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1. Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data.

Author

Maiga, Mohamed, Dembele, Laurent, Courlet, Perrine, Khandelwal, Akash, Dara, Antoine, Sogore, Fanta, Diakité, Ousmaila, Maiga, Fatoumata O., Dao, François, Sissoko, Sekou, Barre, Yacouba, Goita, Siaka, Diakite, Mahamadou, Diakite, Seidina A. S., Djimde, Abdoulaye A., Oeuvray, Claude, Spangenberg, Thomas, Wicha, Sebastian G., and Demarta-Gatsi, Claudia

Subjects
DRUG interactions, SIMULATED patients, DRUG development, PLASMODIUM falciparum, DRUG utilization, PHARMACOGENOMICS
Abstract

The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development. Here the authors use drug susceptibility data from Plasmodium falciparum field isolates in a pharmacometric model to evaluate cabamiquine and pyronaridine efficacy, both individually and in combination. The combined treatment shows over 90% parasite reduction in most simulated cases, providing valuable guidance for clinical dose selection in real-world settings. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Variability in white blood cell count during uncomplicated malaria and implications for parasite density estimation : a WorldWide Antimalarial Resistance Network individual patient data meta-analysis

Author

Wynberg, Elke, Commons, Robert J., Humphreys, Georgina, Ashurst, Hazel, Burrow, Rebekah, Adjei, George O., Adjuik, Martin, Anstey, Nicholas M., Anvikar, Anup, Baird, Kevin J., Barber, Bridget E., Barennes, Hubert, Baudin, Elisabeth, Bell, David J., Bethell, Delia, Binh, Tran Quang, Borghini, Isabelle, Chu, Cindy S., Daher, Andre, D'Alessandro, Umberto, Das, Debashish, Davis, Timothy Me, de Vries, Peter J., Djimde, Abdoulaye A., Dondorp, Arjen M., Dorsey, Grant, Faucher, Jean-Francois F., Fogg, Carole, Gaye, Oumar, Grigg, Matthew, Hatz, Christoph, Kager, Piet A., Lacerda, Marcus, Laman, Moses, Mårtensson, Andreas, Menan, Herve Ignace Eby, Monteiro, Wuelton M., Moore, Brioni R., Nosten, Francois, Ogutu, Bernhards, Osorio, Lyda, Penali, Louis K., Pereira, Dhelio B., Rahim, Awab G., Ramharter, Michael, Sagara, Issaka, Schramm, Birgit, Seidlein, Lorenz, Siqueira, Andre M., Sirima, Sodiomon B., Starzengruber, Peter, Sutanto, Inge, Taylor, Walter R., Toure, Offianan A., Utzinger, Jurg, Valea, Innocent, Valentini, Giovanni, White, Nicholas J., William, Timothy, Woodrow, Charles J., Richmond, Caitlin L., Guerin, Philippe J., Price, Ric N., Stepniewska, Kasia, Wynberg, Elke, Commons, Robert J., Humphreys, Georgina, Ashurst, Hazel, Burrow, Rebekah, Adjei, George O., Adjuik, Martin, Anstey, Nicholas M., Anvikar, Anup, Baird, Kevin J., Barber, Bridget E., Barennes, Hubert, Baudin, Elisabeth, Bell, David J., Bethell, Delia, Binh, Tran Quang, Borghini, Isabelle, Chu, Cindy S., Daher, Andre, D'Alessandro, Umberto, Das, Debashish, Davis, Timothy Me, de Vries, Peter J., Djimde, Abdoulaye A., Dondorp, Arjen M., Dorsey, Grant, Faucher, Jean-Francois F., Fogg, Carole, Gaye, Oumar, Grigg, Matthew, Hatz, Christoph, Kager, Piet A., Lacerda, Marcus, Laman, Moses, Mårtensson, Andreas, Menan, Herve Ignace Eby, Monteiro, Wuelton M., Moore, Brioni R., Nosten, Francois, Ogutu, Bernhards, Osorio, Lyda, Penali, Louis K., Pereira, Dhelio B., Rahim, Awab G., Ramharter, Michael, Sagara, Issaka, Schramm, Birgit, Seidlein, Lorenz, Siqueira, Andre M., Sirima, Sodiomon B., Starzengruber, Peter, Sutanto, Inge, Taylor, Walter R., Toure, Offianan A., Utzinger, Jurg, Valea, Innocent, Valentini, Giovanni, White, Nicholas J., William, Timothy, Woodrow, Charles J., Richmond, Caitlin L., Guerin, Philippe J., Price, Ric N., and Stepniewska, Kasia

Abstract

Background: The World Health Organization (WHO) recommends that when peripheral malarial parasitaemia is quantified by thick film microscopy, an actual white blood cell (WBC) count from a concurrently collected blood sample is used in calculations. However, in resource-limited settings an assumed WBC count is often used instead. The aim of this study was to describe the variability in WBC count during acute uncomplicated malaria, and estimate the impact of using an assumed value of WBC on estimates of parasite density and clearance. Methods: Uncomplicated malaria drug efficacy studies that measured WBC count were selected from the WorldWide Antimalarial Resistance Network data repository for an individual patient data meta-analysis of WBC counts. Regression models with random intercepts for study-site were used to assess WBC count variability at presentation and during follow-up. Inflation factors for parasitaemia density, and clearance estimates were calculated for methods using assumed WBC counts (8000 cells/mu L and age-stratified values) using estimates derived from the measured WBC value as reference. Results: Eighty-four studies enrolling 27,656 patients with clinically uncomplicated malaria were included. Geometric mean WBC counts (x 1000 cells/mu L) in age groups < 1, 1-4, 5-14 and >= 15 years were 10.5, 8.3, 7.1, 5.7 and 7.5, 7.0, 6.5, 6.0 for individuals with falciparum (n = 24,978) and vivax (n = 2678) malaria, respectively. At presentation, higher WBC counts were seen among patients with higher parasitaemia, severe anaemia and, for individuals with vivax malaria, in regions with shorter regional relapse periodicity. Among falciparum malaria patients, using an assumed WBC count of 8000 cells/mu L resulted in parasite density underestimation by a median (IQR) of 26% (4-41%) in infants < 1 year old but an overestimation by 50% (16-91%) in adults aged = 15 years. Use of age-stratified assumed WBC values removed systematic bias but did not improve pr

Published
2023
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3. Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy : an individual participant data meta-analysis

Author

Dahal, Prabin, Simpson, Julie Anne, Abdulla, Salim, Achan, Jane, Adam, Ishag, Agarwal, Aarti, Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Bassat, Quique, Borrmann, Steffen, Bousema, Teun, Bukirwa, Hasifa, Carrara, Verena, I, Corsi, Marco, D'Alessandro, Umberto, Davis, Timothy M. E., Deloron, Philippe, Desai, Meghna, Dimbu, Pedro Rafael, Djalle, Djibrine, Djimde, Abdoulaye, Dorsey, Grant, Drakeley, Chris J., Duparc, Stephan, Edstein, Michael D., Espie, Emmanuelle, Faiz, Abul, Falade, Catherine, Fanello, Caterina, Faucher, Jean-Francois, Faye, Babacar, Fortes, Filomeno de Jesus, Gadalla, Nahla B., Gaye, Oumar, Gil, J. Pedro, Gilayeneh, Julius, Greenwood, Brian, Grivoyannis, Anastasia, Hien, Tran Tinh, Hwang, Jimee, Janssens, Bart, Juma, Elizabeth, Kamugisha, Erasmus, Karema, Corine, Karunajeewa, Harin A., Kiechel, Jean R., Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Lee, Sue J., Marsh, Kevin, Mårtensson, Andreas, Mayxay, Mayfong, Menan, Herve, Mens, Petra, Mutabingwa, Theonest K., Ndiaye, Jean-Louis, Ngasala, Billy, Noedl, Harald, Nosten, Francois, Offianan, Andre Toure, Ogutu, Bernhards R., Olliaro, Piero L., Ouedraogo, Jean Bosco, Piola, Patrice, Plowe, Christopher, V, Plucinski, Mateusz M., Pratt, Oliver James, Premji, Zulfikarali, Ramharter, Michael, Rogier, Christophe, Vitare, Primum, Rombo, Lars, Rosenthal, Philip J., Sibley, Carol, Sirima, Sodiomon, Smithuis, Frank, Staedke, Sarah G., Sutanto, Inge, Talisuna, Ambrose Otau, Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel, Thriemer, Kamala, Thuy-Nhien, Nguyen, Udhayakumar, Venkatachalam, Ursing, Johan D., van Herp, Michel, van Lenthe, Marit, van Vugt, Michele, William, Yavo, Winnips, Cornelis, Zaloumis, Sophie, Zongo, Issaka, White, Nick J., Guerin, Philippe J., Stepniewska, Kasia, Price, Ric N., Arinaitwe, Emmanuel, Dahal, Prabin, Simpson, Julie Anne, Abdulla, Salim, Achan, Jane, Adam, Ishag, Agarwal, Aarti, Allan, Richard, Anvikar, Anupkumar R., Ashley, Elizabeth A., Bassat, Quique, Borrmann, Steffen, Bousema, Teun, Bukirwa, Hasifa, Carrara, Verena, I, Corsi, Marco, D'Alessandro, Umberto, Davis, Timothy M. E., Deloron, Philippe, Desai, Meghna, Dimbu, Pedro Rafael, Djalle, Djibrine, Djimde, Abdoulaye, Dorsey, Grant, Drakeley, Chris J., Duparc, Stephan, Edstein, Michael D., Espie, Emmanuelle, Faiz, Abul, Falade, Catherine, Fanello, Caterina, Faucher, Jean-Francois, Faye, Babacar, Fortes, Filomeno de Jesus, Gadalla, Nahla B., Gaye, Oumar, Gil, J. Pedro, Gilayeneh, Julius, Greenwood, Brian, Grivoyannis, Anastasia, Hien, Tran Tinh, Hwang, Jimee, Janssens, Bart, Juma, Elizabeth, Kamugisha, Erasmus, Karema, Corine, Karunajeewa, Harin A., Kiechel, Jean R., Kironde, Fred, Kofoed, Poul-Erik, Kremsner, Peter G., Lee, Sue J., Marsh, Kevin, Mårtensson, Andreas, Mayxay, Mayfong, Menan, Herve, Mens, Petra, Mutabingwa, Theonest K., Ndiaye, Jean-Louis, Ngasala, Billy, Noedl, Harald, Nosten, Francois, Offianan, Andre Toure, Ogutu, Bernhards R., Olliaro, Piero L., Ouedraogo, Jean Bosco, Piola, Patrice, Plowe, Christopher, V, Plucinski, Mateusz M., Pratt, Oliver James, Premji, Zulfikarali, Ramharter, Michael, Rogier, Christophe, Vitare, Primum, Rombo, Lars, Rosenthal, Philip J., Sibley, Carol, Sirima, Sodiomon, Smithuis, Frank, Staedke, Sarah G., Sutanto, Inge, Talisuna, Ambrose Otau, Tarning, Joel, Taylor, Walter R. J., Temu, Emmanuel, Thriemer, Kamala, Thuy-Nhien, Nguyen, Udhayakumar, Venkatachalam, Ursing, Johan D., van Herp, Michel, van Lenthe, Marit, van Vugt, Michele, William, Yavo, Winnips, Cornelis, Zaloumis, Sophie, Zongo, Issaka, White, Nick J., Guerin, Philippe J., Stepniewska, Kasia, Price, Ric N., and Arinaitwe, Emmanuel

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

Published
2022
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4. Haematological consequences of acute uncomplicated falciparum malaria : a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data

Author

Mansoor, Rashid, Commons, Robert J., Douglas, Nicholas M., Abuaku, Benjamin, Achan, Jane, Adam, Ishag, Adjei, George O., Adjuik, Martin, Alemayehu, Bereket H., Allan, Richard, Allen, Elizabeth N., Anvikar, Anupkumar R., Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ashurst, Hazel, Asih, Puji B. S., Bakyaita, Nathan, Barennes, Hubert, Barnes, Karen, I, Basco, Leonardo, Bassat, Quique, Baudin, Elisabeth, Bell, David J., Bethell, Delia, Bjorkman, Anders, Boulton, Caroline, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Burrow, Rebekah, Carrara, Verena, I, Cot, Michel, D'Alessandro, Umberto, Das, Debashish, Das, Sabyasachi, Davis, Timothy M. E., Desai, Meghna, Djimde, Abdoulaye A., Dondorp, Arjen M., Dorsey, Grant, Drakeley, Chris J., Duparc, Stephan, Espie, Emmanuelle, Etard, Jean-Francois, Falade, Catherine, Faucher, Jean Francois, Filler, Scott, Fogg, Carole, Fukuda, Mark, Gaye, Oumar, Genton, Blaise, Rahim, Awab Ghulam, Gilayeneh, Julius, Gonzalez, Raquel, Grais, Rebecca F., Grandesso, Francesco, Greenwood, Brian, Grivoyannis, Anastasia, Hatz, Christoph, Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ishengoma, Deus, Juma, Elizabeth, Kachur, S. Patrick, Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kazienga, Adama, Kiechel, Jean-Rene, Kofoed, Poul-Erik, Koram, Kwadwo, Kremsner, Peter G., Lalloo, David G., Laman, Moses, Lee, Sue J., Lell, Bertrand, Maiga, Amelia W., Mårtensson, Andreas, Mayxay, Mayfong, Mbacham, Wilfred, McGready, Rose, Menan, Herve, Menard, Didier, Mockenhaupt, Frank, Moore, Brioni R., Muller, Olaf, Nahum, Alain, Ndiaye, Jean-Louis, Newton, Paul N., Ngasala, Billy E., Nikiema, Frederic, Nji, Akindeh M., Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Ojurongbe, Olusola, Osorio, Lyda, Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Pareek, Anil, Penali, Louis K., Piola, Patrice, Plucinski, Mateusz, Premji, Zul, Ramharter, Michael, Richmond, Caitlin L., Rombo, Lars, Rosenthal, Philip J., Salman, Sam, Same-Ekobo, Albert, Sibley, Carol, Sirima, Sodiomon B., Smithuis, Frank M., Some, Fabrice A., Staedke, Sarah G., Starzengruber, Peter, Strub-Wourgaft, Nathalie, Sutanto, Inge, Swarthout, Todd D., Syafruddin, Din, Talisuna, Ambrose O., Taylor, Walter R., Temu, Emmanuel A., Thwing, Julie, I, Tinto, Halidou, Tjitra, Emiliana, Toure, Offianan A., Tran, T. Hien, Ursing, Johan, Valea, Innocent, Valentini, Giovanni, van Vugt, Michele, von Seidlein, Lorenz, Ward, Stephen A., Were, Vincent, White, Nicholas J., Woodrow, Charles J., Yavo, William, Yeka, Adoke, Zongo, Issaka, Simpson, Julie A., Guerin, Philippe J., Stepniewska, Kasia, Price, Ric N., Roper, Cally, Mansoor, Rashid, Commons, Robert J., Douglas, Nicholas M., Abuaku, Benjamin, Achan, Jane, Adam, Ishag, Adjei, George O., Adjuik, Martin, Alemayehu, Bereket H., Allan, Richard, Allen, Elizabeth N., Anvikar, Anupkumar R., Arinaitwe, Emmanuel, Ashley, Elizabeth A., Ashurst, Hazel, Asih, Puji B. S., Bakyaita, Nathan, Barennes, Hubert, Barnes, Karen, I, Basco, Leonardo, Bassat, Quique, Baudin, Elisabeth, Bell, David J., Bethell, Delia, Bjorkman, Anders, Boulton, Caroline, Bousema, Teun, Brasseur, Philippe, Bukirwa, Hasifa, Burrow, Rebekah, Carrara, Verena, I, Cot, Michel, D'Alessandro, Umberto, Das, Debashish, Das, Sabyasachi, Davis, Timothy M. E., Desai, Meghna, Djimde, Abdoulaye A., Dondorp, Arjen M., Dorsey, Grant, Drakeley, Chris J., Duparc, Stephan, Espie, Emmanuelle, Etard, Jean-Francois, Falade, Catherine, Faucher, Jean Francois, Filler, Scott, Fogg, Carole, Fukuda, Mark, Gaye, Oumar, Genton, Blaise, Rahim, Awab Ghulam, Gilayeneh, Julius, Gonzalez, Raquel, Grais, Rebecca F., Grandesso, Francesco, Greenwood, Brian, Grivoyannis, Anastasia, Hatz, Christoph, Hodel, Eva Maria, Humphreys, Georgina S., Hwang, Jimee, Ishengoma, Deus, Juma, Elizabeth, Kachur, S. Patrick, Kager, Piet A., Kamugisha, Erasmus, Kamya, Moses R., Karema, Corine, Kayentao, Kassoum, Kazienga, Adama, Kiechel, Jean-Rene, Kofoed, Poul-Erik, Koram, Kwadwo, Kremsner, Peter G., Lalloo, David G., Laman, Moses, Lee, Sue J., Lell, Bertrand, Maiga, Amelia W., Mårtensson, Andreas, Mayxay, Mayfong, Mbacham, Wilfred, McGready, Rose, Menan, Herve, Menard, Didier, Mockenhaupt, Frank, Moore, Brioni R., Muller, Olaf, Nahum, Alain, Ndiaye, Jean-Louis, Newton, Paul N., Ngasala, Billy E., Nikiema, Frederic, Nji, Akindeh M., Noedl, Harald, Nosten, Francois, Ogutu, Bernhards R., Ojurongbe, Olusola, Osorio, Lyda, Ouedraogo, Jean-Bosco, Owusu-Agyei, Seth, Pareek, Anil, Penali, Louis K., Piola, Patrice, Plucinski, Mateusz, Premji, Zul, Ramharter, Michael, Richmond, Caitlin L., Rombo, Lars, Rosenthal, Philip J., Salman, Sam, Same-Ekobo, Albert, Sibley, Carol, Sirima, Sodiomon B., Smithuis, Frank M., Some, Fabrice A., Staedke, Sarah G., Starzengruber, Peter, Strub-Wourgaft, Nathalie, Sutanto, Inge, Swarthout, Todd D., Syafruddin, Din, Talisuna, Ambrose O., Taylor, Walter R., Temu, Emmanuel A., Thwing, Julie, I, Tinto, Halidou, Tjitra, Emiliana, Toure, Offianan A., Tran, T. Hien, Ursing, Johan, Valea, Innocent, Valentini, Giovanni, van Vugt, Michele, von Seidlein, Lorenz, Ward, Stephen A., Were, Vincent, White, Nicholas J., Woodrow, Charles J., Yavo, William, Yeka, Adoke, Zongo, Issaka, Simpson, Julie A., Guerin, Philippe J., Stepniewska, Kasia, Price, Ric N., and Roper, Cally

Abstract

Background Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia. Methods Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall >= 25% at day 3 and day 7. Results A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0-19.7 g/dL) in Africa, 11.6 g/dL (range 5.0-20.0 g/dL) in Asia and 12.3 g/dL (range 6.9-17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to >= 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.7

Published
2022
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5. Plasmodium malariae structure and genetic diversity in sub-Saharan Africa determined from microsatellite variants and linked SNPs in orthologues of antimalarial resistance genes.

Author

Oriero, Eniyou C., Demba, Martha A., Diop, Mouhamadou F., Ishengoma, Deus S., Amenga-Etego, Lucas N., Ghansah, Anita, Apinjoh, Tobias, Issiaka, Soulama, Djimde, Abdoulaye, D'Alessandro, Umberto, Meremikwu, Martin, and Amambua-Ngwa, Alfred

Subjects
GENETIC variation, HUMAN biology, SINGLE nucleotide polymorphisms, MICROSATELLITE repeats, LINKAGE disequilibrium
Abstract

Plasmodium malariae, a neglected human malaria parasite, contributes up to 10% of malaria infections in sub-Saharan Africa (sSA). Though P. malariae infection is considered clinically benign, it presents mostly as coinfections with the dominant P. falciparum. Completion of its reference genome has paved the way to further understand its biology and interactions with the human host, including responses to antimalarial interventions. We characterized 75 P. malariae isolates from seven endemic countries in sSA using highly divergent microsatellites. The P. malariae infections were highly diverse and five subpopulations from three ancestries (independent of origin of isolates) were determined. Sequences of 11 orthologous antimalarial resistance genes, identified low frequency single nucleotide polymorphisms (SNPs), strong linkage disequilibrium between loci that may be due to antimalarial drug selection. At least three sub-populations were detectable from a subset of denoised SNP data from mostly the mitochondrial cytochrome b coding region. This evidence of diversity and selection calls for including P. malariae in malaria genomic surveillance towards improved tools and strategies for malaria elimination. [ABSTRACT FROM AUTHOR]

Published
2022
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6. Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing.

Author

Manske, Magnus, Miotto, Olivo, Campino, Susana, Auburn, Sarah, Almagro-Garcia, Jacob, Maslen, Gareth, O'Brien, Jack, Djimde, Abdoulaye, Doumbo, Ogobara, Zongo, Issaka, Ouedraogo, Jean-Bosco, Michon, Pascal, Mueller, Ivo, Siba, Peter, Nzila, Alexis, Borrmann, Steffen, Kiara, Steven M., Marsh, Kevin, Jiang, Hongying, and Su, Xin-Zhuan

Subjects
PLASMODIUM falciparum, NUCLEOTIDE sequence, GENETICS, INFECTION, DNA, MALARIA prevention
Abstract

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P.?falciparum genome. [ABSTRACT FROM AUTHOR]

Published
2012
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7. A global network for investigating the genomic epidemiology of malaria.

Author

Achidi, Eric Akum, Agbenyega, Tsiri, Allen, Stephen, Amodu, Olukemi, Bojang, Kalifa, Conway, David, Corran, Patrick, Deloukas, Panos, Djimde, Abdoulaye, Dolo, Amagana, Doumbo, Ogobara, Drakeley, Chris, Duffy, Patrick, Dunstan, Sarah, Evans, Jennifer, Farrar, Jeremy, Fernando, Deepika, Hien, Tran Tinh, Horstmann, Rolf, and Ibrahim, Muntaser

Subjects
GENOMICS, MALARIA prevention, RESEARCH ethics, DEVELOPING countries, EPIDEMIOLOGICAL research
Abstract

Large-scale studies of genomic variation could assist efforts to eliminate malaria. But there are scientific, ethical and practical challenges to carrying out such studies in developing countries, where the burden of disease is greatest. The Malaria Genomic Epidemiology Network (MalariaGEN) is now working to overcome these obstacles, using a consortial approach that brings together researchers from 21 countries. [ABSTRACT FROM AUTHOR]

Published
2008
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8. A barcode of organellar genome polymorphisms identifies the geographic origin of Plasmodium falciparum strains.

Author

Preston, Mark D., Campino, Susana, Assefa, Samuel A., Echeverry, Diego F., Ocholla, Harold, Amambua-Ngwa, Alfred, Stewart, Lindsay B., Conway, David J., Borrmann, Steffen, Michon, Pascal, Zongo, Issaka, Ouédraogo, Jean-Bosco, Djimde, Abdoulaye A., Doumbo, Ogobara K., Nosten, Francois, Pain, Arnab, Bousema, Teun, Drakeley, Chris J., Fairhurst, Rick M., and Sutherland, Colin J.

Published
2014
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