J, Ngasala, B, Nikiema, F, Nsanzabana, C, Ntoumi, F, Oguike, M, Ogutu, B, Olliaro, P, Omar, SA, Ouedraogo, J, Owusu-Agyei, S, Penali, L, Pene, M, Peshu, J, Piola, P, Plowe, C, Premji, Z, Price, R, Randrianarivelojosia, M, Rombo, L, Roper, C, Rosenthal, P, Sagara, I, Same-Ekobo, A, Sawa, P, Schallig, H, Schramm, B, Seck, A, Shekalaghe, SA, Sibley, C, Sinou, V, Sirima, S, Som, F, Sow, D, Staedke, S, Stepniewska, K, Sutherland, C, Swarthout, T, Sylla, K, Talisuna, A, Taylor, W, Temu, E, Thwing, J, Tine, R, Tinto, H, Tommasini, S, Toure, O, Ursing, J, Vaillant, M, Valentini, G, Van den Broek, I, Van Vugt, M, Ward, SA, Winstanley, P, Yavo, W, Yeka, A, Zolia, Y, Zongo, I, Based, W, Unité de Recherche sur le Paludisme [Antananarivo, Madagascar], Institut Pasteur de Madagascar, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Male, Infektionsmedicin, Antimalarial, MESH: Africa, law.invention, Amodiaquine/therapeutic use, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, law, 030212 general & internal medicine, Artemether, Prospective Studies, Malaria, Falciparum, Prospective cohort study, MESH: Plasmodium falciparum, Medicine(all), MESH: Middle Aged, MESH: Malaria, Falciparum, Malaria, Falciparum/drug therapy, General Medicine, Middle Aged, MESH: Infant, Artemisinins, 3. Good health, Drug Combinations, Meta-analysis, parasite, Quinolines, Drug Therapy, Combination, Artemisinin based Combination Therapy (ACT), MESH: Quinolines, medicine.drug, Falciparum, Infectious Medicine, medicine.medical_specialty, 030231 tropical medicine, Plasmodium falciparum, ARTEMISININ-RESISTANT MALARIA PLASMODIUM-FALCIPARUM PARASITE CLEARANCE ARTEMETHER-LUMEFANTRINE COMBINATION THERAPY IN-VIVO EFFICACY ARTESUNATE CHILDREN PHARMACOKINETICS, Quinolines/administration & dosage, African patients, 03 medical and health sciences, Antimalarials, Internal medicine, MESH: Artemisinins, parasitic diseases, Artemisinin combination therapy, medicine, Humans, MESH: Africa South of the Sahara, Falciparum malaria, Risk factor, MESH: Amodiaquine, Africa South of the Sahara, Parasite clearance, MESH: Drug Combinations, MESH: Humans, business.industry, Amodiaquine, Infant, Odds ratio, MESH: Antimalarials, MESH: Male, MESH: Prospective Studies, Surgery, Malaria, Clinical trial, Artemisinins/administration & dosage, MESH: Drug Therapy, Combination, chemistry, Artesunate, Africa, Commentary, Antimalarials/administration & dosage, business
Abstract

WWARN Artemisinin based Combination Therapy (ACT) Africa Baseline Study Group; International audience; Background: Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong sub-region and poses a major global public health threat. Slow parasite clearance is a key clinical manifestation of reduced susceptibility to artemisinin. This study was designed to establish the baseline values for clearance in patients from Sub-Saharan African countries with uncomplicated malaria treated with artemisinin-based combination therapies (ACTs). Methods: A literature review in PubMed was conducted in March 2013 to identify all prospective clinical trials (uncontrolled trials, controlled trials and randomized controlled trials), including ACTs conducted in Sub-Saharan Africa, between 1960 and 2012. Individual patient data from these studies were shared with the WorldWide Antimalarial Resistance Network (WWARN) and pooled using an a priori statistical analytical plan. Factors affecting early parasitological response were investigated using logistic regression with study sites fitted as a random effect. The risk of bias in included studies was evaluated based on study design, methodology and missing data. Results: In total, 29,493 patients from 84 clinical trials were included in the analysis, treated with artemether-lumefantrine (n = 13,664), artesunate-amodiaquine (n = 11,337) and dihydroartemisinin-piperaquine (n = 4,492). The overall parasite clearance rate was rapid. The parasite positivity rate (PPR) decreased from 59.7 % (95 % CI: 54.5–64.9) on day 1 to 6.7 % (95 % CI: 4.8–8.7) on day 2 and 0.9 % (95 % CI: 0.5–1.2) on day 3. The 95th percentile of observed day 3 PPR was 5.3 %. Independent risk factors predictive of day 3 positivity were: high baseline parasitaemia (adjusted odds ratio (AOR) = 1.16 (95 % CI: 1.08–1.25); per 2-fold increase in parasite density, P 37.5 °C) (AOR = 1.50 (95 % CI: 1.06–2.13), P = 0.022); severe anaemia (AOR = 2.04 (95 % CI: 1.21–3.44), P = 0.008); areas of low/moderate transmission setting (AOR = 2.71 (95 % CI: 1.38–5.36), P = 0.004); and treatment with the loose formulation of artesunate-amodiaquine (AOR = 2.27 (95 % CI: 1.14–4.51), P = 0.020, compared to dihydroartemisinin-piperaquine). Conclusions: The three ACTs assessed in this analysis continue to achieve rapid early parasitological clearance across the sites assessed in Sub-Saharan Africa. A threshold of 5 % day 3 parasite positivity from a minimum sample size of 50 patients provides a more sensitive benchmark in Sub-Saharan Africa compared to the current recommended threshold of 10 % to trigger further investigation of artemisinin susceptibility.

Published
2015
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15. MalERA : un updated research agenda for insecticide and drug resistance in malaria elimination and eradication

Author

Churcher, T., Chanda, E., Coetzee, M., Davenport, M., Diabate, A., Djimde, A., Dondorp, A. M., Donnelly, M., Hemingway, J., Huijben, S., Kachur, P., Kamau, E., Knox, T. B., Lobo, N. F., Mayor, A., Menard, D., Paaijmans, K., Picot, S., Plowe, C. V., Price, R., Rabinovich, R., Ranson, H., Reddy, M., Rees, S., Ringwald, P., Sibley, C. H., Simard, Frédéric, Wondji, C. S., The malERA Refresh Consultative Panel on Insecticide and Drug Resistance (collab.), Churcher, T., Chanda, E., Coetzee, M., Davenport, M., Diabate, A., Djimde, A., Dondorp, A. M., Donnelly, M., Hemingway, J., Huijben, S., Kachur, P., Kamau, E., Knox, T. B., Lobo, N. F., Mayor, A., Menard, D., Paaijmans, K., Picot, S., Plowe, C. V., Price, R., Rabinovich, R., Ranson, H., Reddy, M., Rees, S., Ringwald, P., Sibley, C. H., Simard, Frédéric, Wondji, C. S., and The malERA Refresh Consultative Panel on Insecticide and Drug Resistance (collab.)

Abstract

Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts. Suboptimal responses to drugs and insecticides are both spreading geographically and emerging independently and are being seen at increasing intensities. Whilst resistance is unavoidable, its effects can be mitigated through resistance management practices, such as exposing the parasite or vector to more than one selective agent. Resistance contributed to the failure of the 20th century Global Malaria Eradication Programme, and yet the global response to this issue continues to be slow and poorly coordinated-too often, too little, too late. The Malaria Eradication Research Agenda (malERA) Refresh process convened a panel on resistance of both insecticides and antimalarial drugs. This paper outlines developments in the field over the past 5 years, highlights gaps in knowledge, and proposes a research agenda focused on managing resistance. A deeper understanding of the complex biological processes involved and how resistance is selected is needed, together with evidence of its public health impact. Resistance management will require improved use of entomological and parasitological data in decision making, and optimisation of the useful life of new and existing products through careful implementation, combination, and evaluation. A proactive, collaborative approach is needed from basic science and the development of new tools to programme and policy interventions that will ensure that the armamentarium of drugs and insecticides is sufficient to deal with the challenges of malaria control and its elimination.

Published
2017

16. malERA: An updated research agenda for insecticide and drug resistance in malaria elimination and eradication

Author

Churcher, T, Chanda, E, Coetzee, M, Davenport, M, Diabate, A, Djimde, A, Dondorp, A, Donnelly, M, Hemingway, J, Huijben, S, Kachur, P, Kamau, E, Knox, T, Lobo, N, Mayor, A, Menard, D, Paaijmans, K, Picot, S, Plowe, C, Price, R, Rabinovich, R, Ranson, H, Reddy, M, Rees, S, Ringwald, P, Sibley, C, Simard, F, Wondji, C, and Pa, T

Subjects
Insecticides, Plasmodium, Mosquito Control, Artemether/lumefantrine, ARTEMISININ RESISTANCE, Drug Resistance, lcsh:Medicine, Drug resistance, Pharmacology, Insecticide Resistance, 0302 clinical medicine, Dihydroartemisinin/piperaquine, Dihydrofolate reductase, Medicine and Health Sciences, Public and Occupational Health, 030212 general & internal medicine, MULTIDRUG-RESISTANCE, SUB-SAHARAN AFRICA, Protozoans, Collection Review, Malarial Parasites, Drugs, Eukaryota, Agriculture, 11 Medical And Health Sciences, General Medicine, 3. Good health, DIHYDROPTEROATE SYNTHASE MUTATIONS, Agrochemicals, Life Sciences & Biomedicine, medicine.drug, Drug Research and Development, 030231 tropical medicine, Malària, Biology, Microbiology, VECTOR ANOPHELES-GAMBIAE, Antimalarials, 03 medical and health sciences, Medicine, General & Internal, ARTEMETHER-LUMEFANTRINE, General & Internal Medicine, Microbial Control, Malaria elimination, Parasite Groups, Parasitic Diseases, medicine, Animals, Humans, CHLOROQUINE-RESISTANCE, Disease Eradication, DIHYDROARTEMISININ-PIPERAQUINE, Chloroquine resistance, Science & Technology, Health Care Policy, Artemisinin resistance, lcsh:R, Organisms, Biology and Life Sciences, PLASMODIUM-FALCIPARUM MALARIA, Drug Policy, Tropical Diseases, Parasitic Protozoans, Malaria, Health Care, Multiple drug resistance, biology.protein, Parasitology, DIHYDROFOLATE-REDUCTASE, Antimicrobial Resistance, Apicomplexa
Abstract

Resistance to first-line treatments for Plasmodium falciparum malaria and the insecticides used for Anopheles vector control are threatening malaria elimination efforts. Suboptimal responses to drugs and insecticides are both spreading geographically and emerging independently and are being seen at increasing intensities. Whilst resistance is unavoidable, its effects can be mitigated through resistance management practices, such as exposing the parasite or vector to more than one selective agent. Resistance contributed to the failure of the 20th century Global Malaria Eradication Programme, and yet the global response to this issue continues to be slow and poorly coordinated—too often, too little, too late. The Malaria Eradication Research Agenda (malERA) Refresh process convened a panel on resistance of both insecticides and antimalarial drugs. This paper outlines developments in the field over the past 5 years, highlights gaps in knowledge, and proposes a research agenda focused on managing resistance. A deeper understanding of the complex biological processes involved and how resistance is selected is needed, together with evidence of its public health impact. Resistance management will require improved use of entomological and parasitological data in decision making, and optimisation of the useful life of new and existing products through careful implementation, combination, and evaluation. A proactive, collaborative approach is needed from basic science and the development of new tools to programme and policy interventions that will ensure that the armamentarium of drugs and insecticides is sufficient to deal with the challenges of malaria control and its elimination., Janet Hemingway and colleagues examine progress in research on insecticide and drug resistance in malaria elimination and eradication and propose a research agenda.

Published
2017
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17. Genomic epidemiology of artemisinin resistant malaria

Author

Amato, R., Miotto, O., Woodrow, C.J., Almagro-Garcia, J., Sinha, I., Campino, S., Mead, D., Drury, E., Kekre, M., Sanders, M., Amambua-Ngwa, A., Amaratunga, C., Amenga-Etego, L., Andrianaranjaka, V., Apinjoh, T., Ashley, E., Auburn, S., Awandare, G.A., Baraka, V., Barry, Alyssa, Boni, M.F., Borrmann, S., Bousema, T., Branch, O., Bull, P.C., Chotivanich, K., Conway, D.J., Craig, A., Day, N.P., Djimdé, A., Dolecek, C., Dondorp, A.M., Drakeley, C., Duffy, P., Echeverry, D.F., Egwang, T.G., Fairhurst, R.M., Faiz, A., Fanello, C.I., Hien, T.T., Hodgson, A., Imwong, M., Ishengoma, D., Lim, P., Lon, C., Marfurt, J., Marsh, K., Mayxay, M., Michon, P., Mobegi, V., Mokuolu, O.A., Montgomery, J., Mueller, I., Kyaw, M.P., Newton, P.N., Nosten, F., Noviyanti, R., Nzila, A., Ocholla, H., Oduro, A., Onyamboko, M., Ouedraogo, J.B., Phyo, A.P.P., Plowe, C., Price, R.N., Pukrittayakamee, S., Randrianarivelojosia, M., Ringwald, P., Ruiz, L., Saunders, D., Shayo, A., Siba, P., Takala-Harrison, S., Thanh, T.N.N., Thathy, V., Verra, F., Wendler, J., White, N.J., Ye, H., Cornelius, V.J., Giacomantonio, R., Muddyman, D., Henrichs, C., Malangone, C., Jyothi, D., Pearson, R.D., Rayner, J.C., McVean, G., Rockett, K.A., Miles, A., Vauterin, P., Jeffery, B., Manske, M., Stalker, J., Macinnis, B., Kwiatkowski, D.P., Amato, R., Miotto, O., Woodrow, C.J., Almagro-Garcia, J., Sinha, I., Campino, S., Mead, D., Drury, E., Kekre, M., Sanders, M., Amambua-Ngwa, A., Amaratunga, C., Amenga-Etego, L., Andrianaranjaka, V., Apinjoh, T., Ashley, E., Auburn, S., Awandare, G.A., Baraka, V., Barry, Alyssa, Boni, M.F., Borrmann, S., Bousema, T., Branch, O., Bull, P.C., Chotivanich, K., Conway, D.J., Craig, A., Day, N.P., Djimdé, A., Dolecek, C., Dondorp, A.M., Drakeley, C., Duffy, P., Echeverry, D.F., Egwang, T.G., Fairhurst, R.M., Faiz, A., Fanello, C.I., Hien, T.T., Hodgson, A., Imwong, M., Ishengoma, D., Lim, P., Lon, C., Marfurt, J., Marsh, K., Mayxay, M., Michon, P., Mobegi, V., Mokuolu, O.A., Montgomery, J., Mueller, I., Kyaw, M.P., Newton, P.N., Nosten, F., Noviyanti, R., Nzila, A., Ocholla, H., Oduro, A., Onyamboko, M., Ouedraogo, J.B., Phyo, A.P.P., Plowe, C., Price, R.N., Pukrittayakamee, S., Randrianarivelojosia, M., Ringwald, P., Ruiz, L., Saunders, D., Shayo, A., Siba, P., Takala-Harrison, S., Thanh, T.N.N., Thathy, V., Verra, F., Wendler, J., White, N.J., Ye, H., Cornelius, V.J., Giacomantonio, R., Muddyman, D., Henrichs, C., Malangone, C., Jyothi, D., Pearson, R.D., Rayner, J.C., McVean, G., Rockett, K.A., Miles, A., Vauterin, P., Jeffery, B., Manske, M., Stalker, J., Macinnis, B., and Kwiatkowski, D.P.

Published
2016

18. Genomic epidemiology of artemisinin resistant malaria

Author

Amato, R, Miotto, O, Woodrow, CJ, Almagro-Garcia, J, Sinha, I, Campino, S, Mead, D, Drury, E, Kekre, M, Sanders, M, Amambua-Ngwa, A, Amaratunga, C, Amenga-Etego, L, Andrianaranjaka, V, Apinjoh, T, Ashley, E, Auburn, S, Awandare, GA, Baraka, V, Barry, A, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Chotivanich, K, Conway, DJ, Craig, A, Day, NP, Djimde, A, Dolecek, C, Dondorp, AM, Drakeley, C, Duffy, P, Echeverry, DF, Egwang, TG, Fairhurst, RM, Faiz, MA, Fanello, CI, Tran, TH, Hodgson, A, Imwong, M, Ishengoma, D, Lim, P, Lon, C, Marfurt, J, Marsh, K, Mayxay, M, Michon, P, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Kyaw, MP, Newton, PN, Nosten, F, Noviyanti, R, Nzila, A, Ocholla, H, Oduro, A, Onyamboko, M, Ouedraogo, J-B, Phyo, APP, Plowe, C, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Ringwald, P, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Takala-Harrison, S, Thanh, T-NN, Thathy, V, Verra, F, Wendler, J, White, NJ, Ye, H, Cornelius, VJ, Giacomantonio, R, Muddyman, D, Henrichs, C, Malangone, C, Jyothi, D, Pearson, RD, Rayner, JC, McVean, G, Rockett, KA, Miles, A, Vauterin, P, Jeffery, B, Manske, M, Stalker, J, Maclnnis, B, Kwiatkowski, DP, Amato, R, Miotto, O, Woodrow, CJ, Almagro-Garcia, J, Sinha, I, Campino, S, Mead, D, Drury, E, Kekre, M, Sanders, M, Amambua-Ngwa, A, Amaratunga, C, Amenga-Etego, L, Andrianaranjaka, V, Apinjoh, T, Ashley, E, Auburn, S, Awandare, GA, Baraka, V, Barry, A, Boni, MF, Borrmann, S, Bousema, T, Branch, O, Bull, PC, Chotivanich, K, Conway, DJ, Craig, A, Day, NP, Djimde, A, Dolecek, C, Dondorp, AM, Drakeley, C, Duffy, P, Echeverry, DF, Egwang, TG, Fairhurst, RM, Faiz, MA, Fanello, CI, Tran, TH, Hodgson, A, Imwong, M, Ishengoma, D, Lim, P, Lon, C, Marfurt, J, Marsh, K, Mayxay, M, Michon, P, Mobegi, V, Mokuolu, OA, Montgomery, J, Mueller, I, Kyaw, MP, Newton, PN, Nosten, F, Noviyanti, R, Nzila, A, Ocholla, H, Oduro, A, Onyamboko, M, Ouedraogo, J-B, Phyo, APP, Plowe, C, Price, RN, Pukrittayakamee, S, Randrianarivelojosia, M, Ringwald, P, Ruiz, L, Saunders, D, Shayo, A, Siba, P, Takala-Harrison, S, Thanh, T-NN, Thathy, V, Verra, F, Wendler, J, White, NJ, Ye, H, Cornelius, VJ, Giacomantonio, R, Muddyman, D, Henrichs, C, Malangone, C, Jyothi, D, Pearson, RD, Rayner, JC, McVean, G, Rockett, KA, Miles, A, Vauterin, P, Jeffery, B, Manske, M, Stalker, J, Maclnnis, B, and Kwiatkowski, DP

Abstract

The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions.

Published
2016

19. Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine

Author

Seder, R. A., Chang, L.-J., Enama, M. E., Zephir, K. L., Sarwar, U. N., Gordon, I. J., Holman, L. A., James, E. R., Billingsley, P. F., Gunasekera, A., Richman, A., Chakravarty, S., Manoj, A., Velmurugan, S., Li, M., Ruben, A. J., Li, T., Eappen, A. G., Stafford, R. E., Plummer, S. H., Hendel, C. S., Novik, L., Costner, P. J. M., Mendoza, F. H., Saunders, J. G., Nason, M. C., Richardson, J. H., Murphy, J., Davidson, S. A., Richie, T. L., Sedegah, M., Sutamihardja, A., Fahle, G. A., Lyke, K. E., Laurens, M. B., Roederer, M., Tewari, K., Epstein, J. E., Sim, B. K. L., Ledgerwood, J. E., Graham, B. S., Hoffman, S. L., DiGiovanni, C., Williams, P., Luongo, N., Mitchell, J., Florez, M. B., Larkin, B., Berkowitz, N., Wilson, B., Clarke, T., Vasilenko, O., Yamshchikov, G., Sitar, S., Stanford, L., Pittman, I., Bailer, R. T., Casazza, J., Decederfelt, H., Starling, J., Williams, E. C., Lau, A., Antonara, S., Brocious, J., Kemp, M., Inglese, J., Dranchak, P., Abot, E. N., Reyes, S., Ganeshan, H., Belmonte, M., Huang, J., Belmonte, A., Komisar, J., Abebe, Y., Getachew, Y., Patil, A., Matheny, S., Nelson, K., Overby, J., Pich, V., Wen, Y., Fan, R., Fomumbod, E., Awe, A., Chakiath, C., King, M., Orozco, M. S., Murshedkar, T., Padilla, D., Jiang, B., Gao, L., Kc, N., Xu, R., Adams, M., Plowe, C., Loblein, H., Renehan, P. Z., Kunchai, M., and Diep, L.

Subjects
parasitic diseases
Abstract

Malaria Sporozoite Vaccine Each year, hundreds of millions of people are infected with Plasmodium falciparum, the mosquito-borne parasite that causes malaria. A preventative vaccine is greatly needed. Seder et al. (p. 1359, published online 8 August; see the Perspective by Good) now report the results from a phase I clinical trial where subjects were immunized intravenously with a whole, attenuated sporozoite vaccine. Three of 9 subjects who received four doses and zero of 6 subjects who received five doses of the vaccine went on to develop malaria after controlled malaria infection. Both antibody titers and cellular immune responses correlated positively with the dose of vaccine received, suggesting that both arms of the adaptive immune response may have participated in the observed protection. Consistent, high-level, vaccine-induced protection against human malaria has only been achieved by inoculation of Plasmodium falciparum (Pf) sporozoites (SPZ) by mosquito bites. We report that the PfSPZ Vaccine—composed of attenuated, aseptic, purified, cryopreserved PfSPZ—was safe and wel-tolerated when administered four to six times intravenously (IV) to 40 adults. Zero of six subjects receiving five doses and three of nine subjects receiving four doses of 1.35 × 105 PfSPZ Vaccine and five of six nonvaccinated controls developed malaria after controlled human malaria infection (P = 0.015 in the five-dose group and P = 0.028 for overall, both versus controls). PfSPZ-specific antibody and T cell responses were dose-dependent. These data indicate that there is a dose-dependent immunological threshold for establishing high-level protection against malaria that can be achieved with IV administration of a vaccine that is safe and meets regulatory standards. Intravenous immunization with an attenuated whole malaria sporozoite vaccine protected volunteers in a phase I clinical trial. [Also see Perspective by Good] Intravenous immunization with an attenuated whole malaria sporozoite vaccine protected volunteers in a phase I clinical trial. [Also see Perspective by Good]

Published
2013

20. Defining the In Vivo Phenotype of Artemisinin-Resistant Falciparum Malaria: A Modelling Approach

Author

Smith, TA, White, LJ, Flegg, JA, Phyo, AP, Wiladpai-ngern, JH, Bethell, D, Plowe, C, Anderson, T, Nkhoma, S, Nair, S, Tripura, R, Stepniewska, K, Pan-Ngum, W, Silamut, K, Cooper, BS, Lubell, Y, Ashley, EA, Nguon, C, Nosten, F, White, NJ, Dondorp, AM, Smith, TA, White, LJ, Flegg, JA, Phyo, AP, Wiladpai-ngern, JH, Bethell, D, Plowe, C, Anderson, T, Nkhoma, S, Nair, S, Tripura, R, Stepniewska, K, Pan-Ngum, W, Silamut, K, Cooper, BS, Lubell, Y, Ashley, EA, Nguon, C, Nosten, F, White, NJ, and Dondorp, AM

Abstract

BACKGROUND: Artemisinin-resistant falciparum malaria has emerged in Southeast Asia, posing a major threat to malaria control. It is characterised by delayed asexual-stage parasite clearance, which is the reference comparator for the molecular marker 'Kelch 13' and in vitro sensitivity tests. However, current cut-off values denoting slow clearance based on the proportion of individuals remaining parasitaemic on the third day of treatment ('day-3'), or on peripheral blood parasite half-life, are not well supported. We here explore the parasite clearance distributions in an area of artemisinin resistance with the aim refining the in vivo phenotypic definitions. METHODS AND FINDINGS: Data from 1,518 patients on the Thai-Myanmar and Thai-Cambodian borders with parasite half-life assessments after artesunate treatment were analysed. Half-lives followed a bimodal distribution. A statistical approach was developed to infer the characteristics of the component distributions and their relative contribution to the composite mixture. A model representing two parasite subpopulations with geometric mean (IQR) parasite half-lives of 3.0 (2.4-3.9) hours and 6.50 (5.7-7.4) hours was consistent with the data. For individual patients, the parasite half-life provided a predicted likelihood of an artemisinin-resistant infection which depends on the population prevalence of resistance in that area. Consequently, a half-life where the probability is 0.5 varied between 3.5 and 5.5 hours. Using this model, the current 'day-3' cut-off value of 10% predicts the potential presence of artemisinin-resistant infections in most but not all scenarios. These findings are relevant to the low-transmission setting of Southeast Asia. Generalisation to a high transmission setting as in regions of Sub-Saharan Africa will need additional evaluation. CONCLUSIONS: Characterisation of overlapping distributions of parasite half-lives provides quantitative insight into the relationship between parasite clearanc

Published
2015

22. A global network for genomic epidemiology of malaria

Author

Malaria Genomic Epidemiology Network, Achidi, Ea, Agbenyega, T, Allen, S, Amodu, O, Bojang, K, Conway, D, Corran, P, Deloukas, P, Djimde, A, Dolo, A, Doumbo, O, Drakeley, C, Duffy, P, Dunstan, S, Evans, J, Farrar, J, Fernando, D, Tran, Th, Horstmann, R, Ibrahim, M, Karunaweera, N, Kokwaro, G, Koram, K, Kwiatkowski, D, Lemnge, M, Makani, J, Marsh, K, Michon, P, Modiano, D, Molyneux, Me, Mueller, I, Mutabingwa, T, Parker, M, Peshu, N, Plowe, C, Puijalon, O, Ragoussis, J, Reeder, J, Reyburn, H, Riley, E, Rogers, J, Sakuntabhai, A, Singhasivanon, P, Sirima, S, Sirugo, G, Tall, A, Taylor, T, Thera, M, Troye Blomberg, M, Williams, T, Wilson, M, Amenga Etego, L, Apinjoh, To, Bougouma, E, Dewasurendra, R, Diakite, M, Enimil, A, Hussein, A, Ishengoma, D, Jallow, M, Lin, E, Ly, A, Mangano, Valentina, Manjurano, A, Manning, L, Ndila, Cm, Nyirongo, V, Oluoch, T, Nguyen, Tn, Suriyaphol, P, Toure, O, Rockett, Ka, Vanderwal, A, Clark, T, Wrigley, R, Alcock, D, Auburn, S, Barnwell, D, Bull, S, Campino, S, Devries, J, Elzein, A, Fitzpatrick, K, Ghansah, A, Green, A, Hart, L, Hilton, E, Hubbart, C, Hughes, C, Jeffreys, Ae, Kivinen, K, Macinnis, B, Manske, M, Maslen, G, Mccreight, M, Mendy, A, Moyes, C, Nyika, A, Potter, C, Risley, P, Rowlands, K, Sanjoaquin, M, Small, K, Somaskantharajah, E, Stevens, M, Teo, Y, Watson, R, Carucci, D, Cook, K, Doyle, A, Duombo, O, Gottlieb, M, and Kwiatkowski, D.

Published
2008

24. Pneumocystis pneumonia in HIV-positive adults, Malawi

Author

Oosterhout, J. J. G., Miriam Laufer, Perez, M. A., Graham, S. M., Chimbiya, N., Thesing, P. C., Álvarez-Martinez, M. J., Wilson, P. E., Chagomerana, M., Zijlstra, E. E., Taylor, T. E., Plowe, C. V., and Meshnick, S. R.

Subjects
Microbial pathogenesis and host defense [UMCN 4.1]
Abstract

Contains fulltext : 51540.pdf ( ) (Open Access)

Published
2007

25. Controlled Human Malaria Infection of Tanzanians by Intradermal Injection of Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites

Author

Shekalaghe, S., Rutaihwa, M., Billingsley, P.F., Chemba, M., Daubenberger, C.A., James, E.R., Mpina, M., Juma, O. Ali, Schindler, T., Huber, E., Gunasekera, A., Manoj, A., Simon, B., Saverino, E., Church, L.W., Hermsen, C.C., Sauerwein, R.W., Plowe, C., Venkatesan, M., Sasi, P., Lweno, O., Mutani, P., Hamad, A., Mohammed, A., Urassa, A., Mzee, T., Padilla, D., Ruben, A., Sim, B.K., Tanner, M., Abdulla, S., Hoffman, S.L., Shekalaghe, S., Rutaihwa, M., Billingsley, P.F., Chemba, M., Daubenberger, C.A., James, E.R., Mpina, M., Juma, O. Ali, Schindler, T., Huber, E., Gunasekera, A., Manoj, A., Simon, B., Saverino, E., Church, L.W., Hermsen, C.C., Sauerwein, R.W., Plowe, C., Venkatesan, M., Sasi, P., Lweno, O., Mutani, P., Hamad, A., Mohammed, A., Urassa, A., Mzee, T., Padilla, D., Ruben, A., Sim, B.K., Tanner, M., Abdulla, S., and Hoffman, S.L.

Abstract

Item does not contain fulltext, Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria interventions in > 1,500 volunteers since development of methods for infecting mosquitoes by feeding on Plasmodium falciparum (Pf) gametocyte cultures. Such CHMIs have never been used in Africa. Aseptic, purified, cryopreserved Pf sporozoites, PfSPZ Challenge, were used to infect Dutch volunteers by intradermal injection. We conducted a double-blind, placebo-controlled trial to assess safety and infectivity of PfSPZ Challenge in adult male Tanzanians. Volunteers were injected intradermally with 10,000 (N = 12) or 25,000 (N = 12) PfSPZ or normal saline (N = 6). PfSPZ Challenge was well tolerated and safe. Eleven of 12 and 10 of 11 subjects, who received 10,000 and 25,000 PfSPZ respectively, developed parasitemia. In 10,000 versus 25,000 PfSPZ groups geometric mean days from injection to Pf positivity by thick blood film was 15.4 versus 13.5 (P = 0.023). Alpha-thalassemia heterozygosity had no apparent effect on infectivity. PfSPZ Challenge was safe, well tolerated, and infectious.

Published
2014

27. Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

Author

Takala-Harrison, Shannon, Clark, T, Jacob, Christopher, Cummings, MP, Miotto, Olivo, Dondorp, Arjen M., Fukuda, Mark, Nosten, Francois, Noedl, H, Imwong, Mallika, Bethell, Delia, Se, Y, Lon, Chantap, Tyner, SD, Saunders, David, Socheat, Duong, Ariey, F, Phyo, Aung, Starzengruber, P, Fuehrer, H, Swoboda, P, Stepniewska, Kasia, Flegg, J, Arze, C, Cerqueira, GC, Silva, Joana, Ricklefs, SM, Porcella, S, Stephens, RM, Adams, Matthew, Kenefic, L, Campino, Susana, Auburn, Sarah, MacInnes, Bronwyn, Kwiatkowski, Dominic, Su, Xin-Zhuan, White, Nicholas, RINGWALD, P, Plowe, C, Takala-Harrison, Shannon, Clark, T, Jacob, Christopher, Cummings, MP, Miotto, Olivo, Dondorp, Arjen M., Fukuda, Mark, Nosten, Francois, Noedl, H, Imwong, Mallika, Bethell, Delia, Se, Y, Lon, Chantap, Tyner, SD, Saunders, David, Socheat, Duong, Ariey, F, Phyo, Aung, Starzengruber, P, Fuehrer, H, Swoboda, P, Stepniewska, Kasia, Flegg, J, Arze, C, Cerqueira, GC, Silva, Joana, Ricklefs, SM, Porcella, S, Stephens, RM, Adams, Matthew, Kenefic, L, Campino, Susana, Auburn, Sarah, MacInnes, Bronwyn, Kwiatkowski, Dominic, Su, Xin-Zhuan, White, Nicholas, RINGWALD, P, and Plowe, C

Published
2013

28. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing

Author

Manske, Magnus, Miotto, Olivo, Campino, Susana, Auburn, Sarah, Almagro-Gracia, J, Maslen, Gareth, O'Brien, J, Djimde, Abdoulaye, Doumbo, Ogobara, Zongo, Issaka, Ouedraogo, Jean, Michon, Pascal, Mueller, Ivo, Siba, Peter, Nzila, Alexis, Borrman, Steffen, Kiara, Steven, Marsh, Kevin, Jiang, Hongying, Su, Xin-Zhuan, Amaratunga, Chanaki, Fairhurst, Rick, Socheat, Duong, Nosten, François, Imwong, Mallika, White, Nicholas J, Sanders, Mandy, Anastasi, Elisa, Alcock, Daniel, Drury, Eleanor, Oyola, S, Quail, Michael, Turner, Daniel, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, Kate, Sutherland, Colin, Roper, C, Mangano, Valentina, Modiano, d, Tan, J, Ferdig, M, Amambua-Ngwa, A, Conway, D, Takala-Harrison, S, Plowe, C, Rayner, J, Rockett, Kirk, Clark, Taane, Newbold, Christopher, Berriman, M, MacInnis, Bronwyn, Kwiatkowski, Dominic, Manske, Magnus, Miotto, Olivo, Campino, Susana, Auburn, Sarah, Almagro-Gracia, J, Maslen, Gareth, O'Brien, J, Djimde, Abdoulaye, Doumbo, Ogobara, Zongo, Issaka, Ouedraogo, Jean, Michon, Pascal, Mueller, Ivo, Siba, Peter, Nzila, Alexis, Borrman, Steffen, Kiara, Steven, Marsh, Kevin, Jiang, Hongying, Su, Xin-Zhuan, Amaratunga, Chanaki, Fairhurst, Rick, Socheat, Duong, Nosten, François, Imwong, Mallika, White, Nicholas J, Sanders, Mandy, Anastasi, Elisa, Alcock, Daniel, Drury, Eleanor, Oyola, S, Quail, Michael, Turner, Daniel, Ruano-Rubio, V, Jyothi, D, Amenga-Etego, L, Hubbart, C, Jeffreys, A, Rowlands, Kate, Sutherland, Colin, Roper, C, Mangano, Valentina, Modiano, d, Tan, J, Ferdig, M, Amambua-Ngwa, A, Conway, D, Takala-Harrison, S, Plowe, C, Rayner, J, Rockett, Kirk, Clark, Taane, Newbold, Christopher, Berriman, M, MacInnis, Bronwyn, and Kwiatkowski, Dominic

Published
2012

29. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S

Author

Agarwal, A., Guindo, A., Cissoko, Y., James Taylor, Coulibaly, D., Kone, A., Kayentao, K., Djimde, A., Plowe, C. V., Doumbo, O., Wellems, T. E., and Diallo, D.

Subjects
Heterozygote, Immunology, Hemoglobin, Sickle, Homozygote, Hemoglobin C, virus diseases, Cell Biology, Hematology, Anemia, Sickle Cell, Hemoglobin C Disease, Mali, Biochemistry, digestive system diseases, Case-Control Studies, parasitic diseases, Splenomegaly, Odds Ratio, Humans, Malaria, Falciparum
Abstract

The malaria hypothesis proposes a survival advantage for individuals with hemoglobin variants in areas of endemicPlasmodium falciparum malaria. Hemoglobin C (HbC) is a possible example in West Africa, where this hemoglobin has a centric distribution with high frequencies among certain populations including the Dogon ethnic group. To test whether HbC is associated with protection from malaria, we performed a case-control study in the Dogon of Bandiagara, Mali. HbC was present in 68 of 391 (17.4%) of uncomplicated malaria control cases, whereas it was detected in only 3 of 67 cases (4.5%) of severe malaria (odds ratio [OR], 0.22;P = .01). Further, HbC was present in only 1 of 34 cases (2.9%) with cerebral manifestations, the most common presentation of severe malaria in this population (OR, 0.14; P = .03). Episodes of uncomplicated malaria and parasitemias (4800-205 050/μL) were identified in cases of homozygous HbC (HbCC), which indicates thatP falciparum parasites are able to efficiently replicate within HbCC erythrocytes in vivo. These findings suggest that HbC does not protect against infection or uncomplicated malaria but can protect against severe malaria in the Dogon population of Bandiagara, Mali. The data also suggest that the protective effect associated with HbC may be greater than that of HbS in this population.

Published
2000

30. Genome-wide and fine-resolution association analysis of malaria in West Africa

Author

Jallow, M, Teo, Y, Small, K, Rockett, K, Deloukas, P, Clark, T, Kivinen, K, Bojang, K, Conway, D, Pinder, M, Sirugo, G, Sisay-Joof, F, Usen, S, Auburn, Sarah, SJ Bumpstead, S, Campino, S, Coffey, A, Dunham, A, Fry, A, Green, A, Gwilliam, R, Hunt, S, Inouye, M, Jeffreys, A, Mendy, A, Palotie, A, Potter, S, Ragoussis, J, Rogers, J, Rowlands, K, Somaskantharajah, E, Whittaker, P, Widden, C, Donnelly, P, Howie, B, Marchini, J, Morris, A, Sanjoaquin, M, Achidi, E, Agbenyega, T, Allen, A, Amodu, O, Corran, P, Djimde, A, Dolo, A, Doumbo, O, Drakeley, C, Dunstan, S, Evans, J, Farrar, J, Fernando, D, Hien, T, Horstmann, R, Ibrahim, M, Karunaweera, N, Kokwaro, G, Koram, K, Lemnge, M, Makani, J, Marsh, K, Michon, P, Modiano, D, Molyneux, M, Mueller, I, Parker, M, Peshu, N, Plowe, C, Puijalon, O, Reeder, J, Reyburn, H, Riley, E, Sakuntabhai, A, Singhasivanon, P, Sirima, S, Tall, A, Taylor, T, Thera, M, Troye-Blomberg, M, Williams, T, Wilson, M, Kwiatkowski, D, Jallow, M, Teo, Y, Small, K, Rockett, K, Deloukas, P, Clark, T, Kivinen, K, Bojang, K, Conway, D, Pinder, M, Sirugo, G, Sisay-Joof, F, Usen, S, Auburn, Sarah, SJ Bumpstead, S, Campino, S, Coffey, A, Dunham, A, Fry, A, Green, A, Gwilliam, R, Hunt, S, Inouye, M, Jeffreys, A, Mendy, A, Palotie, A, Potter, S, Ragoussis, J, Rogers, J, Rowlands, K, Somaskantharajah, E, Whittaker, P, Widden, C, Donnelly, P, Howie, B, Marchini, J, Morris, A, Sanjoaquin, M, Achidi, E, Agbenyega, T, Allen, A, Amodu, O, Corran, P, Djimde, A, Dolo, A, Doumbo, O, Drakeley, C, Dunstan, S, Evans, J, Farrar, J, Fernando, D, Hien, T, Horstmann, R, Ibrahim, M, Karunaweera, N, Kokwaro, G, Koram, K, Lemnge, M, Makani, J, Marsh, K, Michon, P, Modiano, D, Molyneux, M, Mueller, I, Parker, M, Peshu, N, Plowe, C, Puijalon, O, Reeder, J, Reyburn, H, Riley, E, Sakuntabhai, A, Singhasivanon, P, Sirima, S, Tall, A, Taylor, T, Thera, M, Troye-Blomberg, M, Williams, T, Wilson, M, and Kwiatkowski, D

Published
2009

35. Serum Levels of the Proinflammatory Cytokines Interleukin-1 Beta (IL-1β), IL-6, IL-8, IL-10, Tumor Necrosis Factor Alpha, and IL-12(p70) in Malian Children with Severe Plasmodium falciparum Malaria and Matched Uncomplicated Malaria or Healthy Controls

Author

Lyke, K. E., primary, Burges, R., additional, Cissoko, Y., additional, Sangare, L., additional, Dao, M., additional, Diarra, I., additional, Kone, A., additional, Harley, R., additional, Plowe, C. V., additional, Doumbo, O. K., additional, and Sztein, M. B., additional

Published
2004
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42. Chlorproguanil-dapsone versus sulfadoxine-pyrimethamine for sequential episodes of uncomplicated falciparum malaria in Kenya and Malawi: a randomised clinical trial.

Author

Sulo, J, Chimpeni, P, Hatcher, J, Kublin, J G, Plowe, C V, Molyneux, M E, Marsh, K, Taylor, T E, Watkins, WM, and Winstanley, P A

Abstract

Background Chlorproguanil-dapsone exerts lower resistance pressure on Plasmodium falciparum than does sulfadoxine-pyrimethamine, but is rapidly eliminated. We aimed to find out whether chlorproguanil-dapsone results in a higher retreatment rate for malaria than sulfadoxine-pyrimethamine.Methods In a randomised trial of paediatric outpatients with uncomplicated falciparum malaria, patients received either chlorproguanil-dapsone or sulfadoxine-pyrimethamine and were followed up for up to 1 year. Sites were in Kenya (n=410) and Malawi (n=500). We used per-protocol analysis to assess the primary outcome of annual malaria incidence.Findings Drop-outs were 117 of 410 (28·5%) in Kenya, and 342 of 500 (68·4%) in Malawi. Follow-up was for a median of 338 days (IQR 128–360) and 342 days (152–359) in Kilifi (chlorproguanil-dapsone and sulfadoxine-pyrimethamine, respectively), and for 120 days (33–281) and 84 days (26–224) in Blantyre. Mean annual malaria incidence was 2·5 versus 2·1 in Kenya (relative risk 1·16, 95% CI 0·98–1·37), and 2·2 versus 2·8 in Malawi (0·77, 0·63–0·94). 4·3% versus 12·8%, and 5·4% versus 20·1%, of patients were withdrawn for treatment failure in Kenya and Malawi, respectively. In Kenya haemoglobin concentration of 50 g/L or less caused exit in 6·9% of chlorproguanil-dapsone patients and 1·5% of sulfadoxine-pyrimethamine patients, but most anaemia occurred before re-treatment. In Malawi only one patient exited because of anaemia.Interpretation Despite the rapid elimination of chlorproguanil-dapsone, children treated with this drug did not have a higher incidence of malaria episodes than those treated with sulfadoxine-pyrimethamine. Treatment failure was more common with sulfadoxine-pyrimethamine. Cause of anaemia in Kenya was probably not adverse reaction to chlorproguanil-dapsone, but this observation requires further study. [Copyright &y& Elsevier]

Published
2002
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43. Serum Levels of the Proinflammatory Cytokines Interleukin-1 Beta (IL-1β), IL-6, IL-8, IL-10, Tumor Necrosis Factor Alpha, and IL-12(p70) in Malian Children with Severe Plasmodium falciparumMalaria and Matched Uncomplicated Malaria or Healthy Controls

Author

Lyke, K. E., Burges, R., Cissoko, Y., Sangare, L., Dao, M., Diarra, I., Kone, A., Harley, R., Plowe, C. V., Doumbo, O. K., and Sztein, M. B.

Abstract

ABSTRACTInflammatory cytokines play an important role in human immune responses to malarial disease. However, the role of these mediators in disease pathogenesis, and the relationship between host protection and injury remains unclear. A total of 248 cases of severe Plasmodium falciparummalaria among children aged 3 months to 14 years residing in Bandiagara, Mali, were matched to cases of uncomplicated malaria and healthy controls. Using modified World Health Organization criteria for defining severe malaria, we identified 100 cases of cerebral malaria (coma, seizure, and obtundation), 17 cases of severe anemia (hemoglobin, <5 g/dl), 18 cases combined cerebral malaria with severe anemia, and 92 cases with hyperparasitemia (asexual trophozoites, >500,000/mm3). Significantly elevated levels (given as geometric mean concentrations in picograms/milliliter) of interleukin-6 (IL-6; 485.2 versus 54.1; P= <0.001), IL-10 (1,099.3 versus 14.1; P= <0.001), tumor necrosis factor alpha (10.1 versus 7.7; P= <0.001), and IL-12(p70) (48.9 versus 31.3; P= 0.004) in serum were found in severe cases versus healthy controls. Significantly elevated levels of IL-6 (485.2 versus 141.0; P= <0.001) and IL-10 (1,099.3 versus 133.9; P= <0.001) were seen in severe malaria cases versus uncomplicated malaria controls. Cerebral malaria was associated with significantly elevated levels of IL-6 (754.5 versus 311.4; P= <0.001) and IL-10 (1,405.6 versus 868.6; P= 0.006) compared to severe malaria cases without cerebral manifestations. Conversely, lower levels of IL-6 (199.2 versus 487.6; P= 0.03) and IL-10 (391.1 versus 1,160.9; P= 0.002) were noted in children with severe anemia compared to severe malaria cases with hemoglobin at >5 g/dl. Hyperparasitemia was associated with significantly lower levels of IL-6 (336.6 versus 602.1; P= 0.002). These results illustrate the complex relationships between inflammatory cytokines and disease in P. falciparummalaria.

Published
2004
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47. Kenyan Plasmodium falciparumField Isolates: Correlation between Pyrimethamine and Chlorcycloguanil Activity In Vitro and Point Mutations in the Dihydrofolate Reductase Domain

Author

Nzila-Mounda, A., Mberu, E. K., Sibley, C. H., Plowe, C. V., Winstanley, P. A., and Watkins, W. M.

Abstract

ABSTRACTSixty-nine Kenyan Plasmodium falciparumfield isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P< 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 ± 6.94 and 0.24 ± 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P< 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

Published
1998
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49. Clinical manifestations of new versus recrudescent malaria infections following anti-malarial drug treatment

Author

Shaukat Ayesha M, Gilliams Elizabeth A, Kenefic Leo J, Laurens Matthew B, Dzinjalamala Fraction K, Nyirenda Osward M, Thesing Phillip C, Jacob Christopher G, Molyneux Malcolm E, Taylor Terrie E, Plowe Christopher V, and Laufer Miriam K

Subjects
Malaria, Sulphadoxine-pyrimethamine, Drug efficacy, Genotyping, Recrudescent infections, New infections, Malawi, Anaemia, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Distinguishing new from recrudescent infections in post-treatment episodes of malaria is standard in anti-malarial drug efficacy trials. New infections are not considered malaria treatment failures and as a result, the prevention of subsequent episodes of malaria infection is not reported as a study outcome. However, in moderate and high transmission settings, new infections are common and the ability of a short-acting medication to cure an initial infection may be outweighed by its inability to prevent the next imminent infection. The clinical benefit of preventing new infections has never been compared to that of curing the initial infection. Methods Children enrolled in a sulphadoxine-pyrimethamine efficacy study in Blantyre, Malawi from 1998–2004 were prospectively evaluated. Six neutral microsatellites were used to classify new and recrudescent infections in children aged less than 10 years with recurrent malaria infections. Children from the study who did not experience recurrent parasitaemia comprised the baseline group. The odds of fever and anaemia, the rate of haemoglobin recovery and time to recurrence were compared among the groups. Results Fever and anemia were more common among children with parasitaemia compared to those who remained infection-free throughout the study period. When comparing recrudescent vs. new infections, the incidence of fever was not statistically different. However, children with recrudescent infections had a less robust haematological recovery and also experienced recurrence sooner than those whose infection was classified as new. Conclusions The results of this study confirm the paramount importance of providing curative treatment for all malaria infections. Although new and recrudescent infections caused febrile illnesses at a similar rate, recurrence due to recrudescent infection did have a worsened haemological outcome than recurrence due to new infections. Local decision-makers should take into account the results of genotyping to distinguish new from recrudescent infections when determining treatment policy on a population level. It is appropriate to weigh recrudescent malaria more heavily than new infection in assessing treatment efficacy.

Published
2012
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50. Using CF11 cellulose columns to inexpensively and effectively remove human DNA from Plasmodium falciparum-infected whole blood samples

Author

Venkatesan Meera, Amaratunga Chanaki, Campino Susana, Auburn Sarah, Koch Oliver, Lim Pharath, Uk Sambunny, Socheat Duong, Kwiatkowski Dominic P, Fairhurst Rick M, and Plowe Christopher V

Subjects
CF11, Cellulose powder, Leukocyte depletion, Plasmodium falciparum, Malaria, Next-generation sequencing, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Genome and transcriptome studies of Plasmodium nucleic acids obtained from parasitized whole blood are greatly improved by depletion of human DNA or enrichment of parasite DNA prior to next-generation sequencing and microarray hybridization. The most effective method currently used is a two-step procedure to deplete leukocytes: centrifugation using density gradient media followed by filtration through expensive, commercially available columns. This method is not easily implemented in field studies that collect hundreds of samples and simultaneously process samples for multiple laboratory analyses. Inexpensive syringes, hand-packed with CF11 cellulose powder, were recently shown to improve ex vivo cultivation of Plasmodium vivax obtained from parasitized whole blood. This study was undertaken to determine whether CF11 columns could be adapted to isolate Plasmodium falciparum DNA from parasitized whole blood and achieve current quantity and purity requirements for Illumina sequencing. Methods The CF11 procedure was compared with the current two-step standard of leukocyte depletion using parasitized red blood cells cultured in vitro and parasitized blood obtained ex vivo from Cambodian patients with malaria. Procedural variations in centrifugation and column size were tested, along with a range of blood volumes and parasite densities. Results CF11 filtration reliably produces 500 nanograms of DNA with less than 50% human DNA contamination, which is comparable to that obtained by the two-step method and falls within the current quality control requirements for Illumina sequencing. In addition, a centrifuge-free version of the CF11 filtration method to isolate P. falciparum DNA at remote and minimally equipped field sites in malaria-endemic areas was validated. Conclusions CF11 filtration is a cost-effective, scalable, one-step approach to remove human DNA from P. falciparum-infected whole blood samples.

Published
2012
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